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Sample records for acid-related orphan receptor

  1. Retinoic Acid-Related Orphan Receptors (RORs): Regulatory Functions in Immunity, Development, Circadian Rhythm, and Metabolism

    PubMed Central

    Cook, Donald N.; Kang, Hong Soon; Jetten, Anton M.

    2015-01-01

    In this overview, we provide an update on recent progress made in understanding the mechanisms of action, physiological functions, and roles in disease of retinoic acid related orphan receptors (RORs). We are particularly focusing on their roles in the regulation of adaptive and innate immunity, brain function, retinal development, cancer, glucose and lipid metabolism, circadian rhythm, metabolic and inflammatory diseases and neuropsychiatric disorders. We also summarize the current status of ROR agonists and inverse agonists, including their regulation of ROR activity and their therapeutic potential for management of various diseases in which RORs have been implicated. PMID:26878025

  2. Increasing human Th17 differentiation through activation of orphan nuclear receptor retinoid acid-related orphan receptor γ (RORγ) by a class of aryl amide compounds.

    PubMed

    Zhang, Wei; Zhang, Jing; Fang, Leiping; Zhou, Ling; Wang, Shuai; Xiang, Zhijun; Li, Yuan; Wisely, Bruce; Zhang, Guifeng; An, Gang; Wang, Yonghui; Leung, Stewart; Zhong, Zhong

    2012-10-01

    In a screen for small-molecule inhibitors of retinoid acid-related orphan receptor γ (RORγ), we fortuitously discovered that a class of aryl amide compounds behaved as functional activators of the interleukin 17 (IL-17) reporter in Jurkat cells. Three of these compounds were selected for further analysis and found to activate the IL-17 reporter with potencies of ∼0.1 μM measured by EC₅₀. These compounds were shown to directly bind to RORγ by circular dichroism-based thermal stability experiments. Furthermore, they can enhance an in vitro Th17 differentiation process in human primary T cells. As RORγ remains an orphan nuclear receptor, discovery of these aryl amide compounds as functional agonists will now provide pharmacological tools for us to dissect functions of RORγ and facilitate drug discovery efforts for immune-modulating therapies.

  3. The E3 Deubiquitinase USP17 Is a Positive Regulator of Retinoic Acid-related Orphan Nuclear Receptor γt (RORγt) in Th17 Cells*

    PubMed Central

    Han, Lei; Yang, Jing; Wang, Xiuwen; Wu, Qingsi; Yin, Shuying; Li, Zhiyuan; Zhang, Jing; Xing, Yue; Chen, Zuojia; Tsun, Andy; Li, Dan; Piccioni, Miranda; Zhang, Yu; Guo, Qiang; Jiang, Lindi; Bao, Liming; Lv, Ling; Li, Bin

    2014-01-01

    Stable retinoic acid-related orphan nuclear receptor γt (RORγt) expression is pivotal for the development and function of Th17 cells. Here we demonstrate that expression of the transcription factor RORγt can be regulated through deubiquitination, which prevents proteasome-mediated degradation. We establish that USP17 stabilizes RORγt protein expression by reducing RORγt polyubiquitination at its Lys-360 residue. In contrast, knockdown of endogenous USP17 in Th17 cells resulted in decreased RORγt protein levels and down-regulation of Th17-related genes. Furthermore, USP17 expression was up-regulated in CD4+ T cells from systemic lupus erythematosus patients. Our data reveal a molecular mechanism in which RORγt expression in Th17 cells can be positively regulated by USP17, thereby modulating Th17 cell functions. PMID:25070893

  4. Control of Gene Expression by the Retinoic Acid-Related Orphan Receptor Alpha in HepG2 Human Hepatoma Cells

    PubMed Central

    Chauvet, Caroline; Vanhoutteghem, Amandine; Duhem, Christian; Saint-Auret, Gaëlle; Bois-Joyeux, Brigitte; Djian, Philippe; Staels, Bart; Danan, Jean-Louis

    2011-01-01

    Retinoic acid-related Orphan Receptor alpha (RORα; NR1F1) is a widely distributed nuclear receptor involved in several (patho)physiological functions including lipid metabolism, inflammation, angiogenesis, and circadian rhythm. To better understand the role of this nuclear receptor in liver, we aimed at displaying genes controlled by RORα in liver cells by generating HepG2 human hepatoma cells stably over-expressing RORα. Genes whose expression was altered in these cells versus control cells were displayed using micro-arrays followed by qRT-PCR analysis. Expression of these genes was also altered in cells in which RORα was transiently over-expressed after adenoviral infection. A number of the genes found were involved in known pathways controlled by RORα, for instance LPA, NR1D2 and ADIPOQ in lipid metabolism, ADIPOQ and PLG in inflammation, PLG in fibrinolysis and NR1D2 and NR1D1 in circadian rhythm. This study also revealed that genes such as G6PC, involved in glucose homeostasis, and AGRP, involved in the control of body weight, are also controlled by RORα. Lastly, SPARC, involved in cell growth and adhesion, and associated with liver carcinogenesis, was up-regulated by RORα. SPARC was found to be a new putative RORα target gene since it possesses, in its promoter, a functional RORE as evidenced by EMSAs and transfection experiments. Most of the other genes that we found regulated by RORα also contained putative ROREs in their regulatory regions. Chromatin immunoprecipitation (ChIP) confirmed that the ROREs present in the SPARC, PLG, G6PC, NR1D2 and AGRP genes were occupied by RORα in HepG2 cells. Therefore these genes must now be considered as direct RORα targets. Our results open new routes on the roles of RORα in glucose metabolism and carcinogenesis within cells of hepatic origin. PMID:21818335

  5. Gene silencing by nuclear orphan receptors.

    PubMed

    Zhang, Ying; Dufau, Maria L

    2004-01-01

    Nuclear orphan receptors represent a large and diverse subgroup in the nuclear receptor superfamily. Although putative ligands for these orphan members remain to be identified, some of these receptors possess intrinsic activating, inhibitory, or dual regulatory functions in development, differentiation, homeostasis, and reproduction. In particular, gene-silencing events elicited by chicken ovalbumin upstream promoter-transcription factors (COUP-TFs); dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1 (DAX-1); germ cell nuclear factor (GCNF); short heterodimer partner (SHP); and testicular receptors 2 and 4 (TR2 and TR4) are among the best characterized. These orphan receptors are critical in controlling basal activities or hormonal responsiveness of numerous target genes. They employ multiple and distinct mechanisms to mediate target gene repression. Complex cross-talk exists between these orphan receptors at their cognate DNA binding elements and an array of steroid?nonsteroid hormone receptors, other transcriptional activators, coactivators and corepressors, histone modification enzyme complexes, and components of basal transcriptional components. Therefore, perturbation induced by these orphan receptors at multiple levels, including DNA binding activities, receptor homo- or heterodimerization, recruitment of cofactor proteins, communication with general transcriptional machinery, and changes at histone acetylation status and chromatin structures, may contribute to silencing of target gene expression in a specific promoter or cell-type context. Moreover, the findings derived from gene-targeting studies have demonstrated the significance of these orphan receptors' function in physiologic settings. Thus, COUP-TFs, DAX-1, GCNF, SHP, and TR2 and 4 are known to be required for multiple physiologic and biologic functions, including neurogenesis and development of the heart and vascular system steroidogenesis and sex

  6. Human and rat TR4 orphan receptors specify a subclass of the steroid receptor superfamily.

    PubMed Central

    Chang, C; Da Silva, S L; Ideta, R; Lee, Y; Yeh, S; Burbach, J P

    1994-01-01

    We have identified a member of the steroid receptor superfamily and cloned it from human and rat hypothalamus, prostate, and testis cDNA libraries. The open reading frame between first ATG and terminator TGA can encode 615 (human) and 596 (rat) amino acids with calculated molecular mass of 67.3 (human) and 65.4 (rat) kDa. The amino acid sequence of this protein, called TR4 orphan receptor, is closely related to the previously identified TR2 orphan receptor. The high homology between TR2 and TR4 orphan receptor suggests that these two orphan receptors constitute a unique subfamily within the steroid receptor superfamily. These two orphan receptors are differentially expressed in rat tissues. Unlike TR2 orphan receptors, the TR4 orphan receptor appears to be predominantly located in granule cells of the hippocampus and the cerebellum, suggesting that it may play some role(s) in transcriptional regulation in these neurons. Images PMID:8016112

  7. An orphan nuclear hormone receptor that lacks a DNA binding domain and heterodimerizes with other receptors.

    PubMed

    Seol, W; Choi, H S; Moore, D D

    1996-05-31

    SHP is an orphan member of the nuclear hormone receptor superfamily that contains the dimerization and ligand-binding domain found in other family members but lacks the conserved DNA binding domain. In the yeast two-hybrid system, SHP interacted with several conventional and orphan members of the receptor superfamily, including retinoid receptors, the thyroid hormone receptor, and the orphan receptor MB67. SHP also interacted directly with these receptors in vitro. In mammalian cells, SHP specifically inhibited transactivation by the superfamily members with which it interacted. These results suggest that SHP functions as a negative regulator of receptor-dependent signaling pathways. PMID:8650544

  8. The Orphan Nuclear Receptors at Their 25th Year Reunion

    PubMed Central

    Mullican, Shannon E.; DiSpirito, Joanna R.; Lazar, Mitchell A.

    2013-01-01

    The Nuclear Receptor superfamily includes many receptors identified based on their similarity to steroid hormone receptors but without a known ligand. The study of how these receptors are diversely regulated to interact with genomic regions to control a plethora of biological processes has provided critical insight into development, physiology and the molecular pathology of disease. Here we provide a compendium of these so-called Orphan Receptors, and focus on what has been learned about their modes of action, physiological functions, and therapeutic promise. PMID:24096517

  9. Structures and regulation of non-X orphan nuclear receptors: A retinoid hypothesis.

    PubMed

    Zhi, Xiaoyong; Zhou, X Edward; Melcher, Karsten; Xu, H Eric

    2016-03-01

    Nuclear receptors are defined as a family of ligand regulated transcription factors [1-6]. While this definition reflects that ligand binding is a key property of nuclear receptors, it is still a heated subject of debate if all the nuclear receptors (48 human members) can bind ligands (ligands referred here to both physiological and synthetic ligands). Recent studies in nuclear receptor structure biology and pharmacology have undoubtedly increased our knowledge of nuclear receptor functions and their regulation. As a result, they point to new avenues for the discovery and development of nuclear receptor regulators, including nuclear receptor ligands. Here we review the recent literature on orphan nuclear receptor structural analysis and ligand identification, particularly on the orphan nuclear receptors that do not heterodimerize with retinoid X receptors, which we term as non-X orphan receptors. We also propose a speculative "retinoid hypothesis" for a subset of non-X orphan nuclear receptors, which we hope to help shed light on orphan nuclear receptor biology and drug discovery. This article is part of a Special Issue entitled 'Orphan Nuclear Receptors'.

  10. Structures and regulation of non-X orphan nuclear receptors: A retinoid hypothesis.

    PubMed

    Zhi, Xiaoyong; Zhou, X Edward; Melcher, Karsten; Xu, H Eric

    2016-03-01

    Nuclear receptors are defined as a family of ligand regulated transcription factors [1-6]. While this definition reflects that ligand binding is a key property of nuclear receptors, it is still a heated subject of debate if all the nuclear receptors (48 human members) can bind ligands (ligands referred here to both physiological and synthetic ligands). Recent studies in nuclear receptor structure biology and pharmacology have undoubtedly increased our knowledge of nuclear receptor functions and their regulation. As a result, they point to new avenues for the discovery and development of nuclear receptor regulators, including nuclear receptor ligands. Here we review the recent literature on orphan nuclear receptor structural analysis and ligand identification, particularly on the orphan nuclear receptors that do not heterodimerize with retinoid X receptors, which we term as non-X orphan receptors. We also propose a speculative "retinoid hypothesis" for a subset of non-X orphan nuclear receptors, which we hope to help shed light on orphan nuclear receptor biology and drug discovery. This article is part of a Special Issue entitled 'Orphan Nuclear Receptors'. PMID:26159912

  11. Inflammation: a role for NR4A orphan nuclear receptors?

    PubMed

    McMorrow, Jason P; Murphy, Evelyn P

    2011-04-01

    Inflammation is paradoxical; it is essential for protection following biological, chemical or physical stimuli, but inappropriate or misdirected inflammation is responsible for tissue injury in a variety of inflammatory diseases. The polarization of immune cells is critical in controlling the stages of inflammatory response. The acute phase of inflammation is characterized by a T-lymphocyte:Th2 cytokine profile and involves a co-ordinated migration of immune cells to the site of injury where production of cytokines and acute-phase proteins brings about healing. However, persistent inflammation can result in inappropriate and prolonged T-lymphocyte:Th1 cytokine-mediated action and reaction of self-molecules, leading to a chronic phase in diseases such as RA (rheumatoid arthritis), Ps (psoriasis) and atherosclerosis. The inflammatory response is also controlled by activated macrophage cells, with classically activated (M1) cells producing a wide variety of pro-inflammatory mediators, while alternatively activated (M2) macrophages participate in anti-inflammatory response. Members of the NR4A subfamily (NR4A1/NUR77, NR4A2/NURR1 and NR4A3/NOR1) of orphan NRs (nuclear receptors) have emerged as key transcriptional regulators of cytokine and growth factor action in diseases affecting our aging population. As ligand-independent and constitutively active receptors, the activity of these transcription factors is tightly controlled at the level of expression, post-translational modification and subcellular localization. NR4A subfamily members are aberrantly expressed in inflamed human synovial tissue, psoriatic skin, atherosclerotic lesions, lung and colorectal cancer cells. Significantly, prolonged or inappropriate inflammatory responses contribute to the pathogenesis of these diseases. In activated cells, NR4A receptors are rapidly and potently induced, suggesting that these receptors may act as important transcriptional mediators of inflammatory signals. NR4A receptors

  12. High-throughput screening of antagonists for the orphan G-protein coupled receptor GPR139

    PubMed Central

    Wang, Jia; Zhu, Lin-yun; Liu, Qing; Hentzer, Morten; Smith, Garrick Paul; Wang, Ming-wei

    2015-01-01

    Aim: To discover antagonists of the orphan G-protein coupled receptor GPR139 through high-throughput screening of a collection of diverse small molecules. Methods: Calcium mobilization assays were used to identify initial hits and for subsequent confirmation studies. Results: Five small molecule antagonists, representing 4 different scaffolds, were identified following high-throughput screening of 16 000 synthetic compounds. Conclusion: The findings provide important tools for further study of this orphan G-protein coupled receptor. PMID:26027661

  13. The Orphan Nuclear Receptor TR4 Is a Vitamin A-activated Nuclear Receptor

    SciTech Connect

    Zhou, X. Edward; Suino-Powell, Kelly M.; Xu, Yong; Chan, Cee-Wah; Tanabe, Osamu; Kruse, Schoen W.; Reynolds, Ross; Engel, James Douglas; Xu, H. Eric

    2015-11-30

    Testicular receptors 2 and 4 (TR2/4) constitute a subgroup of orphan nuclear receptors that play important roles in spermatogenesis, lipid and lipoprotein regulation, and the development of the central nervous system. Currently, little is known about the structural features and the ligand regulation of these receptors. Here we report the crystal structure of the ligand-free TR4 ligand binding domain, which reveals an autorepressed conformation. The ligand binding pocket of TR4 is filled by the C-terminal half of helix 10, and the cofactor binding site is occupied by the AF-2 helix, thus preventing ligand-independent activation of the receptor. However, TR4 exhibits constitutive transcriptional activity on multiple promoters, which can be further potentiated by nuclear receptor coactivators. Mutations designed to disrupt cofactor binding, dimerization, or ligand binding substantially reduce the transcriptional activity of this receptor. Importantly, both retinol and retinoic acid are able to promote TR4 to recruit coactivators and to activate a TR4-regulated reporter. These findings demonstrate that TR4 is a ligand-regulated nuclear receptor and suggest that retinoids might have a much wider regulatory role via activation of orphan receptors such as TR4.

  14. New Insights into Orphan Nuclear Receptor SHP in Liver Cancer

    PubMed Central

    Zou, An; Lehn, Sarah; Magee, Nancy; Zhang, Yuxia

    2015-01-01

    Small heterodimer partner (SHP; NR0B2) is a unique orphan nuclear receptor (NR) that contains a putative ligand-binding domain but lacks a DNA-binding domain. SHP is a transcriptional corepressor affecting diverse metabolic processes including bile acid synthesis, cholesterol and lipid metabolism, glucose and energy homeostasis, and reproductive biology via interaction with multiple NRs and transcriptional factors (TFs). Hepatocellular carcinoma (HCC) is one of the most deadly human cancers worldwide with few therapeutic options and poor prognosis. Recently, it is becoming clear that SHP plays an antitumor role in the development of liver cancer. In this review, we summarize the most recent findings regarding the new SHP interaction partners, new structural insights into SHP’s gene repressing activity, and SHP protein posttranslational modifications by bile acids. We also discuss the pleiotropic role of SHP in regulating cell proliferation, apoptosis, DNA methylation, and inflammation that are related to antitumor role of SHP in HCC. Improving our understanding of SHP’s antitumor role in the development of liver cancer will provide new insights into developing novel treatments or prevention strategies. Future research will focus on developing more efficacious and specific synthetic SHP ligands for pharmaceutical applications in liver cancer and several metabolic diseases such as hypercholesterolemia, obesity, diabetes, and fatty liver disease. PMID:26504773

  15. Ligand regulation of retinoic acid receptor-related orphan receptors: implications for development of novel therapeutics

    PubMed Central

    Solt, Laura A.; Griffin, Patrick R.; Burris, Thomas P.

    2016-01-01

    Purpose of review In the late 1980s, the cloning of several nuclear receptors led to the intense search and isolation of new members of this superfamily. Despite their identification, many of these receptors were dubbed ‘orphan’ receptors, as their physiological ligands remained unknown. Recent reports have presented evidence for one family of orphan receptors, the retinoic acid receptor-related orphan receptors (RORs), in several pathologies, including osteoporosis, several autoimmune diseases, asthma, cancer, diabetes and obesity. The present review summarizes the studies identifying ligands for the RORs and evaluates their role as targets for potential therapeutics. Recent findings Significant progress was made in the initial identification of ligands for the RORs when X-ray crystallographic studies identified several molecules within the ligand-binding pockets of RORα and RORβ. Recently, we identified endogenous and synthetic ligands for RORα and RORγ, thereby solidifying their function as ligand-dependent transcription factors. Summary Recent studies have established roles for the RORs in physiological development and the advent of disease. Identification of ligands for the RORs, both endogenous and synthetic, has established these receptors as attractive new therapeutic targets for the treatment of ROR-related diseases. PMID:20463469

  16. Orphan receptor IL-17RD regulates Toll-like receptor signalling via SEFIR/TIR interactions.

    PubMed

    Mellett, Mark; Atzei, Paola; Bergin, Ronan; Horgan, Alan; Floss, Thomas; Wurst, Wolfgang; Callanan, John J; Moynagh, Paul N

    2015-01-01

    Receptor families of the innate immune response engage in 'cross-talk' to tailor optimal immune responses against invading pathogens. However, these responses are subject to multiple levels of regulation to keep in check aberrant inflammatory signals. Here, we describe a role for the orphan receptor interleukin-17 receptor D (IL-17RD) in negatively regulating Toll-like receptor (TLR)-induced responses. Deficiency of IL-17RD expression in cells leads to enhanced pro-inflammatory signalling and gene expression in response to TLR stimulation, and Il17rd(-/-) mice are more susceptible to TLR-induced septic shock. We demonstrate that the intracellular Sef/IL-17R (SEFIR) domain of IL-17RD targets TIR adaptor proteins to inhibit TLR downstream signalling thus revealing a paradigm involving cross-regulation of members of the IL-17R and TLR families.

  17. Bmal1 is a direct transcriptional target of the orphan nuclear receptor, NR2F1

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Orphan nuclear receptor NR2F1 (also known as COUP-TFI, Chicken Ovalbumin Upstream Promoter Transcription Factor I) is a highly conserved member of the nuclear receptor superfamily. NR2F1 plays a critical role during embryonic development, particularly in the central and peripheral nervous systems a...

  18. Synergistic activation of the human orphan nuclear receptor SHP gene promoter by basic helix–loop–helix protein E2A and orphan nuclear receptor SF-1

    PubMed Central

    Kim, Han-Jong; Kim, Joon-Young; Park, Yun-Yong; Choi, Hueng-Sik

    2003-01-01

    The orphan nuclear receptor small heterodimer partner (SHP; NR0B2) is an unusual orphan nuclear receptor that lacks a conventional DNA-binding domain and acts as a modulator of transcriptional activities of a number of nuclear receptors. We have previously reported that the orphan nuclear receptor ERRγ activates the SHP promoter. In this study, we have found that basic helix–loop–helix (bHLH) transcription factors, the E2A proteins (E47, E12 and E2/5), activated the human but not the mouse SHP promoter. In contrast, the tissue-specific E47 heterodimer partner BETA2 repressed the E47- mediated transactivation of the human SHP (hSHP) promoter. Using serial deletions and E-box mutant constructs of the hSHP promoter, we identified two E-boxes (E6 and E7) as E47-responsive E-boxes, which are not conserved in the mouse SHP promoter. Moreover, gel shift, chromatin immunoprecipitation (ChIP) and northern blot assays demonstrated that E47 directly binds to the hSHP promoter in vivo and in vitro and that Id proteins inhibited E47 binding to the hSHP promoter. Finally, we found that E47 and steroidogenic factor 1 (SF-1), a regulator of the SHP promoter, synergistically activate the human but not the mouse SHP promoter. Our findings suggest that the E2A proteins differentially regulate the human and mouse SHP promoters and cooperate with orphan nuclear receptor SF-1 for transcriptional activation of the hSHP promoter. PMID:14627819

  19. Development of novel silicon-containing inverse agonists of retinoic acid receptor-related orphan receptors.

    PubMed

    Toyama, Hirozumi; Nakamura, Masaharu; Nakamura, Masahiko; Matsumoto, Yotaro; Nakagomi, Madoka; Hashimoto, Yuichi

    2014-03-15

    Retinoic acid receptor (RAR)-related orphan receptors (RORs) regulate a variety of physiological processes, including hepatic gluconeogenesis, lipid metabolism, circadian rhythm and immune function. The RAR agonist: all-trans retinoic acid was reported to be an RORβ inverse agonist, but no information is available regarding ROR activity of its synthetic analogue Am580. Therefore, we screened Am580 and some related tetramethyltetrahydronaphthalene derivatives and carried out structural development studies, including substitution of carbon atoms with silicon, with the aim of creating a potent ROR transcriptional inhibitor. The phenyl amide disila compound 22 showed the most potent ROR-inhibitory activity among the compounds examined. Its activity towards RORα, RORβ and RORγ was increased compared to that of Am580. The IC₅₀ values for RORα, RORβ and RORγ are 1.3, >10 and 4.5 μM, respectively.

  20. Inhibition of androgen receptor (AR) function by the reproductive orphan nuclear receptor DAX-1.

    PubMed

    Holter, Elin; Kotaja, Noora; Mäkela, Sari; Strauss, Leena; Kietz, Silke; Jänne, Olli A; Gustafsson, Jan-Ake; Palvimo, Jorma J; Treuter, Eckardt

    2002-03-01

    DAX-1 (NROB1) is an atypical member of the nuclear receptor family that is predominantly expressed in mammalian reproductive tissues. While a receptor function of DAX-1 remains enigmatic, previous work has indicated that DAX-1 inhibits the activity of the orphan receptor steroidogenic factor 1 and the estrogen receptors (ERs), presumably via direct occupation of the coactivator-binding surface and subsequent recruitment of additional corepressors. In vivo evidence points at a particular role of DAX-1 for the development and maintenance of male reproductive functions. In this study, we have identified the androgen receptor (AR) NR3C4 as a novel target for DAX-1. We show that DAX-1 potently inhibits ligand-dependent transcriptional activation as well as the interaction between the N- and C-terminal activation domains of AR. We provide evidence for direct interactions of the two receptors that involve the N-terminal repeat domain of DAX-1 and the C-terminal ligand-binding and activation domain of AR. Moreover, DAX-1, known to shuttle between the cytoplasm and the nucleus, is capable of relocalizing AR in both cellular compartments, suggesting that intracellular tethering is associated with DAX-1 inhibition. These results implicate novel inhibitory mechanisms of DAX-1 action with particular relevance for the modulation of androgen-dependent gene transcription in the male reproductive system. PMID:11875111

  1. Constitutive Activity among Orphan Class-A G Protein Coupled Receptors

    PubMed Central

    Martin, Adam L.; Steurer, Michael A.; Aronstam, Robert S.

    2015-01-01

    The purpose of this study was to evaluate the extent of constitutive activity among orphan class-A G protein coupled receptors within the cAMP signaling pathway. Constitutive signaling was revealed by changes in gene expression under control of the cAMP response element. Gene expression was measured in Chinese hamster ovary cells transiently co-transfected with plasmids containing a luciferase reporter and orphan receptor. Criteria adopted for defining constitutive activation were: 1) 200% elevation over baseline reporter gene expression; 2) 40% inhibition of baseline expression; and 3) 40% inhibition of expression stimulated by 3 μM forskolin. Five patterns of activity were noted: 1) inhibition under both baseline and forskolin stimulated expression (GPR15, GPR17, GPR18, GPR20, GPR25, GPR27, GPR31, GPR32, GPR45, GPR57, GPR68, GPR83, GPR84, GPR132, GPR150, GPR176); 2) no effect on baseline expression, but inhibition of forskolin stimulated expression (GPR4, GPR26, GPR61, GPR62, GPR78, GPR101, GPR119); 3) elevation of baseline signaling coupled with inhibition of forskolin stimulated expression (GPR6, GPR12); 4) elevation of baseline signaling without inhibition of forskolin stimulated expression (GPR3, GPR21, GPR52, GPR65); and 5) no effect on expression (GPR1, GPR19, GPR22, GPR34, GPR35, GPR39, GPR63, GPR82, GPR85, GPR87). Constitutive activity was observed in 75% of the orphan class-A receptors examined (30 of 40). This constitutive signaling cannot be explained by simple overexpression of the receptor. Inhibition of cAMP mediated expression was far more common (65%) than stimulation of expression (15%). Orphan receptors that were closely related based on amino acid homology tended to have similar effects on gene expression. These results suggest that identification of inverse agonists may be a fruitful approach for categorizing these orphan receptors and targeting them for pharmacological intervention. PMID:26384023

  2. Constitutive Activity among Orphan Class-A G Protein Coupled Receptors.

    PubMed

    Martin, Adam L; Steurer, Michael A; Aronstam, Robert S

    2015-01-01

    The purpose of this study was to evaluate the extent of constitutive activity among orphan class-A G protein coupled receptors within the cAMP signaling pathway. Constitutive signaling was revealed by changes in gene expression under control of the cAMP response element. Gene expression was measured in Chinese hamster ovary cells transiently co-transfected with plasmids containing a luciferase reporter and orphan receptor. Criteria adopted for defining constitutive activation were: 1) 200% elevation over baseline reporter gene expression; 2) 40% inhibition of baseline expression; and 3) 40% inhibition of expression stimulated by 3 μM forskolin. Five patterns of activity were noted: 1) inhibition under both baseline and forskolin stimulated expression (GPR15, GPR17, GPR18, GPR20, GPR25, GPR27, GPR31, GPR32, GPR45, GPR57, GPR68, GPR83, GPR84, GPR132, GPR150, GPR176); 2) no effect on baseline expression, but inhibition of forskolin stimulated expression (GPR4, GPR26, GPR61, GPR62, GPR78, GPR101, GPR119); 3) elevation of baseline signaling coupled with inhibition of forskolin stimulated expression (GPR6, GPR12); 4) elevation of baseline signaling without inhibition of forskolin stimulated expression (GPR3, GPR21, GPR52, GPR65); and 5) no effect on expression (GPR1, GPR19, GPR22, GPR34, GPR35, GPR39, GPR63, GPR82, GPR85, GPR87). Constitutive activity was observed in 75% of the orphan class-A receptors examined (30 of 40). This constitutive signaling cannot be explained by simple overexpression of the receptor. Inhibition of cAMP mediated expression was far more common (65%) than stimulation of expression (15%). Orphan receptors that were closely related based on amino acid homology tended to have similar effects on gene expression. These results suggest that identification of inverse agonists may be a fruitful approach for categorizing these orphan receptors and targeting them for pharmacological intervention. PMID:26384023

  3. Orphan nuclear receptors as drug targets for the treatment of prostate and breast cancers.

    PubMed

    Roshan-Moniri, Mani; Hsing, Michael; Butler, Miriam S; Cherkasov, Artem; Rennie, Paul S

    2014-12-01

    Nuclear receptors (NRs), a family of 48 transcriptional factors, have been studied intensively for their roles in cancer development and progression. The presence of distinctive ligand binding sites capable of interacting with small molecules has made NRs attractive targets for developing cancer therapeutics. In particular, a number of drugs have been developed over the years to target human androgen- and estrogen receptors for the treatment of prostate cancer and breast cancer. In contrast, orphan nuclear receptors (ONRs), which in many cases lack known biological functions or ligands, are still largely under investigated. This review is a summary on ONRs that have been implicated in prostate and breast cancers, specifically retinoic acid-receptor-related orphan receptors (RORs), liver X receptors (LXRs), chicken ovalbumin upstream promoter transcription factors (COUP-TFs), estrogen related receptors (ERRs), nerve growth factor 1B-like receptors, and ‘‘dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1’’ (DAX1). Discovery and development of small molecules that can bind at various functional sites on these ONRs will help determine their biological functions. In addition, these molecules have the potential to act as prototypes for future drug development. Ultimately, the therapeutic value of targeting the ONRs may go well beyond prostate and breast cancers. PMID:25455729

  4. Orphan Nuclear Receptor Estrogen-Related Receptor γ (ERRγ) Is Key Regulator of Hepatic Gluconeogenesis*

    PubMed Central

    Kim, Don-Kyu; Ryu, Dongryeol; Koh, Minseob; Lee, Min-Woo; Lim, Donghyun; Kim, Min-Jung; Kim, Yong-Hoon; Cho, Won-Jea; Lee, Chul-Ho; Park, Seung Bum; Koo, Seung-Hoi; Choi, Hueng-Sik

    2012-01-01

    Glucose homeostasis is tightly controlled by hormonal regulation of hepatic glucose production. Dysregulation of this system is often associated with insulin resistance and diabetes, resulting in hyperglycemia in mammals. Here, we show that the orphan nuclear receptor estrogen-related receptor γ (ERRγ) is a novel downstream mediator of glucagon action in hepatic gluconeogenesis and demonstrate a beneficial impact of the inverse agonist GSK5182. Hepatic ERRγ expression was increased by fasting-dependent activation of the cAMP-response element-binding protein-CRTC2 pathway. Overexpression of ERRγ induced Pck1 and G6PC gene expression and glucose production in primary hepatocytes, whereas abolition of ERRγ gene expression attenuated forskolin-mediated induction of gluconeogenic gene expression. Deletion and mutation analyses of the Pck1 promoter showed that ERRγ directly regulates the Pck1 gene transcription via ERR response elements of the Pck1 promoter as confirmed by ChIP assay and in vivo imaging analysis. We also demonstrate that GSK5182, an inverse agonist of ERRγ, specifically inhibits the transcriptional activity of ERRγ in a PGC-1α dependent manner. Finally, the ERRγ inverse agonist ameliorated hyperglycemia through inhibition of hepatic gluconeogenesis in db/db mice. Control of hepatic glucose production by an ERRγ-specific inverse agonist is a new potential therapeutic approach for the treatment of type 2 diabetes. PMID:22549789

  5. Discovery of three novel orphan G-protein-coupled receptors.

    PubMed

    Marchese, A; Sawzdargo, M; Nguyen, T; Cheng, R; Heng, H H; Nowak, T; Im, D S; Lynch, K R; George, S R; O'dowd, B F

    1999-02-15

    We have discovered three novel human genes, GPR34, GPR44, and GPR45, encoding family A G-protein-coupled receptors (GPCRs). The receptor encoded by GPR34 is most similar to the P2Y receptor subfamily, while the receptor encoded by GPR44 is most similar to chemoattractant receptors. The receptor encoded by GPR45 is the mammalian orthologue of a putative lysophosphatidic acid receptor from Xenopus laevis. Partial sequence of GPR34 was discovered during a search of the GenBank database of expressed sequence tags (ESTs). This sequence information was used both to isolate the full-length translational open reading frame from a human genomic library and to assemble a contig from additional GPR34 EST cDNAs. Northern blot and in situ hybridization analyses revealed GPR34 mRNA transcripts in several human and rat brain regions. Also, we used polymerase chain reaction (PCR) to amplify human genomic DNA using degenerate oligonucleotides designed from sequences encoding transmembrane domains 3 and 7 of opioid and somatostatin receptors. Two PCR products partially encoding novel GPCRs, named GPR44 and GPR45, were discovered and used to isolate the full-length translational open reading frames from a human genomic library. Both GPR44 and GPR45 are expressed in the central nervous system and periphery. For chromosomal localization, fluorescence in situ hybridization analysis was performed to assign GPR34 to chromosomes 4p12 and Xp11. 3, GPR44 to chromosome 11q12-q13.3, and GPR45 to chromosome 2q11. 1-q12. PMID:10036181

  6. Characterization of the G-protein linked orphan receptor GPRN1/RDC1.

    PubMed

    Law, N M; Rosenzweig, S A

    1994-05-30

    Site specific antibodies were raised against the second intracellular loop of the G-protein coupled orphan receptor GPRN1 for analysis of receptor protein expression from a number of sources. Immunoblot analyses showed GPRN1 to be a 60 kDa membrane bound glycoprotein. It was found in AR4-2J, PC12 and SK-N-MC cell lines. High amounts of GPRN1 were found in rat stomach, liver, lung, brain, small intestine and pancreas, with lower amounts in spleen and kidney: none was detectable in rat heart. This distribution differs markedly from that of the closely related orphan receptor RDC1. The receptor shows high evolutionary conservation: immunoreactive 60 kDa GPRN1 was detected in membrane glycoprotein fractions from the livers of rat, toad, chick, stingray and shark. It is therefore predicted that GPRN1 and RDC1 represent two tissue specific subtypes of a 60 kDa receptor for a ligand which has likely been highly conserved throughout evolution and which is active upon many organs of the body.

  7. Evidence for an interaction of neuronostatin with the orphan G protein-coupled receptor, GPR107.

    PubMed

    Yosten, Gina L C; Redlinger, Lauren J; Samson, Willis K

    2012-11-01

    Neuronostatin, derived from the somatostatin preprohormone, is a recently described peptide that is produced by several tissues involved in cardiovascular regulation and metabolism, including the hypothalamus. Injection of neuronostatin into the lateral cerebroventricle led to a dose-related increase in mean arterial pressure (MAP) in rats. Any attempt to inhibit the production of neuronostatin would alter somatostatin production as well, making determination of the physiological relevance of the peptide's pharmacologic effects by compromise of production approaches impossible. Therefore, we employed an alternative approach to identify and compromise the production of the neuronostatin receptor. Because neuronostatin was shown to signal via a PKA-dependent mechanism, we hypothesized that the neuronostatin receptor was a G protein-coupled receptor (GPCR), in particular, one of the orphan GPCRs for which the ligand is unknown. Therefore, we screened neuronostatin-responsive tissues, including hypothalamus, heart, pancreatic α-cells, and the gastric tumor cell line KATOIII, for expression of orphan GPCRs. Four orphan GPCRs were expressed by all cell types, including GPR56 and GPR107. Knockdown of GPR107, but not GPR56 or GPR146, led to a loss of responsiveness to neuronostatin by KATOIII cells. Rats injected with siRNA directed against GPR107 (2 μg/day for 2 days) into the lateral cerebroventricle did not exhibit an increase in MAP in response to neuronostatin treatment. Rats with compromised GPR107 expression also displayed blunted reactivity in a baroreflex sensitivity test, indicating that GPR107 and neuronostatin may be important regulators of cardiovascular function. Thus, GPR107 is a promising candidate receptor for neuronostatin, and neuronostatin, interacting with GPR107, may play an important role in the central control of cardiovascular function. PMID:22933024

  8. Structural insights into gene repression by the orphan nuclear receptor SHP.

    PubMed

    Zhi, Xiaoyong; Zhou, X Edward; He, Yuanzheng; Zechner, Christoph; Suino-Powell, Kelly M; Kliewer, Steven A; Melcher, Karsten; Mangelsdorf, David J; Xu, H Eric

    2014-01-14

    Small heterodimer partner (SHP) is an orphan nuclear receptor that functions as a transcriptional repressor to regulate bile acid and cholesterol homeostasis. Although the precise mechanism whereby SHP represses transcription is not known, E1A-like inhibitor of differentiation (EID1) was isolated as a SHP-interacting protein and implicated in SHP repression. Here we present the crystal structure of SHP in complex with EID1, which reveals an unexpected EID1-binding site on SHP. Unlike the classical cofactor-binding site near the C-terminal helix H12, the EID1-binding site is located at the N terminus of the receptor, where EID1 mimics helix H1 of the nuclear receptor ligand-binding domain. The residues composing the SHP-EID1 interface are highly conserved. Their mutation diminishes SHP-EID1 interactions and affects SHP repressor activity. Together, these results provide important structural insights into SHP cofactor recruitment and repressor function and reveal a conserved protein interface that is likely to have broad implications for transcriptional repression by orphan nuclear receptors.

  9. Structural insights into gene repression by the orphan nuclear receptor SHP

    PubMed Central

    Zhi, Xiaoyong; Zhou, X. Edward; He, Yuanzheng; Zechner, Christoph; Suino-Powell, Kelly M.; Kliewer, Steven A.; Melcher, Karsten; Mangelsdorf, David J.; Xu, H. Eric

    2014-01-01

    Small heterodimer partner (SHP) is an orphan nuclear receptor that functions as a transcriptional repressor to regulate bile acid and cholesterol homeostasis. Although the precise mechanism whereby SHP represses transcription is not known, E1A-like inhibitor of differentiation (EID1) was isolated as a SHP-interacting protein and implicated in SHP repression. Here we present the crystal structure of SHP in complex with EID1, which reveals an unexpected EID1-binding site on SHP. Unlike the classical cofactor-binding site near the C-terminal helix H12, the EID1-binding site is located at the N terminus of the receptor, where EID1 mimics helix H1 of the nuclear receptor ligand-binding domain. The residues composing the SHP–EID1 interface are highly conserved. Their mutation diminishes SHP–EID1 interactions and affects SHP repressor activity. Together, these results provide important structural insights into SHP cofactor recruitment and repressor function and reveal a conserved protein interface that is likely to have broad implications for transcriptional repression by orphan nuclear receptors. PMID:24379397

  10. Insights into Orphan Nuclear Receptors as Prognostic Markers and Novel Therapeutic Targets for Breast Cancer

    PubMed Central

    Aesoy, Reidun; Clyne, Colin D.; Chand, Ashwini L.

    2015-01-01

    There is emerging evidence asserting the importance of orphan nuclear receptors (ONRs) in cancer initiation and progression. In breast cancer, there is a lot unknown about ONRs in terms of their expression profile and their transcriptional targets in the various stages of tumor progression. With the classification of breast tumors into distinct molecular subtypes, we assess ONR expression in the different breast cancer subtypes and with patient outcomes. Complementing this, we review evidence implicating ONR-dependent molecular pathways in breast cancer progression to identify candidate ONRs as potential prognostic markers and/or as therapeutic targets. PMID:26300846

  11. Structural basis for corepressor assembly by the orphan nuclear receptor TLX.

    PubMed

    Zhi, Xiaoyong; Zhou, X Edward; He, Yuanzheng; Searose-Xu, Kelvin; Zhang, Chun-Li; Tsai, Chih-Cheng; Melcher, Karsten; Xu, H Eric

    2015-02-15

    The orphan nuclear receptor TLX regulates neural stem cell self-renewal in the adult brain and functions primarily as a transcription repressor through recruitment of Atrophin corepressors, which bind to TLX via a conserved peptide motif termed the Atro box. Here we report crystal structures of the human and insect TLX ligand-binding domain in complex with Atro box peptides. In these structures, TLX adopts an autorepressed conformation in which its helix H12 occupies the coactivator-binding groove. Unexpectedly, H12 in this autorepressed conformation forms a novel binding pocket with residues from helix H3 that accommodates a short helix formed by the conserved ALXXLXXY motif of the Atro box. Mutations that weaken the TLX-Atrophin interaction compromise the repressive activity of TLX, demonstrating that this interaction is required for Atrophin to confer repressor activity to TLX. Moreover, the autorepressed conformation is conserved in the repressor class of orphan nuclear receptors, and mutations of corresponding residues in other members of this class of receptors diminish their repressor activities. Together, our results establish the functional conservation of the autorepressed conformation and define a key sequence motif in the Atro box that is essential for TLX-mediated repression.

  12. Structural basis for corepressor assembly by the orphan nuclear receptor TLX

    PubMed Central

    Zhou, X. Edward; He, Yuanzheng; Searose-Xu, Kelvin; Zhang, Chun-Li; Tsai, Chih-Cheng; Melcher, Karsten

    2015-01-01

    The orphan nuclear receptor TLX regulates neural stem cell self-renewal in the adult brain and functions primarily as a transcription repressor through recruitment of Atrophin corepressors, which bind to TLX via a conserved peptide motif termed the Atro box. Here we report crystal structures of the human and insect TLX ligand-binding domain in complex with Atro box peptides. In these structures, TLX adopts an autorepressed conformation in which its helix H12 occupies the coactivator-binding groove. Unexpectedly, H12 in this autorepressed conformation forms a novel binding pocket with residues from helix H3 that accommodates a short helix formed by the conserved ALXXLXXY motif of the Atro box. Mutations that weaken the TLX–Atrophin interaction compromise the repressive activity of TLX, demonstrating that this interaction is required for Atrophin to confer repressor activity to TLX. Moreover, the autorepressed conformation is conserved in the repressor class of orphan nuclear receptors, and mutations of corresponding residues in other members of this class of receptors diminish their repressor activities. Together, our results establish the functional conservation of the autorepressed conformation and define a key sequence motif in the Atro box that is essential for TLX-mediated repression. PMID:25691470

  13. Gpr176 is a Gz-linked orphan G-protein-coupled receptor that sets the pace of circadian behaviour

    PubMed Central

    Doi, Masao; Murai, Iori; Kunisue, Sumihiro; Setsu, Genzui; Uchio, Naohiro; Tanaka, Rina; Kobayashi, Sakurako; Shimatani, Hiroyuki; Hayashi, Hida; Chao, Hsu-Wen; Nakagawa, Yuuki; Takahashi, Yukari; Hotta, Yunhong; Yasunaga, Jun-ichirou; Matsuoka, Masao; Hastings, Michael H.; Kiyonari, Hiroshi; Okamura, Hitoshi

    2016-01-01

    G-protein-coupled receptors (GPCRs) participate in a broad range of physiological functions. A priority for fundamental and clinical research, therefore, is to decipher the function of over 140 remaining orphan GPCRs. The suprachiasmatic nucleus (SCN), the brain's circadian pacemaker, governs daily rhythms in behaviour and physiology. Here we launch the SCN orphan GPCR project to (i) search for murine orphan GPCRs with enriched expression in the SCN, (ii) generate mutant animals deficient in candidate GPCRs, and (iii) analyse the impact on circadian rhythms. We thereby identify Gpr176 as an SCN-enriched orphan GPCR that sets the pace of circadian behaviour. Gpr176 is expressed in a circadian manner by SCN neurons, and molecular characterization reveals that it represses cAMP signalling in an agonist-independent manner. Gpr176 acts independently of, and in parallel to, the Vipr2 GPCR, not through the canonical Gi, but via the unique G-protein subclass Gz. PMID:26882873

  14. Molecular cloning of an orphan G-protein-coupled receptor that constitutively activates adenylate cyclase.

    PubMed Central

    Eggerickx, D; Denef, J F; Labbe, O; Hayashi, Y; Refetoff, S; Vassart, G; Parmentier, M; Libert, F

    1995-01-01

    A human gene encoding an orphan G-protein-coupled receptor named ACCA (adenylate cyclase constitutive activator) was isolated from a genomic library using as a probe a DNA fragment obtained by low-stringency PCR. Human ACCA (hACCA) is a protein of 330 amino acids that exhibits all the structural hallmarks of the main family of G-protein-coupled receptors. Expression of hACCA resulted in a dramatic stimulation of adenylate cyclase, similar in amplitude to that obtained with other Gs-coupled receptors fully activated by their respective ligands. This stimulation was obtained in a large variety of stable cell lines derived from various organs, and originating from different mammalian species. hACCA was found to be the human homologue of a recently reported mouse orphan receptor (GPCR21). The mouse ACCA (mACCA) was therefore recloned by PCR, and expression of mACCA in Cos-7 cells demonstrated that the mouse receptor behaved similarly as a constitutive activator of adenylate cyclase. It is not known presently whether the stimulation of adenylate cyclase is the result of a true constitutive activity of the receptor or, alternatively, is the consequence of a permanent stimulation by a ubiquitous ligand. The tissue distribution of mACCA was determined by RNase protection assay. Abundant transcripts were found in the brain, whereas lower amounts were detected in testis, ovary and eye. Various hypotheses concerning the constitutive activity of ACCA and their potential biological significance are discussed. Images Figure 4 Figure 5 PMID:7639700

  15. Identification of the orphan GPCR, P2Y(10) receptor as the sphingosine-1-phosphate and lysophosphatidic acid receptor.

    PubMed

    Murakami, Masanori; Shiraishi, Akira; Tabata, Kenichi; Fujita, Norihisa

    2008-07-11

    Phylogenetic analysis of transmembrane regions of GPCRs using PHYLIP indicated that the orphan receptor P2Y(10) receptor was classified into the cluster consisting nucleotide and lipid receptors. Based on the results, we studied the abilities of nucleotides and lipids to activate the P2Y(10) receptors. As a result, sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) evoked intracellular Ca(2+) increases in the CHO cells stably expressing the P2Y(10) fused with a G(16alpha) protein. These Ca(2+) responses were inhibited by S1P receptor and LPA receptor antagonists. The introduction of siRNA designed for P2Y(10) receptor into the P2Y(10)-CHO cells effectively blocked both S1P- and LPA-induced Ca(2+) increases. RT-PCR analysis showed that the mouse P2Y(10) was expressed in reproductive organs, brain, lung and skeletal muscle, suggesting the receptor plays physiological roles throughout the whole body. In conclusion, the P2Y(10) receptor is the first receptor identified as a dual lysophospholipid receptor. PMID:18466763

  16. The orphan nuclear receptor SHP regulates PGC-1alpha expression and energy production in brown adipocytes.

    PubMed

    Wang, Li; Liu, Jun; Saha, Pradip; Huang, Jiansheng; Chan, Lawrence; Spiegelman, Bruce; Moore, David D

    2005-10-01

    Brown adipocytes increase energy production in response to induction of PGC-1alpha, a dominant regulator of energy metabolism. We have found that the orphan nuclear receptor SHP (NR0B2) is a negative regulator of PGC-1alpha expression in brown adipocytes. Mice lacking SHP show increased basal expression of PGC-1alpha, increased energy expenditure, and resistance to diet-induced obesity. Increased PGC-1alpha expression in SHP null brown adipose tissue is not due to beta-adrenergic activation, since it is also observed in primary cultures of SHP(-/-) brown adipocytes that are not exposed to such stimuli. In addition, acute inhibition of SHP expression in cultured wild-type brown adipocytes increases basal PGC-1alpha expression, and SHP overexpression in SHP null brown adipocytes decreases it. The orphan nuclear receptor ERRgamma is expressed in BAT and its transactivation of the PGC-1alpha promoter is potently inhibited by SHP. We conclude that SHP functions as a negative regulator of energy production in BAT.

  17. Orphan nuclear receptor Nur77 participates in human apolipoprotein A5 gene expression

    SciTech Connect

    Song, Kwang-Hoon

    2010-01-29

    The orphan nuclear receptor Nur77 (NR4A1) has been reported to play a crucial role in the modulation of diverse metabolic processes in liver. Here, we reported the identification of human apolipoprotein A5 (ApoA5), which implicated in lowering plasma triglyceride levels, as a novel target gene of Nur77. Nur77 induced the human ApoA5 promoter activity. Using 5'-deletion and mutagenesis of human ApoA5 promoter analysis and chromatin immunoprecipitation assays, it was shown that Nur77 directly regulated human ApoA5 gene expression by binding to a Nur77 response element (AAAGGTCA) located in the proximal human ApoA5 promoter region. In addition, we demonstrated that blocking of Nur77 transcriptional activity via overexpression of dominant negative Nur77 suppressed human ApoA5 promoter activity and mRNA expression in human hepatoma cells, HepG2. Taken together, our results demonstrated that Nur77 is a novel regulator of human ApoA5 gene expression and provide a new insight into the role of this orphan nuclear receptor in lipoprotein metabolism and triglyceride homeostasis.

  18. Identification of a Synthetic Agonist for the Orphan Nuclear Receptors RORα and RORγ, SR1078

    PubMed Central

    Wang, Yongjun; Kumar, Naresh; Nuhant, Philippe; Cameron, Michael D.; Istrate, Monica A.; Roush, William R.; Griffin, Patrick R.; Burris, Thomas P.

    2010-01-01

    The retinoic acid receptor-related receptors (RORs) are members of the nuclear receptor (NR) superfamily of transcription factors. Several NRs are still characterized as orphan receptors since ligands have not yet been identified for these proteins. Here, we describe the identification of a synthetic RORα/RORγ ligand, SR1078. SR1078 modulates the conformation of RORγ in a biochemical assay and activates RORα and RORγ driven transcription. Furthermore, SR1078 stimulates expression of endogenous ROR target genes in HepG2 cells that express both RORα and RORγ. Pharmacokinetic studies indicate that SR1078 displays reasonable exposure following injection into mice and consistent with SR1078 functioning as a RORα/RORγ agonist, expression of two ROR target genes, glucose-6-phosphatase and fibroblast growth factor 21, were stimulated in the liver. Thus, we have identified the first synthetic RORα/γ agonist and this compound can be utilized as a chemical tool to probe the function of these receptors both in vitro and in vivo. PMID:20735016

  19. Nuclear receptor 4A (NR4A) family - orphans no more.

    PubMed

    Safe, Stephen; Jin, Un-Ho; Morpurgo, Benjamin; Abudayyeh, Ala; Singh, Mandip; Tjalkens, Ronald B

    2016-03-01

    The orphan nuclear receptors NR4A1, NR4A2 and NR4A3 are immediate early genes induced by multiple stressors, and the NR4A receptors play an important role in maintaining cellular homeostasis and disease. There is increasing evidence for the role of these receptors in metabolic, cardiovascular and neurological functions and also in inflammation and inflammatory diseases and in immune functions and cancer. Despite the similarities of NR4A1, NR4A2 and NR4A3 and their interactions with common cis-genomic elements, they exhibit unique activities and cell-/tissue-specific functions. Although endogenous ligands for NR4A receptors have not been identified, there is increasing evidence that structurally-diverse synthetic molecules can directly interact with the ligand binding domain of NR4A1 and act as agonists or antagonists, and ligands for NR4A2 and NR4A3 have also been identified. Since NR4A receptors are key factors in multiple diseases, there are opportunities for the future development of NR4A ligands for clinical applications in treating multiple health problems including metabolic, neurologic and cardiovascular diseases, other inflammatory conditions, and cancer.

  20. DAX-1, an unusual orphan receptor at the crossroads of steroidogenic function and sexual differentiation.

    PubMed

    Lalli, Enzo; Sassone-Corsi, Paolo

    2003-08-01

    The unusual orphan member of the nuclear hormone receptor superfamily DAX-1 (NR0B1) owes its name to its double role in human pathology. On one side, duplications in Xp21, containing the DAX-1 gene, cause phenotypic sex reversal in XY individuals. On the other side, DAX-1 gene mutations are responsible for adrenal hypoplasia congenita, invariably associated with hypogonadotropic hypogonadism. DAX-1 functions as a global negative regulator of steroid hormone production by repressing the expression of multiple genes involved in the steroidogenic pathway. Here we review the mechanism of DAX-1 function in adrenal and gonadal differentiation, with special emphasis on recent results showing the critical role of DAX-1 protein misfolding in the pathogenesis of adrenal hypoplasia congenita. PMID:12775766

  1. Orphan nuclear receptor NGFI-B forms dimers with nonclassical interface.

    PubMed

    Calgaro, Marcos R; Neto, Mario de Oliveira; Figueira, Ana Carolina M; Santos, Maria A M; Portugal, Rodrigo V; Guzzi, Carolina A; Saidemberg, Daniel M; Bleicher, Lucas; Vernal, Javier; Fernandez, Pablo; Terenzi, Hernán; Palma, Mario Sergio; Polikarpov, Igor

    2007-08-01

    The orphan receptor nerve growth factor-induced B (NGFI-B) is a member of the nuclear receptor's subfamily 4A (Nr4a). NGFI-B was shown to be capable of binding both as a monomer to an extended half-site containing a single AAAGGTCA motif and also as a homodimer to a widely separated everted repeat, as opposed to a large number of nuclear receptors that recognize and bind specific DNA sequences predominantly as homo- and/or heterodimers. To unveil the structural organization of NGFI-B in solution, we determined the quaternary structure of the NGFI-B LBD by a combination of ab initio procedures from small-angle X-ray scattering (SAXS) data and hydrogen-deuterium exchange followed by mass spectrometry. Here we report that the protein forms dimers in solution with a radius of gyration of 2.9 nm and maximum dimension of 9.0 nm. We also show that the NGFI-B LBD dimer is V-shaped, with the opening angle significantly larger than that of classical dimer's exemplified by estrogen receptor (ER) or retinoid X receptor (RXR). Surprisingly, NGFI-B dimers formation does not occur via the classical nuclear receptor dimerization interface exemplified by ER and RXR, but instead, involves an extended surface area composed of the loop between helices 3 and 4 and C-terminal fraction of the helix 3. Remarkably, the NGFI-B dimer interface is similar to the dimerization interface earlier revealed for glucocorticoid nuclear receptor (GR), which might be relevant to the recognition of cognate DNA response elements by NGFI-B and to antagonism of NGFI-B-dependent transcription exercised by GR in cells.

  2. Identification of specific ligands for orphan olfactory receptors. G protein-dependent agonism and antagonism of odorants.

    PubMed

    Shirokova, Elena; Schmiedeberg, Kristin; Bedner, Peter; Niessen, Heiner; Willecke, Klaus; Raguse, Jan-Dirk; Meyerhof, Wolfgang; Krautwurst, Dietmar

    2005-03-25

    Olfactory receptors are the largest group of orphan G protein-coupled receptors with an infinitely small number of agonists identified out of thousands of odorants. The de-orphaning of olfactory receptor (OR) is complicated by its combinatorial odorant coding and thus requires large scale odorant and receptor screening and establishing receptor-specific odorant profiles. Here, we report on the stable reconstitution of OR-specific signaling in HeLa/Olf cells via G protein alphaolf and adenylyl cyclase type-III to the Ca2+ influx-mediating olfactory cyclic nucleotide-gated CNGA2 channel. We demonstrate the central role of Galphaolf in odorant-specific signaling out of OR. The employment of the non-typical G protein alpha15 dramatically altered the odorant specificities of 3 of 7 receptors that had been characterized previously by different groups. We further show for two OR that an odorant may be an agonist or antagonist, depending on the G protein used. HeLa/Olf cells proved suitable for high-throughput screening in fluorescence-imaging plate reader experiments, resulting in the de-orphaning of two new OR for the odorant (-)citronellal from an expression library of 93 receptors. To demonstrate the G protein dependence of its odorant response pattern, we screened the most sensitive (-)citronellal receptor Olfr43 versus 94 odorants simultaneously in the presence of Galpha15 or Galphaolf. We finally established an EC50-ranking odorant profile for Olfr43 in HeLa/Olf cells. In summary, we conclude that, in heterologous systems, odorants may function as agonists or antagonists, depending on the G protein used. HeLa/Olf cells provide an olfactory model system for functional expression and de-orphaning of OR.

  3. Interaction between retinoid acid receptor-related orphan receptor alpha (RORA) and neuropeptide S receptor 1 (NPSR1) in asthma.

    PubMed

    Acevedo, Nathalie; Sääf, Annika; Söderhäll, Cilla; Melén, Erik; Mandelin, Jami; Pietras, Christina Orsmark; Ezer, Sini; Karisola, Piia; Vendelin, Johanna; Gennäs, Gustav Boije af; Yli-Kauhaluoma, Jari; Alenius, Harri; von Mutius, Erika; Doekes, Gert; Braun-Fahrländer, Charlotte; Riedler, Josef; van Hage, Marianne; D'Amato, Mauro; Scheynius, Annika; Pershagen, Göran; Kere, Juha; Pulkkinen, Ville

    2013-01-01

    Retinoid acid receptor-related Orphan Receptor Alpha (RORA) was recently identified as a susceptibility gene for asthma in a genome-wide association study. To investigate the impact of RORA on asthma susceptibility, we performed a genetic association study between RORA single nucleotide polymorphisms (SNPs) in the vicinity of the asthma-associated SNP (rs11071559) and asthma-related traits. Because the regulatory region of a previously implicated asthma susceptibility gene, Neuropeptide S receptor 1 (NPSR1), has predicted elements for RORA binding, we hypothesized that RORA may interact biologically and genetically with NPSR1. 37 RORA SNPs and eight NPSR1 SNPs were genotyped in the Swedish birth cohort BAMSE (2033 children) and the European cross-sectional PARSIFAL study (1120 children). Seven RORA SNPs confined into a 49 kb region were significantly associated with physician-diagnosed childhood asthma. The most significant association with rs7164773 (T/C) was driven by the CC genotype in asthma cases (OR = 2.0, 95%CI 1.36-2.93, p = 0.0003 in BAMSE; and 1.61, 1.18-2.19, p = 0.002 in the combined BAMSE-PARSIFAL datasets, respectively), and strikingly, the risk effect was dependent on the Gln344Arg mutation in NPSR1. In cell models, stimulation of NPSR1 activated a pathway including RORA and other circadian clock genes. Over-expression of RORA decreased NPSR1 promoter activity further suggesting a regulatory loop between these genes. In addition, Rora mRNA expression was lower in the lung tissue of Npsr1 deficient mice compared to wildtype littermates during the early hours of the light period. We conclude that RORA SNPs are associated with childhood asthma and show epistasis with NPSR1, and the interaction between RORA and NPSR1 may be of biological relevance. Combinations of common susceptibility alleles and less common functional polymorphisms may modify the joint risk effects on asthma susceptibility. PMID:23565190

  4. ONRLDB--manually curated database of experimentally validated ligands for orphan nuclear receptors: insights into new drug discovery.

    PubMed

    Nanduri, Ravikanth; Bhutani, Isha; Somavarapu, Arun Kumar; Mahajan, Sahil; Parkesh, Raman; Gupta, Pawan

    2015-01-01

    Orphan nuclear receptors are potential therapeutic targets. The Orphan Nuclear Receptor Ligand Binding Database (ONRLDB) is an interactive, comprehensive and manually curated database of small molecule ligands targeting orphan nuclear receptors. Currently, ONRLDB consists of ∼11,000 ligands, of which ∼6500 are unique. All entries include information for the ligand, such as EC50 and IC50, number of aromatic rings and rotatable bonds, XlogP, hydrogen donor and acceptor count, molecular weight (MW) and structure. ONRLDB is a cross-platform database, where either the cognate small molecule modulators of a receptor or the cognate receptors to a ligand can be searched. The database can be searched using three methods: text search, advanced search or similarity search. Substructure search, cataloguing tools, and clustering tools can be used to perform advanced analysis of the ligand based on chemical similarity fingerprints, hierarchical clustering, binning partition and multidimensional scaling. These tools, together with the Tree function provided, deliver an interactive platform and a comprehensive resource for identification of common and unique scaffolds. As demonstrated, ONRLDB is designed to allow selection of ligands based on various properties and for designing novel ligands or to improve the existing ones. Database URL: http://www.onrldb.org/.

  5. ONRLDB—manually curated database of experimentally validated ligands for orphan nuclear receptors: insights into new drug discovery

    PubMed Central

    Nanduri, Ravikanth; Bhutani, Isha; Somavarapu, Arun Kumar; Mahajan, Sahil; Parkesh, Raman; Gupta, Pawan

    2015-01-01

    Orphan nuclear receptors are potential therapeutic targets. The Orphan Nuclear Receptor Ligand Binding Database (ONRLDB) is an interactive, comprehensive and manually curated database of small molecule ligands targeting orphan nuclear receptors. Currently, ONRLDB consists of ∼11 000 ligands, of which ∼6500 are unique. All entries include information for the ligand, such as EC50 and IC50, number of aromatic rings and rotatable bonds, XlogP, hydrogen donor and acceptor count, molecular weight (MW) and structure. ONRLDB is a cross-platform database, where either the cognate small molecule modulators of a receptor or the cognate receptors to a ligand can be searched. The database can be searched using three methods: text search, advanced search or similarity search. Substructure search, cataloguing tools, and clustering tools can be used to perform advanced analysis of the ligand based on chemical similarity fingerprints, hierarchical clustering, binning partition and multidimensional scaling. These tools, together with the Tree function provided, deliver an interactive platform and a comprehensive resource for identification of common and unique scaffolds. As demonstrated, ONRLDB is designed to allow selection of ligands based on various properties and for designing novel ligands or to improve the existing ones. Database URL: http://www.onrldb.org/ PMID:26637529

  6. Nuclear receptor function in skin health and disease: therapeutic opportunities in the orphan and adopted receptor classes.

    PubMed

    Yin, Kelvin; Smith, Aaron G

    2016-10-01

    The skin forms a vital barrier between an organism's external environment, providing protection from pathogens and numerous physical and chemical threats. Moreover, the intact barrier is essential to prevent water and electrolyte loss without which terrestrial life could not be maintained. Accordingly, acute disruption of the skin through physical or chemical trauma needs to be repaired timely and efficiently as sustained skin pathologies ranging from mild irritations and inflammation through to malignancy impact considerably on morbidity and mortality. The Nuclear Hormone Receptor Family of transcriptional regulators has proven to be highly valuable targets for addressing a range of pathologies, including metabolic syndrome and cancer. Indeed members of the classic endocrine sub-group, such as the glucocorticoid, retinoid, and Vitamin D receptors, represent mainstay treatment strategies for numerous inflammatory skin disorders, though side effects from prolonged use are common. Emerging evidence has now highlighted important functional roles for nuclear receptors belonging to the adopted and orphan subgroups in skin physiology and patho-physiology. This review will focus on these subgroups and explore the current evidence that suggests these nuclear receptor hold great promise as future stand-alone or complementary drug targets in treating common skin diseases and maintaining skin homeostasis. PMID:27544210

  7. Nuclear receptor function in skin health and disease: therapeutic opportunities in the orphan and adopted receptor classes.

    PubMed

    Yin, Kelvin; Smith, Aaron G

    2016-10-01

    The skin forms a vital barrier between an organism's external environment, providing protection from pathogens and numerous physical and chemical threats. Moreover, the intact barrier is essential to prevent water and electrolyte loss without which terrestrial life could not be maintained. Accordingly, acute disruption of the skin through physical or chemical trauma needs to be repaired timely and efficiently as sustained skin pathologies ranging from mild irritations and inflammation through to malignancy impact considerably on morbidity and mortality. The Nuclear Hormone Receptor Family of transcriptional regulators has proven to be highly valuable targets for addressing a range of pathologies, including metabolic syndrome and cancer. Indeed members of the classic endocrine sub-group, such as the glucocorticoid, retinoid, and Vitamin D receptors, represent mainstay treatment strategies for numerous inflammatory skin disorders, though side effects from prolonged use are common. Emerging evidence has now highlighted important functional roles for nuclear receptors belonging to the adopted and orphan subgroups in skin physiology and patho-physiology. This review will focus on these subgroups and explore the current evidence that suggests these nuclear receptor hold great promise as future stand-alone or complementary drug targets in treating common skin diseases and maintaining skin homeostasis.

  8. The Nuclear Orphan Receptor NR2F6 Is a Central Checkpoint for Cancer Immune Surveillance

    PubMed Central

    Hermann-Kleiter, Natascha; Klepsch, Victoria; Wallner, Stephanie; Siegmund, Kerstin; Klepsch, Sebastian; Tuzlak, Selma; Villunger, Andreas; Kaminski, Sandra; Pfeifhofer-Obermair, Christa; Gruber, Thomas; Wolf, Dominik; Baier, Gottfried

    2015-01-01

    Summary Nuclear receptor subfamily 2, group F, member 6 (NR2F6) is an orphan member of the nuclear receptor superfamily. Here, we show that genetic ablation of Nr2f6 significantly improves survival in the murine transgenic TRAMP prostate cancer model. Furthermore, Nr2f6−/− mice spontaneously reject implanted tumors and develop host-protective immunological memory against tumor rechallenge. This is paralleled by increased frequencies of both CD4+ and CD8+ T cells and higher expression levels of interleukin 2 and interferon γ at the tumor site. Mechanistically, CD4+ and CD8+ T cell-intrinsic NR2F6 acts as a direct repressor of the NFAT/AP-1 complex on both the interleukin 2 and the interferon γ cytokine promoters, attenuating their transcriptional thresholds. Adoptive transfer of Nr2f6-deficient T cells into tumor-bearing immunocompetent mice is sufficient to delay tumor outgrowth. Altogether, this defines NR2F6 as an intracellular immune checkpoint in effector T cells, governing the amplitude of anti-cancer immunity. PMID:26387951

  9. Distinct repressive properties of the mammalian and fish orphan nuclear receptors SHP and DAX-1.

    PubMed

    Park, Yun-Yong; Teyssier, Catherine; Vanacker, Jean-Marc; Choi, Hueng-Sik

    2007-06-30

    It has been suggested that the structure and function of nuclear receptors are evolutionally conserved. Here, we compare the molecular functions of the nile tilapia (Oreochromis niloticus) small heterodimer partner (nSHP/NR0B2) and the Dosage-sensitive sex reversal AHC critical region on X chromosome gene 1 (nDAX-1/NR0B1) with those of human SHP and DAX-1 (hSHP and hDAX-1, respectively). We found that, upon transient cotransfection of human cells, nDAX-1 repressed the activity of tilapia SF-1 (nSF-1) but not that of human SF-1, although the physical interaction with human SF-1 was retained. Similarly, nSHP repressed the activity of nSF-1, whereas hSHP did not, pointing to divergent evolution of SHP/SF-1 in fish and human. We thus propose that the repressive functions of SHP and DAX-1 have been conserved in fish and mammals although with different transcriptional targets and mechanisms. These differences provide new insights into the physiological diversification of atypical orphan nuclear receptors during vertebrate evolution. PMID:17646707

  10. Expression and retinoic acid regulation of the zebrafish nr2f orphan nuclear receptor genes

    PubMed Central

    Love, Crystal E.; Prince, Victoria E.

    2012-01-01

    Background The vertebrate nuclear receptor subfamily 2, group f (nr2f) genes encode orphan receptors that have the capacity to act as negative regulators of retinoic acid (RA) signaling. Results We describe embryonic and larval expression of four of the six zebrafish nr2f genes, nr2f1a, nr2f1b, nr2f2 and nr2f5. These genes show highly regulated patterns of expression within the CNS, including in the developing hindbrain, as well as in the mesoderm and endoderm. We also investigated the role of RA and Fgf signaling in regulating early nr2f gene expression. RA is not required for nr2f expression in the hindbrain; however, exogenous RA can repress this expression. Conversely, we find that RA positively regulates nr2f1a expression in trunk endoderm and mesoderm. Fgf signaling is not required for nr2f expression onset in the hindbrain; however, it may play a role in maintaining rhombomere-specific expression. Conclusions We report detailed expression analysis of four nr2f genes in all three germ layers. The onset of nr2f expression in the hindbrain does not require RA or Fgf signals. Our finding that RA positively regulates nr2f1a expression in the trunk supports the possibility that Nr2fs function in a negative feedback loop to modulate RA signaling in this region. PMID:22836912

  11. Regulation of Expression of Citrate Synthase by the Retinoic Acid Receptor-Related Orphan Receptor α (RORα)

    PubMed Central

    Crumbley, Christine; Wang, Yongjun; Banerjee, Subhashis; Burris, Thomas P.

    2012-01-01

    The retinoic acid receptor-related orphan receptor α (RORα) is a member of the nuclear receptor superfamily of transcription factors that plays an important role in regulation of the circadian rhythm and metabolism. Mice lacking a functional RORα display a range of metabolic abnormalities including decreased serum cholesterol and plasma triglycerides. Citrate synthase (CS) is a key enzyme of the citric acid cycle that provides energy for cellular function. Additionally, CS plays a critical role in providing citrate derived acetyl-CoA for lipogenesis and cholesterologenesis. Here, we identified a functional RORα response element (RORE) in the promoter of the CS gene. ChIP analysis demonstrates RORα occupancy of the CS promoter and a putative RORE binds to RORα effectively in an electrophoretic mobility shift assay and confers RORα responsiveness to a reporter gene in a cotransfection assay. We also observed a decrease in CS gene expression and CS enzymatic activity in the staggerer mouse, which has a mutation of in the Rora gene resulting in nonfunctional RORα protein. Furthermore, we found that SR1001 a RORα inverse agonist eliminated the circadian pattern of expression of CS mRNA in mice. These data suggest that CS is a direct RORα target gene and one mechanism by which RORα regulates lipid metabolism is via regulation of CS expression. PMID:22485150

  12. Cross-talk between the NR3B and NR4A families of orphan nuclear receptors

    SciTech Connect

    Lammi, Johanna; Rajalin, Ann-Marie; Huppunen, Johanna; Aarnisalo, Piia . E-mail: piia.aarnisalo@helsinki.fi

    2007-07-27

    Estrogen-related receptors (NR3B family) and Nurr1, NGFI-B, and Nor1 (NR4A family) are orphan nuclear receptors lacking identified natural ligands. The mechanisms regulating their transcriptional activities have remained elusive. We have previously observed that the members of NR3B and NR4A families are coexpressed in certain cell types such as osteoblasts and that the ability of Nurr1 to transactivate the osteopontin promoter is repressed by ERRs. We have now studied the cross-talk between NR3B and NR4A receptors. We show that NR3B and NR4A receptors mutually repress each others' transcriptional activity. The repression involves intact DNA-binding domains and dimerization interfaces but does not result from competition for DNA binding or from heterodimerization. The activation functions of NR3B and NR4A receptors are dispensable for the cross-talk. In conclusion, we report that cross-talk between NR3B and NR4A receptors is a mechanism modulating the transcriptional activities of these orphan nuclear receptors.

  13. Schistosoma mansoni tetraspanning orphan receptor (SmTOR): a new vaccine candidate against schistosomiasis

    PubMed Central

    Lochmatter, C; Schneider, C L; Ingram, K; Keiser, J; Schifferli, J A

    2012-01-01

    One approach to fight against schistosomiasis is to develop an efficient vaccine. Schistosoma mansoni tetraspanning orphan receptor (SmTOR) might be a vaccine candidate, as it is a tegument membrane protein expressed most highly in cercariae. In this study we characterized the recombinant first extracellular domain of SmTOR (rSmTORed1) as having the expected property to bind C2 of complement similarly to a smaller peptide of the same domain, and to produce specific and high-titre antibodies in BALB/c mice immunized using complete Freund's adjuvant/incomplete Freund's adjuvant (CFA/IFA). Immunization was protective against parasite infection, as demonstrated by a significant decrease in worm burden in immunized BALB/c mice versus the control groups over two independent trials [64 and 45% reduction for mean adult worm burden in immunized versus phosphate-bufferd saline (PBS) injected mice]. Interestingly, infection by itself did not lead to the generation of anti-rSmTORed1 antibodies, corresponding to the low frequency of specific anti-rSmTORed1 antibodies detected in the sera of patients infected with S. mansoni (2/20; 10%). These data suggest that, as opposed to the natural infection during which SmTOR induces antibodies only rarely, immunization with its smaller first extracellular domain might be more efficient. PMID:23121675

  14. Nuclear orphan receptor TLX affects gene expression, proliferation and cell apoptosis in beta cells.

    PubMed

    Shi, Xiaoli; Xiong, Xiaokan; Dai, Zhe; Deng, Haohua; Sun, Li; Hu, Xuemei; Zhou, Feng; Xu, Yancheng

    Nuclear orphan receptor TLX is an essential regulator of the growth of neural stem cells. However, its exact function in pancreatic islet cells is still unknown. In the present study, gene expression profiling analysis revealed that overexpression of TLX in beta cell line MIN6 causes suppression of 176 genes and upregulation of 49 genes, including a cadre of cell cycle, cell proliferation and cell death control genes, such as Btg2, Ddit3 and Gadd45a. We next examined the effects of TLX overexpression on proliferation, apoptosis and insulin secretion in MIN6 cells. Proliferation analysis using EdU assay showed that overexpression of TLX increased percentage of EdU-positive cells. Cell cycle and apoptosis analysis revealed that overexpression of TLX in MIN6 cells resulted in higher percentage of cells exiting G1 into S-phase, and a 58.8% decrease of cell apoptosis induced by 0.5 mM palmitate. Moreover, TLX overexpression did not cause impairment of insulin secretion. Together, we conclude that TLX is among factors capable of controlling beta cell proliferation and survival, which may serve as a target for the development of novel therapies for diabetes.

  15. The orphan nuclear receptor COUP-TFII is required for angiogenesis and heart development

    PubMed Central

    Pereira, Fred A.; Qiu, Yuhong; Zhou, Ge; Tsai, Ming-Jer; Tsai, Sophia Y.

    1999-01-01

    The embryonic expression of COUP-TFII, an orphan nuclear receptor, suggests that it may participate in mesenchymal–epithelial interactions required for organogenesis. Targeted deletion of the COUP-TFII gene results in embryonic lethality with defects in angiogenesis and heart development. COUP-TFII mutants are defective in remodeling the primitive capillary plexus into large and small microcapillaries. In the COUP-TFII mutant heart, the atria and sinus venosus fail to develop past the primitive tube stage. Reciprocal interactions between the endothelium and the mesenchyme in the vascular system and heart are essential for normal development of these systems. In fact, the expression of Angiopoietin-1, a proangiogenic soluble factor thought to mediate the mesenchymal–endothelial interactions during heart development and vascular remodeling, is down-regulated in COUP-TFII mutants. This down-regulation suggests that COUP-TFII may be required for bidirectional signaling between the endothelial and mesenchymal compartments essential for proper angiogenesis and heart development. PMID:10215630

  16. The Retinoid-Related Orphan Receptor RORα Promotes Keratinocyte Differentiation via FOXN1

    PubMed Central

    Dai, Jun; Brooks, Yang; Lefort, Karine; Getsios, Spiro; Dotto, G. Paolo

    2013-01-01

    RORα is a retinoid-related orphan nuclear receptor that regulates inflammation, lipid metabolism, and cellular differentiation of several non-epithelial tissues. In spite of its high expression in skin epithelium, its functions in this tissue remain unclear. Using gain- and loss-of-function approaches to alter RORα gene expression in human keratinocytes (HKCs), we have found that this transcription factor functions as a regulator of epidermal differentiation. Among the 4 RORα isoforms, RORα4 is prominently expressed by keratinocytes in a manner that increases with differentiation. In contrast, RORα levels are significantly lower in skin squamous cell carcinoma tumors (SCCs) and cell lines. Increasing the levels of RORα4 in HKCs enhanced the expression of structural proteins associated with early and late differentiation, as well as genes involved in lipid barrier formation. Gene silencing of RORα impaired the ability of keratinocytes to differentiate in an in vivo epidermal cyst model. The pro-differentiation function of RORα is mediated at least in part by FOXN1, a well-known pro-differentiation transcription factor that we establish as a novel direct target of RORα in keratinocytes. Our results point to RORα as a novel node in the keratinocyte differentiation network and further suggest that the identification of RORα ligands may prove useful for treating skin disorders that are associated with abnormal keratinocyte differentiation, including cancer. PMID:23922987

  17. Tie1: an orphan receptor provides context for angiopoietin-2/Tie2 signaling.

    PubMed

    Mueller, Sarah B; Kontos, Christopher D

    2016-09-01

    Angiopoietin-1/Tie2 (ANG1/Tie2) signaling is well documented as regulating angiogenesis and vessel maturation. This pathway is complicated by involvement of the orphan receptor Tie1, which has been implicated as both a positive and negative regulator of ANG1/Tie2 signaling, and ANG2, which can serve as both a Tie2 agonist and antagonist, depending on the context. Two papers in this issue of the JCI provide new insight into this complicated pathway. Korhonen et al. reveal that Tie1 acts to modulate the effects of ANG1 and ANG2 on Tie2 in vitro and in vivo. Kim et al. demonstrate that ANG2 acts as a Tie2 agonist in non-pathological conditions, whereas in the setting of inflammation, ANG2 functions as a Tie2 antagonist and promotes vascular dysfunction. Both studies indicate that inflammation promotes cleavage of the ectodomain of Tie1 and that this cleavage event corresponds with the switch of ANG2 from a Tie2 agonist to an antagonist. The results of these studies lay the groundwork for future strategies to therapeutically exploit this pathway in diseases characterized by adverse vascular remodeling and increased permeability. PMID:27548526

  18. The retinoid-related orphan receptor alpha (RORA) gene and fear-related psychopathology

    PubMed Central

    Miller, Mark W.; Wolf, Erika J.; Logue, Mark W.; Baldwin, Clinton T.

    2013-01-01

    Background This study followed on findings from a recent genome-wide association study of PTSD that implicated the retinoid-related orphan receptor alpha (RORA) gene (Logue et al, 2012) by examining its relationship to broader array of disorders. Methods Using data from the same cohort (N = 540), we analyzed patterns of association between 606 single nucleotide polymorphisms (SNPs) spanning the RORA gene and comorbidity factors termed fear, distress (i.e., internalizing factors) and externalizing. Results Results showed that rs17303244 was associated with the fear component of internalizing (i.e., defined by symptoms of panic, agoraphobia, specific phobia, and obsessive-compulsive disorder) at a level of significance that withstood correction for gene-wide multiple testing. Limitations The primary limitations were the modest size of the cohort and the absence of a replication sample. Conclusions Results add to a growing literature implicating the RORA gene in a wide range of neuropsychiatric disorders and offer new insight into possible molecular mechanisms of the effects of traumatic stress on the brain and the role of genetic factors in those processes. PMID:24007783

  19. RAR-related orphan receptor A (RORA): A new susceptibility gene for multiple sclerosis.

    PubMed

    Eftekharian, Mohammad Mahdi; Noroozi, Rezvan; Sayad, Arezou; Sarrafzadeh, Shaghayegh; Toghi, Mehdi; Azimi, Tahereh; Komaki, Alireza; Mazdeh, Mehrdokht; Inoko, Hidetoshi; Taheri, Mohammad; Mirfakhraie, Reza

    2016-10-15

    Retinoic acid receptor-related orphan receptor alpha (RORA) is proposed to promote Th17 cells differentiation that play a crucial role in many inflammatory diseases, including multiple sclerosis (MS). The gene is also involved in regulation of inflammatory responses and neuronal cell development. The aim of the present study is to determine if any relation exists between RORA rs11639084 and rs4774388 gene polymorphisms on the individual susceptibility of multiple sclerosis. 410 patients with clinically definite MS and 500 ethnically-matched healthy controls participated in this study. Genotyping was performed using tetra primer-amplification refractory mutation system-PCR (4P-ARMS-PCR) method for the mentioned polymorphisms in the RORA gene. Both variants showed significant differences in allele and genotype distributions between the studied groups. Genotypes were risk associated in additive (P-value of 0.0003 and odds ratio equal to 1.7 (95% CI: 1.27-2.26)), dominant (P-value of <0.0001 and odds ratio equal to 0.55 (95% CI: 0.41-0.73)) and recessive (P-value of 0.04 and odds ratio equal to 0.33 (95% CI: (0.12-0.96)) models for rs11639084. However, the rs4774388 genotypes were risk associated in recessive model with a P-value of 0.036 and an odds ratio of 0.62 (95% CI: (0.4-0.97)). To the best of our knowledge this is the first report concerning the association between RORΑ gene polymorphisms and MS. The further study of RORΑ related pathways and gene networks might result in the better understanding of the pathophysiology of MS and related symptoms.

  20. Enhanced ethanol catabolism in orphan nuclear receptor SHP-null mice.

    PubMed

    Park, Jung Eun; Lee, Mikang; Mifflin, Ryan; Lee, Yoon Kwang

    2016-05-15

    Deficiency of the orphan nuclear hormone receptor small heterodimer partner (SHP, NR0B2) protects mice from diet-induced hepatic steatosis, in part, via repression of peroxisome proliferator-activated receptor (PPAR)-γ2 (Pparg2) gene expression. Alcoholic fatty liver diseases (AFLD) share many common pathophysiological features with non-AFLD. To study the role of SHP and PPARγ2 in AFLD, we used a strategy of chronic ethanol feeding plus a single binge ethanol feeding to challenge wild-type (WT) and SHP-null (SHP(-/-)) mice with ethanol. The ethanol feeding induced liver fat accumulation and mRNA expression of hepatic Pparg2 in WT mice, which suggests that a high level of PPARγ2 is a common driving force for fat accumulation induced by ethanol or a high-fat diet. Interestingly, ethanol-fed SHP(-/-) mice displayed hepatic fat accumulation similar to that of ethanol-fed WT mice, even though their Pparg2 expression level remained lower. Mortality of SHP(-/-) mice after ethanol binge feeding was significantly reduced and their acetaldehyde dehydrogenase (Aldh2) mRNA level was higher than that of their WT counterparts. After an intoxicating dose of ethanol, SHP(-/-) mice exhibited faster blood ethanol clearance and earlier wake-up time than WT mice. Higher blood acetate, the end product of ethanol metabolism, and lower acetaldehyde levels were evident in the ethanol-challenged SHP(-/-) than WT mice. Ethanol-induced inflammatory responses and lipid peroxidation were also lower in SHP(-/-) mice. The current data show faster ethanol catabolism and extra fat storage through conversion of acetate to acetyl-CoA before its release into the circulation in this ethanol-feeding model in SHP(-/-) mice.

  1. RAR-related orphan receptor A (RORA): A new susceptibility gene for multiple sclerosis.

    PubMed

    Eftekharian, Mohammad Mahdi; Noroozi, Rezvan; Sayad, Arezou; Sarrafzadeh, Shaghayegh; Toghi, Mehdi; Azimi, Tahereh; Komaki, Alireza; Mazdeh, Mehrdokht; Inoko, Hidetoshi; Taheri, Mohammad; Mirfakhraie, Reza

    2016-10-15

    Retinoic acid receptor-related orphan receptor alpha (RORA) is proposed to promote Th17 cells differentiation that play a crucial role in many inflammatory diseases, including multiple sclerosis (MS). The gene is also involved in regulation of inflammatory responses and neuronal cell development. The aim of the present study is to determine if any relation exists between RORA rs11639084 and rs4774388 gene polymorphisms on the individual susceptibility of multiple sclerosis. 410 patients with clinically definite MS and 500 ethnically-matched healthy controls participated in this study. Genotyping was performed using tetra primer-amplification refractory mutation system-PCR (4P-ARMS-PCR) method for the mentioned polymorphisms in the RORA gene. Both variants showed significant differences in allele and genotype distributions between the studied groups. Genotypes were risk associated in additive (P-value of 0.0003 and odds ratio equal to 1.7 (95% CI: 1.27-2.26)), dominant (P-value of <0.0001 and odds ratio equal to 0.55 (95% CI: 0.41-0.73)) and recessive (P-value of 0.04 and odds ratio equal to 0.33 (95% CI: (0.12-0.96)) models for rs11639084. However, the rs4774388 genotypes were risk associated in recessive model with a P-value of 0.036 and an odds ratio of 0.62 (95% CI: (0.4-0.97)). To the best of our knowledge this is the first report concerning the association between RORΑ gene polymorphisms and MS. The further study of RORΑ related pathways and gene networks might result in the better understanding of the pathophysiology of MS and related symptoms. PMID:27653902

  2. Orphan nuclear receptor DAX-1 in human endometrium and its disorders.

    PubMed

    Saito, Sumika; Ito, Kiyoshi; Suzuki, Takashi; Utsunomiya, Hiroki; Akahira, Jun-ichi; Sugihashi, Youko; Niikura, Hitoshi; Okamura, Kunihiro; Yaegashi, Nobuo; Sasano, Hironobu

    2005-10-01

    DAX-1 (dosage-sensitive sex reversal adrenal hypoplasia congenita critical region on the X chromosome gene 1) is a recently characterized member of the orphan nuclear receptor family. DAX-1 functions as a global negative regulator of steroid hormone production. It inhibits adrenal 4 binding protein (Ad4BP)/steroidogenic factor-1 (SF-1) pathway-dependent P450arom expression in cultured human endometriotic stromal cells and acts as a corepressor for estrogen receptors (ER). In this study we first examined the localization of DAX-1 in 46 normal cycling endometria, 36 cases of endometrial hyperplasia and 103 cases of endometrial carcinoma by using immunohistochemistry to elucidate the possible involvement of DAX-1 and its correlation to the status of Ad4BP/SF-1, a universal transcription factor of steroidogenesis. We then evaluated DAX-1 mRNA expression, using quantitative reverse transcription-polymerase chain reaction for DAX-1 in 33 cases of endometrial carcinoma for further characterization. We subsequently correlated these findings with various clinicopathological parameters of the cases. Ad4BP/SF-1 immunoreactivity was not detected in any human endometria examined. A significant inverse correlation was detected between the status of DAX-1 immunoreactivity and histological grade (P = 0.0003) in endometrial carcinoma. The labeling index (LI) values of DAX-1 in normal endometrium during the secretory phase (P < 0.0001) and hyperplasia (P < 0.0001) were significantly higher than that of carcinoma. No significant correlations were detected between DAX-1 immunoreactivity and amounts of aromatase mRNA. There was a statistically significant positive correlation between DAX-1 and ERalpha (P = 0.006) and ERbeta LI (P < 0.001). These findings suggest that DAX-1 may inhibit the proliferation and progression of endometrial carcinoma through inhibition of estrogenic actions, possibly by interacting with ER present in carcinoma cells, rather than regulating in situ

  3. Identification of COUP-TFII Orphan Nuclear Receptor as a Retinoic Acid-Activated Receptor

    SciTech Connect

    Kruse, Schoen W; Suino-Powell, Kelly; Zhou, X Edward; Kretschman, Jennifer E; Reynolds, Ross; Vonrhein, Clemens; Xu, Yong; Wang, Liliang; Tsai, Sophia Y; Tsai, Ming-Jer; Xu, H Eric

    2010-01-12

    The chicken ovalbumin upstream promoter-transcription factors (COUP-TFI and II) make up the most conserved subfamily of nuclear receptors that play key roles in angiogenesis, neuronal development, organogenesis, cell fate determination, and metabolic homeostasis. Although the biological functions of COUP-TFs have been studied extensively, little is known of their structural features or aspects of ligand regulation. Here we report the ligand-free 1.48 {angstrom} crystal structure of the human COUP-TFII ligand-binding domain. The structure reveals an autorepressed conformation of the receptor, where helix {alpha}10 is bent into the ligand-binding pocket and the activation function-2 helix is folded into the cofactor binding site, thus preventing the recruitment of coactivators. In contrast, in multiple cell lines, COUP-TFII exhibits constitutive transcriptional activity, which can be further potentiated by nuclear receptor coactivators. Mutations designed to disrupt cofactor binding, dimerization, and ligand binding, substantially reduce the COUP-TFII transcriptional activity. Importantly, retinoid acids are able to promote COUP-TFII to recruit coactivators and activate a COUP-TF reporter construct. Although the concentration needed is higher than the physiological levels of retinoic acids, these findings demonstrate that COUP-TFII is a ligand-regulated nuclear receptor, in which ligands activate the receptor by releasing it from the autorepressed conformation.

  4. Drug Discovery Opportunities at the Endothelin B Receptor-Related Orphan G Protein-Coupled Receptors, GPR37 and GPR37L1

    PubMed Central

    Smith, Nicola J.

    2015-01-01

    Orphan G protein-coupled receptors (GPCRs) represent a largely untapped resource for the treatment of a variety of diseases, despite sophisticated advances in drug discovery. Two promising orphan GPCRs are the endothelin B receptor-like proteins, GPR37 [ET(B)R-LP, Pael-R] and GPR37L1 [ET(B)R-LP-2]. Originally identified through searches for homologs of endothelin and bombesin receptors, neither GPR37 nor GPR37L1 were found to bind endothelins or related peptides. Instead, GPR37 was proposed to be activated by head activator (HA) and both GPR37 and GPR37L1 have been linked to the neuropeptides prosaposin and prosaptide, although these pairings are yet to be universally acknowledged. Both orphan GPCRs are widely expressed in the brain, where GPR37 has received the most attention for its link to Parkinson’s disease and parkinsonism, while GPR37L1 deletion leads to precocious cerebellar development and hypertension. In this review, the existing pharmacology and physiology of GPR37 and GPR37L1 is discussed and the potential therapeutic benefits of targeting these receptors are explored. PMID:26635605

  5. Parathyroid hormone induces the Nrna family of nuclear orphan receptors in vivo

    SciTech Connect

    Pirih, Flavia Q. . E-mail: fqpirih@ucla.edu; Aghaloo, Tara L. . E-mail: taghaloo@ucla.edu; Bezouglaia, Olga . E-mail: obezougl@ucla.edu; Nervina, Jeanne M. . E-mail: jnervina@ucla.edu; Tetradis, Sotirios; E-mail: sotirist@dent.ucla.edu

    2005-07-01

    Parathyroid hormone (PTH) has both anabolic and catabolic effects on bone metabolism, although the molecular mechanisms mediating these effects are largely unknown. Among the transcription factors induced by Pth in osteoblasts are the nerve growth factor-inducible factor B (NR4A; NGFI-B) family of orphan nuclear receptors: Nurr1, Nur77, and NOR-1. PTH induces NR4A members through the cAMP-protein kinase A (PKA) pathway in vitro. We report here that PTH rapidly and transiently induced expression of all three NR4A genes in PTH-target tissues in vivo. In calvaria, long bones, and kidneys, NR4A induction was maximal 0.5-1 h after a single intraperitoneal (i.p.) injection of 80 {mu}g/kg PTH. Nur77 demonstrated the highest expression, followed, in order, by Nurr1 and NOR-1. In calvaria and long bone, PTH-induced expression of each NR4A gene was detectable at 10 {mu}g/kg i.p. with maximum induction at 40-80 {mu}g/kg. PTH (3-34) did not induce NR4A mRNA levels in calvaria, long bone, and kidney in vivo, confirming our in vitro results that NR4A genes are induced primarily through the cAMP-PKA pathway. The magnitude of PTH-induced NR4A expression was comparable in vivo and in vitro. However, NR4A mRNA levels peaked and returned to baseline faster in vivo. Both in vivo and in vitro, PTH induced NR4A pre-mRNA levels suggesting that induction of these genes is, at least in part, through activation of mRNA synthesis. The in vivo induction of the NR4A family members by PTH suggests their involvement in, at least some, PTH-induced changes in bone metabolism.

  6. The orphan receptor Rev-erbα gene is a target of the circadian clock pacemaker

    PubMed Central

    Triqueneaux, Gérard; Thenot, Sandrine; Kakizawa, Tomoko; Antoch, Marina P; Safi, Rachid; Takahashi, Joseph S; Delaunay, Franck; Laudet, Vincent

    2013-01-01

    Rev-erbα is a ubiquitously expressed orphan nuclear receptor which functions as a constitutive transcriptional repressor and is expressed in vertebrates according to a robust circadian rhythm. We report here that two Rev-erbα mRNA isoforms, namely Rev-erbα1 and Rev-erbα2, are generated through alternative promoter usage and that both show a circadian expression pattern in an in vitro system using serum-shocked fibroblasts. Both promoter regions P1 (Rev-erbα1) and P2 (Rev-erbα2) contain several E-box DNA sequences, which function as response elements for the core circadian-clock components: CLOCK and BMAL1. The CLOCK–BMAL1 heterodimer stimulates the activity of both P1 and P2 promoters in transient transfection assay by 3–6-fold. This activation was inhibited by the overexpression of CRY1, a component of the negative limb of the circadian transcriptional loop. Critical E-box elements were mapped within both promoters. This regulation is conserved in vertebrates since we found that the CLOCK–BMAL1 heterodimer also regulates the zebrafish Rev-erbα gene. In line with these data Rev-erbα circadian expression was strongly impaired in the livers of Clock mutant mice and in the pineal glands of zebrafish embryos treated with Clock and Bmal1 antisense oligonucleotides. Together these data demonstrate that CLOCK is a critical regulator of Rev-erbα circadian gene expression in evolutionarily distant vertebrates and suggest a role for Rev-erbα in the circadian clock output. PMID:15591021

  7. [Role of orphan G protein-coupled receptor 55 in diabetic gastroparesis in mice].

    PubMed

    Lin, Xu-Hong; Wei, Dan-Dan; Wang, Hui-Chao; Wang, Bin; Bai, Chun-Yang; Wang, Ya-Qiang; Li, Guo-En; Li, Hui-Ping; Ren, Xue-Qun

    2014-06-25

    The aim of the present study was to explore the role of orphan G protein-coupled receptor 55 (GPR55) in diabetic gastroparesis (DG). Streptozotocin (STZ) was used to mimic the DG model, and the body weight and blood glucose concentration were tested 4 weeks after STZ injection (i.p.). Electrogastrogram and phenolsulfonphthalein test were used for detecting gastric emptying. Motilin (MTL), gastrin (GAS), vasoactive intestinal peptide (VIP), and somatostatin (SS) levels in plasma were determined using radioimmunology. Real-time PCR and Western blot were applied to identify the expression of GPR55 in gastric tissue, and immunohistochemistry was used to detect the distribution. The effect of lysophosphatidylinositol (LPI), an agonist of GPR55, was observed. STZ mice showed increased blood glucose concentration, lower body weight, decreased amplitude of slow wave, and delayed gastric emptying. LPI antagonized these effects of STZ. Compared to the control group, STZ caused significant decreases of MTL and GAS levels (P < 0.01), as well as increases of SS and VIP levels (P < 0.01). The changes of these hormones induced by STZ were counteracted when using LPI. GPR55 located in mice stomach, and it was up-regulated in DG. Although LPI showed no effects on the distribution and expression of GPR55 in normal mice, it could inhibit STZ-induced GPR55 up-regulation. These results suggest GPR55 is involved in the regulation of gastric movement of DG, and may serve as a new target of DG treatment. LPI, an agonist of GPR55, can protect against STZ-induced DG, and the mechanism may involve the change of GPR55 expression and modification of gastrointestinal movement regulating hormones. PMID:24964851

  8. Calcium signaling via Orai1 is essential for induction of the nuclear orphan receptor pathway to drive Th17 differentiation.

    PubMed

    Kim, Kyun-Do; Srikanth, Sonal; Tan, Yossan-Var; Yee, Ma-Khin; Jew, Marcus; Damoiseaux, Robert; Jung, Michael E; Shimizu, Saki; An, Dong Sung; Ribalet, Bernard; Waschek, James A; Gwack, Yousang

    2014-01-01

    Orai1 is the pore subunit of Ca(2+) release-activated Ca(2+) (CRAC) channels that stimulate downstream signaling pathways crucial for T cell activation. CRAC channels are an attractive therapeutic target for alleviation of autoimmune diseases. Using high-throughput chemical library screening targeting Orai1, we identified a novel class of small molecules that inhibit CRAC channel activity. One of these molecules, compound 5D, inhibited CRAC channel activity by blocking ion permeation. When included during differentiation, Th17 cells showed higher sensitivity to compound 5D than Th1 and Th2 cells. The selectivity was attributable to high dependence of promoters of retinoic-acid-receptor-related orphan receptors on the Ca(2+)-NFAT pathway. Blocking of CRAC channels drastically decreased recruitment of NFAT and histone modifications within key gene loci involved in Th17 differentiation. The impairment in Th17 differentiation by treatment with CRAC channel blocker was recapitulated in Orai1-deficient T cells, which could be rescued by exogenous expression of retinoic-acid-receptor-related orphan receptors or a constitutive active mutant of NFAT. In vivo administration of CRAC channel blockers effectively reduced the severity of experimental autoimmune encephalomyelitis by suppression of differentiation of inflammatory T cells. These results suggest that CRAC channel blockers can be considered as chemical templates for the development of therapeutic agents to suppress inflammatory responses.

  9. Requirements for heterodimerization between the orphan nuclear receptor Nurr1 and retinoid X receptors.

    PubMed

    Sacchetti, Paola; Dwornik, Hélène; Formstecher, Pierre; Rachez, Christophe; Lefebvre, Philippe

    2002-09-20

    The nuclear receptor nurr1 is a transcription factor involved in the development and maintenance of neurons synthesizing the neurotransmitter dopamine. Although the lack of nurr1 expression has dramatic consequences for these cells either in terms of differentiation or survival, the mechanisms by which nurr1 controls gene transcription still remain unclear. In the intent to understand better the modalities of action of this nuclear receptor, we have undertaken a systematic analysis of the transcriptional effects and DNA binding properties of nurr1 as a monomer or when forming dimers with the different isotypes of the retinoic X receptor (RXR). Here, we show that nurr1 acts as a gene activator independently of RXR and through an AF2-independent mechanism. In addition, heterodimerization with RXR is isotype-specific, involves multiple domains in the C-terminal region of nurr1, and requires RXR binding to DNA. RXR(alpha)-nurr1 and RXRgamma-nurr1 heterodimers bind direct repeat response elements and display no specific requirements with respect to half-site spacing. However, the retinoid responsiveness of DNA-bound heterodimers requires the reiteration of at least three nurr1 binding sites, thereby limiting retinoid-induced nurr1 transcriptional activity to specific direct response elements.

  10. Adropin acts in brain to inhibit water drinking: potential interaction with the orphan G protein-coupled receptor, GPR19.

    PubMed

    Stein, Lauren M; Yosten, Gina L C; Samson, Willis K

    2016-03-15

    Adropin, a recently described peptide hormone produced in the brain and liver, has been reported to have physiologically relevant actions on glucose homeostasis and lipogenesis, and to exert significant effect on endothelial function. We describe a central nervous system action of adropin to inhibit water drinking and identify a potential adropin receptor, the orphan G protein-coupled receptor, GPR19. Reduction in GPR19 mRNA levels in medial basal hypothalamus of male rats resulted in the loss of the inhibitory effect of adropin on water deprivation-induced thirst. The identification of a novel brain action of adropin and a candidate receptor for the peptide should extend and accelerate the study of the potential therapeutic value of adropin or its mimetics for the treatment of metabolic disorders. PMID:26739651

  11. TR4 orphan nuclear receptor functions as an apoptosis modulator via regulation of Bcl-2 gene expression

    SciTech Connect

    Kim, Eungseok; Ma, Wen-Lung; Lin, Din-Lii; Inui, Shigeki; Chen, Yuh-Ling; Chang, Chawnshang . E-mail: chang@urmc.rochester.edu

    2007-09-21

    While Bcl-2 plays an important role in cell apoptosis, its relationship to the orphan nuclear receptors remains unclear. Here we report that mouse embryonic fibroblast (MEF) cells prepared from TR4-deficient (TR4{sup -} {sup /-}) mice are more susceptible to UV-irradiation mediated apoptosis compared to TR4-Wildtype (TR4 {sup +/+}) littermates. Substantial increasing TR4{sup -} {sup /-} MEF apoptosis to UV-irradiation was correlated to the down-regulation of Bcl-2 RNA and protein expression and collaterally increased caspase-3 activity. Furthermore, this TR4-induced Bcl-2 gene expression can be suppressed by co-transfection with TR4 coregulators, such as androgen receptor (AR) and receptor-interacting protein 140 (RIP140) in a dose-dependent manner. Together, our results demonstrate that TR4 might function as an apoptosis modulator through induction of Bcl-2 gene expression.

  12. Quantitative expression profiling of G-protein-coupled receptors (GPCRs) in metastatic melanoma: the constitutively active orphan GPCR GPR18 as novel drug target.

    PubMed

    Qin, Y; Verdegaal, E M E; Siderius, M; Bebelman, J P; Smit, M J; Leurs, R; Willemze, R; Tensen, C P; Osanto, S

    2011-02-01

    G-protein-coupled receptors (GPCRs) have been implicated in the tumorigenesis and metastasis of human cancers and are considered amongst the most desirable targets for drug development. Utilizing a robust quantitative PCR array, we quantified expression of 94 human GPCRs, including 75 orphan GPCRs and 19 chemokine receptors, and 36 chemokine ligands, in 40 melanoma metastases from different individuals and benign nevi. Inter-metastatic site comparison revealed that orphan GPR174 and CCL28 are statistically significantly overexpressed in subcutaneous metastases, while P2RY5 is overexpressed in brain metastases. Comparison between metastases (all three metastatic sites) and benign nevi revealed that 16 genes, including six orphan receptors (GPR18, GPR34, GPR119, GPR160, GPR183 and P2RY10) and chemokine receptors CCR5, CXCR4, and CXCR6, were statistically significantly differentially expressed. Subsequent functional experiments in yeast and melanoma cells indicate that GPR18, the most abundantly overexpressed orphan GPCR in all melanoma metastases, is constitutively active and inhibits apoptosis, indicating an important role for GPR18 in tumor cell survival. GPR18 and five other orphan GPCRs with yet unknown biological function may be considered potential novel anticancer targets in metastatic melanoma. PMID:20880198

  13. The Orphan Nuclear Receptor TLX Is an Enhancer of STAT1-Mediated Transcription and Immunity to Toxoplasma gondii

    PubMed Central

    Beiting, Daniel P.; Hidano, Shinya; Baggs, Julie E.; Geskes, Jeanne M.; Fang, Qun; Wherry, E. John; Hunter, Christopher A.; Roos, David S.; Cherry, Sara

    2015-01-01

    The protozoan parasite, Toxoplasma, like many intracellular pathogens, suppresses interferon gamma (IFN-γ)-induced signal transducer and activator of transcription 1 (STAT1) activity. We exploited this well-defined host–pathogen interaction as the basis for a high-throughput screen, identifying nine transcription factors that enhance STAT1 function in the nucleus, including the orphan nuclear hormone receptor TLX. Expression profiling revealed that upon IFN-γ treatment TLX enhances the output of a subset of IFN-γ target genes, which we found is dependent on TLX binding at those loci. Moreover, infection of TLX deficient mice with the intracellular parasite Toxoplasma results in impaired production of the STAT1-dependent cytokine interleukin-12 by dendritic cells and increased parasite burden in the brain during chronic infection. These results demonstrate a previously unrecognized role for this orphan nuclear hormone receptor in regulating STAT1 signaling and host defense and reveal that STAT1 activity can be modulated in a context-specific manner by such “modifiers.” PMID:26196739

  14. Crystallographic Identification and Functional Characterization of Phospholipids as Ligands for the Orphan Nuclear Receptor Steroidogenic Factor-1

    SciTech Connect

    Li, Yong; Choi, Mihwa; Cavey, Greg; Daugherty, Jennifer; Suino, Kelly; Kovach, Amanda; Bingham, Nathan C.; Kliewer, Steven A.; Xu, H.Eric

    2010-11-10

    The orphan nuclear receptor steroidogenic factor 1 (SF-1) regulates the differentiation and function of endocrine glands. Although SF-1 is constitutively active in cell-based assays, it is not known whether this transcriptional activity is modulated by ligands. Here, we describe the 1.5 {angstrom} crystal structure of the SF-1 ligand binding domain in complex with an LXXLL motif from a coregulator protein. The structure reveals the presence of a phospholipid ligand in a surprisingly large pocket ({approx}1600 {angstrom}{sup 3}), with the receptor adopting the canonical active conformation. The bound phospholipid is readily exchanged and modulates SF-1 interactions with coactivators. Mutations designed to reduce the size of the SF-1 pocket or to disrupt hydrogen bonds with the phospholipid abolish SF-1/coactivator interactions and significantly reduce SF-1 transcriptional activity. These findings provide evidence that SF-1 is regulated by endogenous ligands and suggest an unexpected relationship between phospholipids and endocrine development and function.

  15. The Orphan Receptor Tie1 Controls Angiogenesis and Vascular Remodeling by Differentially Regulating Tie2 in Tip and Stalk Cells.

    PubMed

    Savant, Soniya; La Porta, Silvia; Budnik, Annika; Busch, Katrin; Hu, Junhao; Tisch, Nathalie; Korn, Claudia; Valls, Aida Freire; Benest, Andrew V; Terhardt, Dorothee; Qu, Xianghu; Adams, Ralf H; Baldwin, H Scott; Ruiz de Almodóvar, Carmen; Rodewald, Hans-Reimer; Augustin, Hellmut G

    2015-09-22

    Tie1 is a mechanistically poorly characterized endothelial cell (EC)-specific orphan receptor. Yet, Tie1 deletion is embryonic lethal and Tie1 has been implicated in critical vascular pathologies, including atherosclerosis and tumor angiogenesis. Here, we show that Tie1 does not function independently but exerts context-dependent effects on the related receptor Tie2. Tie1 was identified as an EC activation marker that is expressed during angiogenesis by a subset of angiogenic tip and remodeling stalk cells and downregulated in the adult quiescent vasculature. Functionally, Tie1 expression by angiogenic EC contributes to shaping the tip cell phenotype by negatively regulating Tie2 surface presentation. In contrast, Tie1 acts in remodeling stalk cells cooperatively to sustain Tie2 signaling. Collectively, our data support an interactive model of Tie1 and Tie2 function, in which dynamically regulated Tie1 versus Tie2 expression determines the net positive or negative effect of Tie1 on Tie2 signaling.

  16. Control of energy balance by hypothalamic gene circuitry involving two nuclear receptors, neuron-derived orphan receptor 1 and glucocorticoid receptor.

    PubMed

    Kim, Sun-Gyun; Lee, Bora; Kim, Dae-Hwan; Kim, Juhee; Lee, Seunghee; Lee, Soo-Kyung; Lee, Jae W

    2013-10-01

    Nuclear receptors (NRs) regulate diverse physiological processes, including the central nervous system control of energy balance. However, the molecular mechanisms for the central actions of NRs in energy balance remain relatively poorly defined. Here we report a hypothalamic gene network involving two NRs, neuron-derived orphan receptor 1 (NOR1) and glucocorticoid receptor (GR), which directs the regulated expression of orexigenic neuropeptides agouti-related peptide (AgRP) and neuropeptide Y (NPY) in response to peripheral signals. Our results suggest that the anorexigenic signal leptin induces NOR1 expression likely via the transcription factor cyclic AMP response element-binding protein (CREB), while the orexigenic signal glucocorticoid mobilizes GR to inhibit NOR1 expression by antagonizing the action of CREB. Also, NOR1 suppresses glucocorticoid-dependent expression of AgRP and NPY. Consistently, relative to wild-type mice, NOR1-null mice showed significantly higher levels of AgRP and NPY and were less responsive to leptin in decreasing the expression of AgRP and NPY. These results identify mutual antagonism between NOR1 and GR to be a key rheostat for peripheral metabolic signals to centrally control energy balance.

  17. The fate of P2Y-related orphan receptors: GPR80/99 and GPR91 are receptors of dicarboxylic acids.

    PubMed

    Gonzalez, Nathalie Suarez; Communi, Didier; Hannedouche, Sébastien; Boeynaems, Jean-Marie

    2004-12-01

    Several orphan G protein-coupled receptors are structurally close to the family of P2Y nucleotide receptors: GPR80/99 and GPR91 are close to P2Y(1/2/4/6/11) receptors, whereas GPR87, H963 and GPR34 are close to P2Y(12/13/14). Over the years, several laboratories have attempted without success to identify the ligands of those receptors. In early 2004, two papers have been published: One claiming that GPR80/99 is an AMP receptor, called P2Y(15), and the other one showing that GPR80/99 is a receptor for alpha-ketoglutarate, while GPR91 is a succinate receptor. The accompanying paper by Qi et al. entirely supports that GPR80/99 is an alpha-ketoglutarate receptor and not an AMP receptor. The closeness of dicarboxylic acid and P2Y nucleotide receptors might be linked to the negative charges of both types of ligands and the involvement of conserved Arg residues in their neutralization. PMID:18404396

  18. Probing conformational changes in orphan nuclear receptor: the NGFI-B intermediate is a partially unfolded dimer.

    PubMed

    Garcia, Wanius; Figueira, Ana Carolina M; de Oliveira Neto, Mario; de Guzzi, Carolina A; Buzzá, Hilde H; Portugal, Rodrigo V; Calgaro, Marcos R; Polikarpov, Igor

    2008-10-01

    Human nerve growth factor-induced B (NGFI-B) is a member of the NR4A subfamily of orphan nuclear receptors (NRs). Lacking identified ligands, orphan NRs show particular co-regulator proteins binding properties, different from other NRs, and they might have a non-classical quaternary organization. A body of evidence suggests that NRs recognition of and binding to ligands, DNA, homo- and heterodimerization partners and co-regulator proteins involve significant conformational changes of the NR ligand-binding domains (LBDs). To shed light on largely unknown biophysical properties of NGFI-B, here we studied structural organization and unfolding properties of NGFI-B ligand (like)-binding domain induced by chemical perturbation. Our results show that NGFI-B LBD undergoes a two-state guanidine hydrochloride (GndHCl) induced denaturation, as judged by changes in the alpha-helical content of the protein monitored by circular dichroism spectroscopy (CD). In contrast, changes in the tertiary structure of NGFI-B LBD, reported by intrinsic fluorescence, reveal a clear intermediate state. Additionally, SAXS results demonstrate that the intermediate observed by intrinsic fluorescence is a partially folded homodimeric structure, which further unfolds without dissociation at higher GndHCl concentrations. This partially unfolded dimeric assembly of NGFI-B LBD might resemble an intermediate that this domain access momentarily in the native state upon interactions with functional partners.

  19. Bile acid regulates c-Jun expression through the orphan nuclear receptor SHP induction in gastric cells

    SciTech Connect

    Park, Won Il; Park, Min Jung; An, Jin Kwang; Choi, Yung Hyun; Kim, Hye Young; Cheong, JaeHun Yang, Ung Suk

    2008-05-02

    Bile reflux is considered to be one of the most important causative factors in gastric carcinogenesis, due to the attendant inflammatory changes in the gastric mucosa. In this study, we have assessed the molecular mechanisms inherent to the contribution of bile acid to the transcriptional regulation of inflammatory-related genes. In this study, we demonstrated that bile acid induced the expression of the SHP orphan nuclear receptor at the transcriptional level via c-Jun activation. Bile acid also enhanced the protein interaction of NF-{kappa}B and SHP, thereby resulting in an increase in c-Jun expression and the production of the inflammatory cytokine, TNF{alpha}. These results indicate that bile acid performs a critical function in the regulation of the induction of inflammatory-related genes in gastric cells, and that bile acid-mediated gene expression provides a pre-clue for the development of gastric cellular malformation.

  20. A core human primary tumor angiogenesis signature identifies the endothelial orphan receptor ELTD1 as a key regulator of angiogenesis.

    PubMed

    Masiero, Massimo; Simões, Filipa Costa; Han, Hee Dong; Snell, Cameron; Peterkin, Tessa; Bridges, Esther; Mangala, Lingegowda S; Wu, Sherry Yen-Yao; Pradeep, Sunila; Li, Demin; Han, Cheng; Dalton, Heather; Lopez-Berestein, Gabriel; Tuynman, Jurriaan B; Mortensen, Neil; Li, Ji-Liang; Patient, Roger; Sood, Anil K; Banham, Alison H; Harris, Adrian L; Buffa, Francesca M

    2013-08-12

    Limited clinical benefits derived from anti-VEGF therapy have driven the identification of new targets involved in tumor angiogenesis. Here, we report an integrative meta-analysis to define the transcriptional program underlying angiogenesis in human cancer. This approach identified ELTD1, an orphan G-protein-coupled receptor whose expression is induced by VEGF/bFGF and repressed by DLL4 signaling. Extensive analysis of multiple cancer types demonstrates significant upregulation of ELTD1 in tumor-associated endothelial cells, with a higher expression correlating with favorable prognosis. Importantly, ELTD1 silencing impairs endothelial sprouting and vessel formation in vitro and in vivo, drastically reducing tumor growth and greatly improving survival. Collectively, these results provide insight into the regulation of tumor angiogenesis and highlight ELTD1 as key player in blood vessel formation. PMID:23871637

  1. A core human primary tumor angiogenesis signature identifies the endothelial orphan receptor ELTD1 as a key regulator of angiogenesis.

    PubMed

    Masiero, Massimo; Simões, Filipa Costa; Han, Hee Dong; Snell, Cameron; Peterkin, Tessa; Bridges, Esther; Mangala, Lingegowda S; Wu, Sherry Yen-Yao; Pradeep, Sunila; Li, Demin; Han, Cheng; Dalton, Heather; Lopez-Berestein, Gabriel; Tuynman, Jurriaan B; Mortensen, Neil; Li, Ji-Liang; Patient, Roger; Sood, Anil K; Banham, Alison H; Harris, Adrian L; Buffa, Francesca M

    2013-08-12

    Limited clinical benefits derived from anti-VEGF therapy have driven the identification of new targets involved in tumor angiogenesis. Here, we report an integrative meta-analysis to define the transcriptional program underlying angiogenesis in human cancer. This approach identified ELTD1, an orphan G-protein-coupled receptor whose expression is induced by VEGF/bFGF and repressed by DLL4 signaling. Extensive analysis of multiple cancer types demonstrates significant upregulation of ELTD1 in tumor-associated endothelial cells, with a higher expression correlating with favorable prognosis. Importantly, ELTD1 silencing impairs endothelial sprouting and vessel formation in vitro and in vivo, drastically reducing tumor growth and greatly improving survival. Collectively, these results provide insight into the regulation of tumor angiogenesis and highlight ELTD1 as key player in blood vessel formation.

  2. Prostaglandin A2 enhances cellular insulin sensitivity via a mechanism that involves the orphan nuclear receptor NR4A3.

    PubMed

    Zhu, X; Walton, R G; Tian, L; Luo, N; Ho, S-R; Fu, Y; Garvey, W T

    2013-03-01

    We have previously reported that members of the NR4A family of orphan nuclear receptors can augment insulin's ability to stimulate glucose transport in adipocytes. In the current study, we endeavored to test for an insulin-sensitizing effect in muscle cells and to identify a potential transactivator. Lentiviral constructs were used to engineer both hyperexpression and shRNA silencing of NR4A3 in C2C12 myocytes. The NR4A3 hyper-expression construct led to a significant increase in glucose transport rates in the presence of maximal insulin while the NR4A3 knock-down exhibited a significant reduction in insulin-stimulated glucose transport rates. Consistently, insulin-mediated AKT phosphorylation was increased by NR4A3 hyperexpression and decreased following shRNA NR4A3 suppression. Then, we examined effects of prostaglandin A2 (PGA2) on insulin action and NR4A3 transactivation. PGA2 augmented insulin-stimulated glucose uptake in C2C12 myocytes and AKT phosphorylation after 12-h treatment, without significant effects on basal transport or basal AKT phosphorylation. More importantly, we demonstrated that PGA2 led to a greater improvement in insulin-stimulated glucose rates in NR4A3 overexpressing C2C12 myocytes, when compared with Lac-Z controls stimulated with insulin and PGA2. Moreover, the sensitizing effect of PGA2 was significantly diminished in NR4A3 knockdown myocytes compared to scramble controls. These results show for the first time that: (i) PGA2 augments insulin action in myocytes as manifested by enhanced stimulation of glucose transport and AKT phosphorylation; and (ii) the insulin sensitizing effect is dependent upon the orphan nuclear receptor NR4A3. PMID:23104421

  3. Sleeping Beauty Transposition of Chimeric Antigen Receptors Targeting Receptor Tyrosine Kinase-Like Orphan Receptor-1 (ROR1) into Diverse Memory T-Cell Populations

    PubMed Central

    Deniger, Drew C.; Yu, Jianqiang; Huls, M. Helen; Figliola, Matthew J.; Mi, Tiejuan; Maiti, Sourindra N.; Widhopf, George F.; Hurton, Lenka V.; Thokala, Radhika; Singh, Harjeet; Olivares, Simon; Champlin, Richard E.; Wierda, William G.; Kipps, Thomas J.; Cooper, Laurence J. N.

    2015-01-01

    T cells modified with chimeric antigen receptors (CARs) targeting CD19 demonstrated clinical activity against some B-cell malignancies. However, this is often accompanied by a loss of normal CD19+ B cells and humoral immunity. Receptor tyrosine kinase-like orphan receptor-1 (ROR1) is expressed on sub-populations of B-cell malignancies and solid tumors, but not by healthy B cells or normal post-partum tissues. Thus, adoptive transfer of T cells specific for ROR1 has potential to eliminate tumor cells and spare healthy tissues. To test this hypothesis, we developed CARs targeting ROR1 in order to generate T cells specific for malignant cells. Two Sleeping Beauty transposons were constructed with 2nd generation ROR1-specific CARs signaling through CD3ζ and either CD28 (designated ROR1RCD28) or CD137 (designated ROR1RCD137) and were introduced into T cells. We selected for T cells expressing CAR through co-culture with γ-irradiated activating and propagating cells (AaPC), which co-expressed ROR1 and co-stimulatory molecules. Numeric expansion over one month of co-culture on AaPC in presence of soluble interleukin (IL)-2 and IL-21 occurred and resulted in a diverse memory phenotype of CAR+ T cells as measured by non-enzymatic digital array (NanoString) and multi-panel flow cytometry. Such T cells produced interferon-γ and had specific cytotoxic activity against ROR1+ tumors. Moreover, such cells could eliminate ROR1+ tumor xenografts, especially T cells expressing ROR1RCD137. Clinical trials will investigate the ability of ROR1-specific CAR+ T cells to specifically eliminate tumor cells while maintaining normal B-cell repertoire. PMID:26030772

  4. Sleeping Beauty Transposition of Chimeric Antigen Receptors Targeting Receptor Tyrosine Kinase-Like Orphan Receptor-1 (ROR1) into Diverse Memory T-Cell Populations.

    PubMed

    Deniger, Drew C; Yu, Jianqiang; Huls, M Helen; Figliola, Matthew J; Mi, Tiejuan; Maiti, Sourindra N; Widhopf, George F; Hurton, Lenka V; Thokala, Radhika; Singh, Harjeet; Olivares, Simon; Champlin, Richard E; Wierda, William G; Kipps, Thomas J; Cooper, Laurence J N

    2015-01-01

    T cells modified with chimeric antigen receptors (CARs) targeting CD19 demonstrated clinical activity against some B-cell malignancies. However, this is often accompanied by a loss of normal CD19+ B cells and humoral immunity. Receptor tyrosine kinase-like orphan receptor-1 (ROR1) is expressed on sub-populations of B-cell malignancies and solid tumors, but not by healthy B cells or normal post-partum tissues. Thus, adoptive transfer of T cells specific for ROR1 has potential to eliminate tumor cells and spare healthy tissues. To test this hypothesis, we developed CARs targeting ROR1 in order to generate T cells specific for malignant cells. Two Sleeping Beauty transposons were constructed with 2nd generation ROR1-specific CARs signaling through CD3ζ and either CD28 (designated ROR1RCD28) or CD137 (designated ROR1RCD137) and were introduced into T cells. We selected for T cells expressing CAR through co-culture with γ-irradiated activating and propagating cells (AaPC), which co-expressed ROR1 and co-stimulatory molecules. Numeric expansion over one month of co-culture on AaPC in presence of soluble interleukin (IL)-2 and IL-21 occurred and resulted in a diverse memory phenotype of CAR+ T cells as measured by non-enzymatic digital array (NanoString) and multi-panel flow cytometry. Such T cells produced interferon-γ and had specific cytotoxic activity against ROR1+ tumors. Moreover, such cells could eliminate ROR1+ tumor xenografts, especially T cells expressing ROR1RCD137. Clinical trials will investigate the ability of ROR1-specific CAR+ T cells to specifically eliminate tumor cells while maintaining normal B-cell repertoire. PMID:26030772

  5. Orphan Nuclear Receptor ERRα Controls Macrophage Metabolic Signaling and A20 Expression to Negatively Regulate TLR-Induced Inflammation.

    PubMed

    Yuk, Jae-Min; Kim, Tae Sung; Kim, Soo Yeon; Lee, Hye-Mi; Han, Jeongsu; Dufour, Catherine Rosa; Kim, Jin Kyung; Jin, Hyo Sun; Yang, Chul-Su; Park, Ki-Sun; Lee, Chul-Ho; Kim, Jin-Man; Kweon, Gi Ryang; Choi, Hueng-Sik; Vanacker, Jean-Marc; Moore, David D; Giguère, Vincent; Jo, Eun-Kyeong

    2015-07-21

    The orphan nuclear receptor estrogen-related receptor α (ERRα; NR3B1) is a key metabolic regulator, but its function in regulating inflammation remains largely unknown. Here, we demonstrate that ERRα negatively regulates Toll-like receptor (TLR)-induced inflammation by promoting Tnfaip3 transcription and fine-tuning of metabolic reprogramming in macrophages. ERRα-deficient (Esrra(-/-)) mice showed increased susceptibility to endotoxin-induced septic shock, leading to more severe pro-inflammatory responses than control mice. ERRα regulated macrophage inflammatory responses by directly binding the promoter region of Tnfaip3, a deubiquitinating enzyme in TLR signaling. In addition, Esrra(-/-) macrophages showed an increased glycolysis, but impaired mitochondrial respiratory function and biogenesis. Further, ERRα was required for the regulation of NF-κB signaling by controlling p65 acetylation via maintenance of NAD(+) levels and sirtuin 1 activation. These findings unravel a previously unappreciated role for ERRα as a negative regulator of TLR-induced inflammatory responses through inducing Tnfaip3 transcription and controlling the metabolic reprogramming.

  6. The Orphan Nuclear Receptor Nur77 Is a Determinant of Myofiber Size and Muscle Mass in Mice

    PubMed Central

    Tontonoz, Peter; Cortez-Toledo, Omar; Wroblewski, Kevin; Hong, Cynthia; Lim, Laura; Carranza, Rogelio; Conneely, Orla; Metzger, Daniel

    2015-01-01

    We previously showed that the orphan nuclear receptor Nur77 (Nr4a1) plays an important role in the regulation of glucose homeostasis and oxidative metabolism in skeletal muscle. Here, we show using both gain- and loss-of-function models that Nur77 is also a regulator of muscle growth in mice. Transgenic expression of Nur77 in skeletal muscle in mice led to increases in myofiber size. Conversely, mice with global or muscle-specific deficiency in Nur77 exhibited reduced muscle mass and myofiber size. In contrast to Nur77 deficiency, deletion of the highly related nuclear receptor NOR1 (Nr4a3) had minimal effect on muscle mass and myofiber size. We further show that Nur77 mediates its effects on muscle size by orchestrating transcriptional programs that favor muscle growth, including the induction of insulin-like growth factor 1 (IGF1), as well as concomitant downregulation of growth-inhibitory genes, including myostatin, Fbxo32 (MAFbx), and Trim63 (MuRF1). Nur77-mediated increase in IGF1 led to activation of the Akt-mTOR-S6K cascade and the inhibition of FoxO3a activity. The dependence of Nur77 on IGF1 was recapitulated in primary myoblasts, establishing this as a cell-autonomous effect. Collectively, our findings identify Nur77 as a novel regulator of myofiber size and a potential transcriptional link between cellular metabolism and muscle growth. PMID:25605333

  7. Lactate inhibits lipolysis in fat cells through activation of an orphan G-protein-coupled receptor, GPR81.

    PubMed

    Liu, Changlu; Wu, Jiejun; Zhu, Jessica; Kuei, Chester; Yu, Jingxue; Shelton, Jonathan; Sutton, Steven W; Li, Xiaorong; Yun, Su Jin; Mirzadegan, Taraneh; Mazur, Curt; Kamme, Fredrik; Lovenberg, Timothy W

    2009-01-30

    Lactic acid is a well known metabolic by-product of intense exercise, particularly under anaerobic conditions. Lactate is also a key source of energy and an important metabolic substrate, and it has also been hypothesized to be a signaling molecule directing metabolic activity. Here we show that GPR81, an orphan G-protein-coupled receptor highly expressed in fat, is in fact a sensor for lactate. Lactate activates GPR81 in its physiological concentration range of 1-20 mM and suppresses lipolysis in mouse, rat, and human adipocytes as well as in differentiated 3T3-L1 cells. Adipocytes from GPR81-deficient mice lack an antilipolytic response to lactate but are responsive to other antilipolytic agents. Lactate specifically induces internalization of GPR81 after receptor activation. Site-directed mutagenesis of GPR81 coupled with homology modeling demonstrates that classically conserved key residues in the transmembrane binding domains are responsible for interacting with lactate. Our results indicate that lactate suppresses lipolysis in adipose tissue through a direct activation of GPR81. GPR81 may thus be an attractive target for the treatment of dyslipidemia and other metabolic disorders.

  8. Rho-kinase signaling controls nucleocytoplasmic shuttling of class IIa histone deacetylase (HDAC7) and transcriptional activation of orphan nuclear receptor NR4A1.

    PubMed

    Compagnucci, Claudia; Barresi, Sabina; Petrini, Stefania; Bertini, Enrico; Zanni, Ginevra

    2015-04-01

    Rho-kinase (ROCK) has been well documented to play a key role in RhoA-induced actin remodeling. ROCK activation results in myosin light chain (MLC) phosphorylation either by direct action on MLC kinase (MLCK) or by inhibition of MLC phosphatase (MLCP), modulating actin-myosin contraction. We found that inhibition of the ROCK pathway in induced pluripotent stem cells, leads to nuclear export of HDAC7 and transcriptional activation of the orphan nuclear receptor NR4A1 while in cells with constitutive ROCK hyperactivity due to loss of function of the RhoGTPase activating protein Oligophrenin-1 (OPHN1), the orphan nuclear receptor NR4A1 is downregulated. Our study identify a new target of ROCK signaling via myosin phosphatase subunit (MYPT1) and Histone Deacetylase (HDAC7) at the nuclear level and provide new insights in the cellular functions of ROCK.

  9. The nuclear orphan receptor NR4A1 and NR4A3 as tumor suppressors in hematologic neoplasms.

    PubMed

    Wenzl, Kerstin; Troppan, Katharina; Neumeister, Peter; Deutsch, Alexander J A

    2015-01-01

    NR4A1 (Nur77) belongs together with NR4A2 (Nurr1) and NR4A3 (NOR-1) to the nuclear orphan receptors of the NR4A-family. Their activation is generally short lived, the cellular outcome is a stimulus- and cell context-dependent differential activation of NR4A target genes that regulate cell cycle, apoptosis, inflammation, atherogenesis, metabolism, DNA repair and tumorigenesis. NR4A1 and NR4A3 were identified to function as tumor suppressors in acute myeloid leukemia (AML). Deletion of both nuclear receptors led to rapid development of AML in mice. Loss of NR4A1 and NR4A3 was a common feature in human AML patients. Additionally, NR4A1 and NR4A3 hypoallelic mice - mice with a reduced NR4A1 and NR4A3 expression - develop a chronic myeloid malignancy that recapitulates the pathological features of myelodysplastic/ myeloproliferative neoplasms with progression to AML in rare cases. Recently, a reduced NR4A1 and NR4A3 expression was described in aggressive lymphomas and low NR4A1 expression was associated with poor overall survival. Overexpression of NR4A1 in aggressive lymphoma cells led to induction of apoptosis and abrogated tumor growth in a xenograft mouse model. Recently, it was shown that NR4A inducing agents or NR4A agonist possess/induce apoptotic effects in AML and lymphoma cells. Due to this fact and the growing number of NR4A1 and NR4A3 inducing agents and NR4A agonists, both receptors represent new targets for anti tumor therapy.

  10. A phenotypic small molecule screen identifies an orphan ligand-receptor pair that regulates neural stem cell differentiation

    PubMed Central

    Saxe, Jonathan P.; Wu, Hao; Kelly, Theresa K.; Phelps, Michael E.; Sun, Yi E.; Kornblum, Harley I.; Huang, Jing

    2009-01-01

    Summary High-throughput identification of small molecules that selectively modulate molecular, cellular or systems-level properties of the mammalian brain is a significant challenge. Here we report the chemical genetic identification of the orphan ligand phosphoserine (P-Ser) as an enhancer of neurogenesis. P-Ser inhibits neural stem cell/progenitor proliferation and self-renewal, enhances neurogenic fate commitment, and improves neuronal survival. We further demonstrate that the effects of P-Ser are mediated by the group III metabotropic glutamate receptor 4 (mGluR4). siRNA-mediated knockdown of mGluR4 abolished the effects of P-Ser and increased neurosphere proliferation, at least in part through upregulation of mTOR pathway activity. We also found that P-Ser increases neurogenesis in human embryonic stem (ES) cell-derived neural progenitors. This work highlights the tremendous potential of developing effective small molecule drugs for use in regenerative medicine or transplantation therapy. PMID:17884634

  11. An isoform of retinoid-related orphan receptor β directs differentiation of retinal amacrine and horizontal interneurons

    PubMed Central

    Liu, Hong; Kim, Soo-Young; Fu, Yulong; Wu, Xuefeng; Ng, Lily; Swaroop, Anand; Forrest, Douglas

    2013-01-01

    Amacrine and horizontal interneurons integrate visual information as it is relayed through the retina from the photoreceptors to the ganglion cells. The early steps that generate these interneuron networks remain unclear. Here we show that a distinct RORβ1 isoform encoded by the retinoid-related orphan nuclear receptor β gene (Rorb) is critical for both amacrine and horizontal cell differentiation in mice. A fluorescent protein cassette targeted into Rorb revealed RORβ1 as a novel marker of immature amacrine and horizontal cells and of undifferentiated, dividing progenitor cells. RORβ1-deficient mice lose expression of pancreas-specific transcription factor 1a (Ptf1a) but retain forkhead box n4 factor (Foxn4), two early-acting factors necessary for amacrine and horizontal cell generation. RORβ1 and Foxn4 synergistically induce Ptf1a expression, suggesting a central role for RORβ1 in a transcriptional hierarchy that directs this interneuron differentiation pathway. Moreover, ectopic RORβ1 expression in neonatal retina promotes amacrine cell differentiation. PMID:23652001

  12. The orphan nuclear receptor NR4A2 is part of a p53–microRNA-34 network

    PubMed Central

    Beard, Jordan A.; Tenga, Alexa; Hills, Justin; Hoyer, Jessica D.; Cherian, Milu T.; Wang, Yong-Dong; Chen, Taosheng

    2016-01-01

    Nuclear receptor subfamily 4 group A member 2 (NR4A2) is an orphan nuclear receptor that is over-expressed in cancer and promotes cell proliferation, migration, transformation, and chemoresistance. Increased expression and function of NR4A2 have been attributed to various signaling pathways, but little is known about microRNA (miRNA) regulation of NR4A2 in cancer. To investigate the posttranscriptional regulation of NR4A2, we used a 3′ untranslated region (UTR) reporter screen and identified miR-34 as a putative regulator of NR4A2. By using computer predictions, we identified and confirmed an miRNA recognition element in the 3′ UTR of NR4A2 that was responsible for miR-34–mediated suppression. We next demonstrated that overexpression of exogenous miR-34 or activation of the p53 pathway, which regulates endogenous miR-34 expression, decreased NR4A2 expression. Consistent with previous reports, overexpression of NR4A2 blocked the induction of p53 target genes, including mir-34a. This was a phenotypic effect, as NR4A2 overexpression could rescue cells from p53-induced inhibition of proliferation. In summary, our results are the first characterization of a cancer-related miRNA capable of regulating NR4A2 and suggest a network and possible feedback mechanism involving p53, miR-34, and NR4A2. PMID:27121375

  13. Retinoic Acid-Related Orphan Receptor γ (RORγ): A Novel Participant in the Diurnal Regulation of Hepatic Gluconeogenesis and Insulin Sensitivity

    PubMed Central

    Takeda, Yukimasa; Kang, Hong Soon; Freudenberg, Johannes; DeGraff, Laura M.; Jothi, Raja; Jetten, Anton M.

    2014-01-01

    The hepatic circadian clock plays a key role in the daily regulation of glucose metabolism, but the precise molecular mechanisms that coordinate these two biological processes are not fully understood. In this study, we identify a novel connection between the regulation of RORγ by the clock machinery and the diurnal regulation of glucose metabolic networks. We demonstrate that particularly at daytime, mice deficient in RORγ exhibit improved insulin sensitivity and glucose tolerance due to reduced hepatic gluconeogenesis. This is associated with a reduced peak expression of several glucose metabolic genes critical in the control of gluconeogenesis and glycolysis. Genome-wide cistromic profiling, promoter and mutation analysis support the concept that RORγ regulates the transcription of several glucose metabolic genes directly by binding ROREs in their promoter regulatory region. Similar observations were made in liver-specific RORγ-deficient mice suggesting that the changes in glucose homeostasis were directly related to the loss of hepatic RORγ expression. Altogether, our study shows that RORγ regulates several glucose metabolic genes downstream of the hepatic clock and identifies a novel metabolic function for RORγ in the diurnal regulation of hepatic gluconeogenesis and insulin sensitivity. The inhibition of the activation of several metabolic gene promoters by an RORγ antagonist suggests that antagonists may provide a novel strategy in the management of metabolic diseases, including type 2 diabetes. PMID:24831725

  14. Cloning and characterization of new orphan nuclear receptors and their developmental profiles during Tenebrio metamorphosis.

    PubMed

    Mouillet, J F; Bousquet, F; Sedano, N; Alabouvette, J; Nicolaï, M; Zelus, D; Laudet, V; Delachambre, J

    1999-11-01

    Five PCR fragments corresponding to a part of the DNA-binding domain of different hormone nuclear receptors were isolated from Tenebrio molitor mRNAs. The sequence identity of three of them with known Drosophila nuclear receptors strongly suggests that they are the Tenebrio orthologs of seven-up, DHR3 and beta-FTZ-F1, and thus named Tmsvp, TmHR3 and TmFTZ-F1. The full-length sequences of the other two were established. TmHR78 is either a new receptor of the DHR78 family or the same gene which has evolved rapidly, particularly in the E domain. TmGRF belongs to the GCNF1 family and its in vitro translated product binds to the extended half site TCAAGGTCA with high affinity. The periods of expression of the corresponding transcripts in epidermal cells during Tenebrio metamorphosis were analyzed as a function of 20-hydroxyecdysone titers measured in the hemolymph of the animals taken for RNA extraction. Comparison of the expression profiles of these nuclear receptors with those observed during Drosophila metamorphosis revealed similar temporal correlations as a function of ecdysteroid variations, which further supported the sequence identity data for TmSVP, TmHR3, TmFTZ-F1 and TmHR78.

  15. PNRC: a proline-rich nuclear receptor coregulatory protein that modulates transcriptional activation of multiple nuclear receptors including orphan receptors SF1 (steroidogenic factor 1) and ERRalpha1 (estrogen related receptor alpha-1).

    PubMed

    Zhou, D; Quach, K M; Yang, C; Lee, S Y; Pohajdak, B; Chen, S

    2000-07-01

    PNRC (proline-rich nuclear receptor coregulatory protein) was identified using bovine SF1 (steroidogenic factor 1) as the bait in a yeast two-hybrid screening of a human mammary gland cDNA expression library. PNRC is unique in that it has a molecular mass of 35 kDa, significantly smaller than most of the coregulatory proteins reported so far, and it is proline-rich. PNRC's nuclear localization was demonstrated by immunofluorescence and Western blot analyses. In the yeast two-hybrid assays, PNRC interacted with the orphan receptors SF1 and ERRalpha1 in a ligand-independent manner. PNRC was also found to interact with the ligand-binding domains of all the nuclear receptors tested including estrogen receptor (ER), androgen receptor (AR), glucocorticoid receptor (GR), progesterone receptor (PR), thyroid hormone receptor (TR), retinoic acid receptor (RAR), and retinoid X receptor (RXR) in a ligand-dependent manner. Functional AF2 domain is required for nuclear receptors to bind to PNRC. Furthermore, in vitro glutathione-S-transferase pull-down assay was performed to demonstrate a direct contact between PNRC and nuclear receptors such as SF1. Coimmunoprecipitation experiment using Hela cells that express PNRC and ER was performed to confirm the interaction of PNRC and nuclear receptors in vivo in a ligand-dependent manner. PNRC was found to function as a coactivator to enhance the transcriptional activation mediated by SF1, ERR1 (estrogen related receptor alpha-1), PR, and TR. By examining a series of deletion mutants of PNRC using the yeast two-hybrid assay, a 23-amino acid (aa) sequence in the carboxy-terminal region, aa 278-300, was shown to be critical and sufficient for the interaction with nuclear receptors. This region is proline rich and contains a SH3-binding motif, S-D-P-P-S-P-S. Results from the mutagenesis study demonstrated that the two conserved proline (P) residues in this motif are crucial for PNRC to interact with the nuclear receptors. The exact 23

  16. NR4A orphan nuclear receptors in glucose homeostasis: a minireview.

    PubMed

    Close, A F; Rouillard, C; Buteau, J

    2013-12-01

    Type 2 diabetes mellitus is a disorder characterized by insulin resistance and a relative deficit in insulin secretion, both of which result in elevated blood glucose. Understanding the molecular mechanisms underlying the pathophysiology of diabetes could lead to the development of new therapeutic approaches. An ever-growing body of evidence suggests that members of the NR4A family of nuclear receptors could play a pivotal role in glucose homeostasis. This review aims to present and discuss advances so far in the evaluation of the potential role of NR4A in the regulation of glucose homeostasis and the development of type 2 diabetes. PMID:24075454

  17. Phosphoenolpyruvate Carboxykinase, a Key Enzyme That Controls Blood Glucose, Is a Target of Retinoic Acid Receptor-Related Orphan Receptor α

    PubMed Central

    Matsuoka, Hiroshi; Shima, Akiho; Kuramoto, Daisuke; Kikumoto, Daisuke; Matsui, Takashi; Michihara, Akihiro

    2015-01-01

    Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes a committed and rate-limiting step in hepatic gluconeogenesis, and its activity is tightly regulated to maintain blood glucose levels within normal limits. PEPCK activity is primarily regulated through hormonal control of gene transcription. Transcription is additionally regulated via a cAMP response unit, which includes a cAMP response element and four binding sites for CCAAT/enhancer-binding protein (C/EBP). Notably, the cAMP response unit also contains a putative response element for retinoic acid receptor-related orphan receptor α (RORα). In this paper, we characterize the effect of the RORα response element on cAMP-induced transcription. Electrophoresis mobility shift assay indicates that RORα binds this response element in a sequence-specific manner. Furthermore, luciferase reporter assays indicate that RORα interacts with C/EBP at the PEPCK promoter to synergistically enhance transcription. We also found that cAMP-induced transcription depends in part on RORα and its response element. In addition, we show that suppression of RORα by siRNA significantly decreased PEPCK transcription. Finally, we found that a RORα antagonist inhibits hepatic gluconeogenesis in an in vitro glucose production assay. Taken together, the data strongly suggest that PEPCK is a direct RORα target. These results define possible new roles for RORα in hepatic gluconeogenesis. PMID:26383638

  18. Genetic Variants of Retinoic Acid Receptor-Related Orphan Receptor Alpha Determine Susceptibility to Type 2 Diabetes Mellitus in Han Chinese

    PubMed Central

    Zhang, Yuwei; Liu, Yulan; Liu, Yin; Zhang, Yanjie; Su, Zhiguang

    2016-01-01

    Retinoic acid receptor-related orphan receptor alpha (RORA) plays a key role in the regulation of lipid and glucose metabolism and insulin expression that are implicated in the development of type 2 diabetes mellitus (T2DM). However, the effects of genetic variants in the RORA gene on the susceptibility to T2DM remain unknown. Nine tagging single-nucleotide polymorphisms (SNPs) were screened by using the SNaPshot method in 427 patients with T2DM and 408 normal controls. Association between genotypes and haplotypes derived from these SNPs with T2DM was analyzed using different genetic models. Allele and genotype frequencies at rs10851685 were significantly different between T2DM patients and control subjects (allele: p = 0.009, Odds ratios (OR) = 1.36 [95% Confidence intervals (CI) = 1.08–1.72]; genotype: p = 0.029). The minor allele T, at rs10851685, was potentially associated with an increased risk of T2DM in the dominant model, displaying OR of 1.38 (95% CI: 1.04–1.82, p = 0.025) in subjects with genotypes TA+TT vs. AA. In haplotype analysis, we observed that haplotypes GGTGTAACT, GGTGTAACC, and GATATAACT were significantly associated with increased risk of T2DM, while haplotypes GATGAAGTT, AGTGAAGTT, and AATGAAATT were protective against T2DM. These data suggest that the genetic variation in RORA might determine a Chinese Han individual’s susceptibility to T2DM. PMID:27556492

  19. Genetic Variants of Retinoic Acid Receptor-Related Orphan Receptor Alpha Determine Susceptibility to Type 2 Diabetes Mellitus in Han Chinese.

    PubMed

    Zhang, Yuwei; Liu, Yulan; Liu, Yin; Zhang, Yanjie; Su, Zhiguang

    2016-01-01

    Retinoic acid receptor-related orphan receptor alpha (RORA) plays a key role in the regulation of lipid and glucose metabolism and insulin expression that are implicated in the development of type 2 diabetes mellitus (T2DM). However, the effects of genetic variants in the RORA gene on the susceptibility to T2DM remain unknown. Nine tagging single-nucleotide polymorphisms (SNPs) were screened by using the SNaPshot method in 427 patients with T2DM and 408 normal controls. Association between genotypes and haplotypes derived from these SNPs with T2DM was analyzed using different genetic models. Allele and genotype frequencies at rs10851685 were significantly different between T2DM patients and control subjects (allele: p = 0.009, Odds ratios (OR) = 1.36 [95% Confidence intervals (CI) = 1.08-1.72]; genotype: p = 0.029). The minor allele T, at rs10851685, was potentially associated with an increased risk of T2DM in the dominant model, displaying OR of 1.38 (95% CI: 1.04-1.82, p = 0.025) in subjects with genotypes TA+TT vs. AA. In haplotype analysis, we observed that haplotypes GGTGTAACT, GGTGTAACC, and GATATAACT were significantly associated with increased risk of T2DM, while haplotypes GATGAAGTT, AGTGAAGTT, and AATGAAATT were protective against T2DM. These data suggest that the genetic variation in RORA might determine a Chinese Han individual's susceptibility to T2DM. PMID:27556492

  20. Estrogen activation of the nuclear orphan receptor CAR (constitutive active receptor) in induction of the mouse Cyp2b10 gene.

    PubMed

    Kawamoto, T; Kakizaki, S; Yoshinari, K; Negishi, M

    2000-11-01

    The nuclear orphan receptor CAR (constitutively active receptor or constitutive androstane receptor) can be activated in response to xenochemical exposure, such as activation by phenobarbital of a response element called NR1 found in the CYP2B gene. Here various steroids were screened for potential endogenous chemicals that may activate CAR, using the NR1 enhancer and Cyp2b10 induction in transfected HepG2 cell and/or in mouse primary hepatocytes as the experimental criteria. 17beta-Estradiol and estrone activated NR1, whereas estriol, estetrol, estradiol sulfate, and the synthetic estrogen diethylstilbestrol did not. On the other hand, progesterone and androgens repressed NR1 activity in HepG2 cells, and the repressed NR1 activity was fully restored by estradiol. Moreover, estrogen treatment elicited nuclear accumulation of CAR in the mouse livers, as well as primary hepatocytes, and induced the endogenous Cyp2b10 gene. Ovariectomy did not affect either the basal or induced level of CAR in the nucleus of the female livers, while castration slightly increased the basal and greatly increased the induced levels in the liver nucleus of male mice. Thus, endogenous estrogen appears not to regulate CAR in female mice, whereas endogenous androgen may be the repressive factor in male mice. Estrogen at pharmacological levels is an effective activator of CAR in both female and male mice, suggesting a biological and/or toxicological role of this receptor in estrogen metabolism. In addition to mouse CAR, estrogens activated rat CAR, whereas human CAR did not respond well to the estrogens under the experimental conditions. PMID:11075820

  1. Transactivation of the proximal promoter of human oxytocin gene by TR4 orphan receptor

    SciTech Connect

    Wang, C.-P.; Lee, Y.-F.; Chang, C.; Lee, H.-J. . E-mail: hjlee@mail.ndhu.edu.tw

    2006-12-08

    The human testicular receptor 4 (TR4) shares structural homology with members of the nuclear receptor superfamily. Some other members of this superfamily were able to regulate the transcriptional activity of the human oxytocin (OXT) promoter by binding to the first DR0 regulatory site. However, little investigation was conducted systematically in the study of the second dDR4 site of OXT proximal promoter, and the relationship between the first and the second sites of OXT promoter. Here, we demonstrated for the first time that TR4 could increase the proximal promoter activity of the human OXT gene via DR0, dDR4, and OXT (both DR0 and dDR4) elements, respectively. TR4 might induce OXT gene expression through the OXT element in a dose-dependent manner. However, there is no synergistic effect between DR0 and dDR4 elements during TR4 transactivation. Taken together, these results suggested that TR4 should be one of important regulators of OXT gene expression.

  2. The orphan nuclear receptor DAX-1 acts as a novel transcriptional corepressor of PPAR{gamma}

    SciTech Connect

    Kim, Gwang Sik; Lee, Gha Young; Nedumaran, Balachandar; Park, Yun-Yong; Kim, Kyung Tae; Park, Sang Chul; Lee, Young Chul; Kim, Jae Bum Choi, Hueng-Sik

    2008-05-30

    DAX-1 is an atypical nuclear receptor (NR) which functions primarily as a transcriptional corepressor of other NRs via heterodimerization. Peroxisome proliferator-activated receptor (PPAR) {gamma} is a ligand-dependent NR which performs a key function in adipogenesis. In this study, we evaluated a novel cross-talk mechanism between DAX-1 and PPAR{gamma}. Transient transfection assays demonstrated that DAX-1 inhibits the transactivity of PPAR{gamma} in a dose-dependent manner. DAX-1 directly competed with the PPAR{gamma} coactivator (PGC)-1{alpha} for binding to PPAR{gamma}. Endogenous levels of DAX-1 were significantly lower in differentiated 3T3-L1 adipocytes as compared to preadipocytes. Using a retroviral expression system, we demonstrated that DAX-1 overexpression downregulates the expression of PPAR{gamma} target genes, resulting in an attenuation of adipogenesis in 3T3-L1 cells. Our results suggest that DAX-1 acts as a corepressor of PPAR{gamma} and performs a potential function in the regulation of PPAR{gamma}-mediated cellular differentiation.

  3. Novel role for the orphan nuclear receptor Dax1 in embryogenesis, different from steroidogenesis.

    PubMed

    Niakan, Kathy K; Davis, Emily C; Clipsham, Robert C; Jiang, Meisheng; Dehart, Deborah B; Sulik, Kathleen K; McCabe, Edward R B

    2006-07-01

    Cytomegalic adrenal hypoplasia congenita (AHC) is an X-linked disease caused by mutations in DAX1-encoding gene NR0B1, previously thought to function primarily in steroidogenesis. We sought to determine the expression pattern for Dax1 along with known network partners in early embryogenesis and to determine a steroidogenic capacity for the embryo prior to the establishment of the urogenital ridge at embryonic day 9 (E9). Here, we report that murine Dax1 is a unique marker in early embryonic development, distinguishing the extraembryonic (proximal) endoderm from the remainder of the developing embryo. We showed that Wilms tumor 1, steroidogenic factor 1, and estrogen receptor beta were expressed throughout the embryo, but the progesterone, estrogen alpha and androgen receptors, cytochrome P450 (Cyp11a1) and Nur77 were not observed in any of the embryonic layers. Lack of Cyp11A1 expression at this stage confirmed an absence of inherent steroidogenic capacity for the early embryo. The role of Nr0b1 in embryonic stem (ES) cells was investigated using siRNA knockdown, resulting in differentiation toward endoderm-like fate. Nr0b1 conditional knockout in ES cells led to differentiation, confirming our knockdown results. Our investigations suggest that Nr0b1 functions in a novel role in the maintenance of a relatively undifferentiated state. Our results further suggest that the failure of conventional murine Nr0b1 knockout attempts may be due to disregulated differentiation. PMID:16466956

  4. The orphan nuclear receptor DAX-1 acts as a novel transcriptional corepressor of PPARgamma.

    PubMed

    Kim, Gwang Sik; Lee, Gha Young; Nedumaran, Balachandar; Park, Yun-Yong; Kim, Kyung Tae; Park, Sang Chul; Lee, Young Chul; Kim, Jae Bum; Choi, Hueng-Sik

    2008-05-30

    DAX-1 is an atypical nuclear receptor (NR) which functions primarily as a transcriptional corepressor of other NRs via heterodimerization. Peroxisome proliferator-activated receptor (PPAR) gamma is a ligand-dependent NR which performs a key function in adipogenesis. In this study, we evaluated a novel cross-talk mechanism between DAX-1 and PPARgamma. Transient transfection assays demonstrated that DAX-1 inhibits the transactivity of PPARgamma in a dose-dependent manner. DAX-1 directly competed with the PPARgamma coactivator (PGC)-1alpha for binding to PPARgamma. Endogenous levels of DAX-1 were significantly lower in differentiated 3T3-L1 adipocytes as compared to preadipocytes. Using a retroviral expression system, we demonstrated that DAX-1 overexpression downregulates the expression of PPARgamma target genes, resulting in an attenuation of adipogenesis in 3T3-L1 cells. Our results suggest that DAX-1 acts as a corepressor of PPARgamma and performs a potential function in the regulation of PPARgamma-mediated cellular differentiation. PMID:18381063

  5. The Orphan Nuclear Receptor ERRγ Regulates Hepatic CB1 Receptor-Mediated Fibroblast Growth Factor 21 Gene Expression

    PubMed Central

    Jung, Yoon Seok; Lee, Ji-Min; Kim, Don-Kyu; Lee, Yong-Soo; Kim, Ki-Sun; Kim, Yong-Hoon; Kim, Jina; Lee, Myung-Shik; Lee, In-Kyu; Kim, Seong Heon; Cho, Sung Jin; Jeong, Won-Il; Lee, Chul-Ho; Harris, Robert A.; Choi, Hueng-Sik

    2016-01-01

    Background Fibroblast growth factor 21 (FGF21), a stress inducible hepatokine, is synthesized in the liver and plays important roles in glucose and lipid metabolism. However, the mechanism of hepatic cannabinoid type 1 (CB1) receptor-mediated induction of FGF21 gene expression is largely unknown. Results Activation of the hepatic CB1 receptor by arachidonyl-2’-chloroethylamide (ACEA), a CB1 receptor selective agonist, significantly increased FGF21 gene expression. Overexpression of estrogen-related receptor (ERR) γ increased FGF21 gene expression and secretion both in hepatocytes and mice, whereas knockdown of ERRγ decreased ACEA-mediated FGF21 gene expression and secretion. Moreover, ERRγ, but not ERRα and ERRβ, induced FGF21 gene promoter activity. In addition, deletion and mutation analysis of the FGF21 promoter identified a putative ERRγ-binding motif (AGGTGC, a near-consensus response element). A chromatin immunoprecipitation assay revealed direct binding of ERRγ to the FGF21 gene promoter. Finally, GSK5182, an ERRγ inverse agonist, significantly inhibited hepatic CB1 receptor-mediated FGF21 gene expression and secretion. Conclusion Based on our data, we conclude that ERRγ plays a key role in hepatic CB1 receptor-mediated induction of FGF21 gene expression and secretion. PMID:27455076

  6. Transforming Growth Factor-β1 Signaling Represses Testicular Steroidogenesis through Cross-Talk with Orphan Nuclear Receptor Nur77

    PubMed Central

    Park, Eunsook; Song, Chin-Hee; Park, Jae-Il; Ahn, Ryun-Sup; Choi, Hueng-Sik; Ko, CheMyong; Lee, Keesook

    2014-01-01

    Transforming growth factor- β1 (TGF-β1) has been reported to inhibit luteinizing hormone (LH) mediated-steroidogenesis in testicular Leydig cells. However, the mechanism by which TGF-β1 controls the steroidogenesis in Leydig cells is not well understood. Here, we investigated the possibility that TGF-β1 represses steroidogenesis through cross-talk with the orphan nuclear receptor Nur77. Nur77, which is induced by LH/cAMP signaling, is one of major transcription factors that regulate the expression of steroidogenic genes in Leydig cells. TGF-β1 signaling inhibited cAMP-induced testosterone production and the expression of steroidogenic genes such as P450c17, StAR and 3β-HSD in mouse Leydig cells. Further, TGF-β1/ALK5 signaling repressed cAMP-induced and Nur77-activated promoter activity of steroidogenic genes. In addition, TGF-β1/ALK5-activated Smad3 repressed Nur77 transactivation of steroidogenic gene promoters by interfering with Nur77 binding to DNA. In primary Leydig cells isolated from Tgfbr2flox/flox Cyp17iCre mice, TGF-β1-mediated repression of cAMP-induced steroidogenic gene expression was significantly less than that in primary Leydig cells from Tgfbr2flox/flox mice. Taken together, these results suggest that TGF-β1/ALK5/Smad3 signaling represses the expression of steroidogenic genes via the suppression of Nur77 transactivation in testicular Leydig cells. These findings may provide a molecular mechanism involved in the TGF-β1-mediated repression of testicular steroidogenesis. PMID:25140527

  7. A Strategy Combining Differential Low-Throughput Screening and Virtual Screening (DLS-VS) Accelerating the Discovery of new Modulators for the Orphan GPR34 Receptor.

    PubMed

    Diaz, Constantino; Labit-Le Bouteiller, Christine; Yvon, Stéphane; Cambon-Kernëis, Aimée; Roasio, Annette; Jamme, Marie-Françoise; Aries, Amélie; Feuillerat, Claude; Perret, Eric; Guette, Fréderique; Dieu, Pierre; Miloux, Brigitte; Albène, Danielle; Hasel, Nathalie; Kaghad, Mourad; Ferran, Edgardo; Lupker, Jan; Ferrara, Pascual

    2013-02-01

    The DLS-VS strategy was developed as an integrated method for identifying chemical modulators for orphan GPCRs. It combines differential low-throughput screening (DLS) and virtual screening (VS). The two cascaded techniques offer complementary advantages and allow the experimental testing of a minimal number of compounds. First, DLS identifies modulators specific for the considered receptor among a set of receptors, through the screening of a small library with diverse chemical compounds. Then, an active molecular model of the receptor is built by homology to a validated template, and it is progressively refined by rotamers modification for key side-chains, by VS of the already screened library, and by iterative selection of the model generating the best enrichment. The refined active model is finally used for the VS of a large chemical library and the selection of a small set of compounds for experimental testing. Applied to the orphan receptor GPR34, the DLS-VS strategy combined the experimental screening of 20 000 compounds and the virtual screening of 1 250 000 compounds. It identified one agonist and eight inverse agonists, showing a high chemical diversity. We describe the method. The strategy can be applied to other GPCRs. PMID:27481282

  8. An Orphan Seven-Transmembrane Domain Receptor Expressed Widely in the Brain Functions as a Coreceptor for Human Immunodeficiency Virus Type 1 and Simian Immunodeficiency Virus

    PubMed Central

    Edinger, Aimee L.; Hoffman, Trevor L.; Sharron, Matthew; Lee, Benhur; Yi, Yanji; Choe, Wonkyu; Kolson, Dennis L.; Mitrovic, Branka; Zhou, Yiqing; Faulds, Daryl; Collman, Ronald G.; Hesselgesser, Joseph; Horuk, Richard; Doms, Robert W.

    1998-01-01

    Both CD4 and an appropriate coreceptor are necessary for infection of cells by human immunodeficiency virus type 1 (HIV-1) and most strains of HIV-2. The chemokine receptors CCR5 and CXCR4 are the major HIV-1 coreceptors, although some virus strains can also utilize alternative coreceptors such as CCR3 to infect cells. In contrast, most if not all simian immunodeficiency virus (SIV) strains use CCR5 as a coreceptor, and many SIV strains can use CCR5 independently of CD4. In addition, several orphan seven-transmembrane receptors which can serve as HIV-1 and SIV coreceptors have been identified. Here we report that APJ, an orphan seven-transmembrane domain receptor with homology to the angiotensin receptor family, functions as a coreceptor for a number of HIV-1 and SIV strains. APJ was expressed widely in the human brain and in NT2N neurons. APJ transcripts were also detected by reverse transcription-PCR in the CD4-positive T-cell line C8166, but not in peripheral blood leukocytes, microglia, phytohemagglutinin (PHA)- or PHA/interleukin-2-stimulated peripheral blood mononuclear cells, monocytes, or monocyte-derived macrophages. The widespread distribution of APJ in the central nervous system coupled with its use as a coreceptor by some HIV-1 strains indicates that it may play a role in neuropathogenesis. PMID:9733831

  9. In Silico Adoption of an Orphan Nuclear Receptor NR4A1

    PubMed Central

    Lanig, Harald; Reisen, Felix; Whitley, David; Schneider, Gisbert; Banting, Lee; Clark, Timothy

    2015-01-01

    A 4.1μs molecular dynamics simulation of the NR4A1 (hNur77) apo-protein has been undertaken and a previously undetected druggable pocket has become apparent that is located remotely from the ‘traditional’ nuclear receptor ligand-binding site. A NR4A1/bis-indole ligand complex at this novel site has been found to be stable over 1 μs of simulation and to result in an interesting conformational transmission to a remote loop that has the capacity to communicate with a NBRE within a RXR-α/NR4A1 heterodimer. Several features of the simulations undertaken indicate how NR4A1 can be affected by alternate-site modulators. PMID:26270486

  10. Expression and Functional Role of Orphan Receptor GPR158 in Prostate Cancer Growth and Progression

    PubMed Central

    Patel, Nitin; Itakura, Tatsuo; Jeong, Shinwu; Liao, Chun-Peng; Roy-Burman, Pradip; Zandi, Ebrahim; Groshen, Susan; Pinski, Jacek; Coetzee, Gerhard A.; Gross, Mitchell E.; Fini, M. Elizabeth

    2015-01-01

    Prostate cancer (PCa) is the second-leading cause of cancer-related mortality, after lung cancer, in men from developed countries. In its early stages, primary tumor growth is dependent on androgens, thus generally can be controlled by androgen deprivation therapy (ADT). Eventually however, the disease progresses to castration-resistant prostate cancer (CRPC), a lethal form in need of more effective treatments. G-protein coupled receptors (GPCRs) comprise a large clan of cell surface proteins that have been implicated as therapeutic targets in PCa growth and progression. The findings reported here provide intriguing evidence of a role for the newly characterized glutamate family member GPR158 in PCa growth and progression. We found that GPR158 promotes PCa cell proliferation independent of androgen receptor (AR) functionality and that this requires its localization in the nucleus of the cell. This suggests that GPR158 acts by mechanisms different from other GPCRs. GPR158 expression is stimulated by androgens and GPR158 stimulates AR expression, implying a potential to sensitize tumors to low androgen conditions during ADT via a positive feedback loop. Further, we found GPR158 expression correlates with a neuroendocrine (NE) differentiation phenotype and promotes anchorage-independent colony formation implying a role for GPR158 in therapeutic progression and tumor formation. GPR158 expression was increased at the invading front of prostate tumors that formed in the genetically defined conditional Pten knockout mouse model, and co-localized with elevated AR expression in the cell nucleus. Kaplan-Meier analysis on a dataset from the Memorial Sloan Kettering cancer genome portal showed that increased GPR158 expression in tumors is associated with lower disease-free survival. Our findings strongly suggest that pharmaceuticals targeting GPR158 activities could represent a novel and innovative approach to the prevention and management of CRPC. PMID:25693195

  11. Expression and functional role of orphan receptor GPR158 in prostate cancer growth and progression.

    PubMed

    Patel, Nitin; Itakura, Tatsuo; Jeong, Shinwu; Liao, Chun-Peng; Roy-Burman, Pradip; Zandi, Ebrahim; Groshen, Susan; Pinski, Jacek; Coetzee, Gerhard A; Gross, Mitchell E; Fini, M Elizabeth

    2015-01-01

    Prostate cancer (PCa) is the second-leading cause of cancer-related mortality, after lung cancer, in men from developed countries. In its early stages, primary tumor growth is dependent on androgens, thus generally can be controlled by androgen deprivation therapy (ADT). Eventually however, the disease progresses to castration-resistant prostate cancer (CRPC), a lethal form in need of more effective treatments. G-protein coupled receptors (GPCRs) comprise a large clan of cell surface proteins that have been implicated as therapeutic targets in PCa growth and progression. The findings reported here provide intriguing evidence of a role for the newly characterized glutamate family member GPR158 in PCa growth and progression. We found that GPR158 promotes PCa cell proliferation independent of androgen receptor (AR) functionality and that this requires its localization in the nucleus of the cell. This suggests that GPR158 acts by mechanisms different from other GPCRs. GPR158 expression is stimulated by androgens and GPR158 stimulates AR expression, implying a potential to sensitize tumors to low androgen conditions during ADT via a positive feedback loop. Further, we found GPR158 expression correlates with a neuroendocrine (NE) differentiation phenotype and promotes anchorage-independent colony formation implying a role for GPR158 in therapeutic progression and tumor formation. GPR158 expression was increased at the invading front of prostate tumors that formed in the genetically defined conditional Pten knockout mouse model, and co-localized with elevated AR expression in the cell nucleus. Kaplan-Meier analysis on a dataset from the Memorial Sloan Kettering cancer genome portal showed that increased GPR158 expression in tumors is associated with lower disease-free survival. Our findings strongly suggest that pharmaceuticals targeting GPR158 activities could represent a novel and innovative approach to the prevention and management of CRPC. PMID:25693195

  12. The orphan nuclear receptor Nur77 inhibits low shear stress-induced carotid artery remodeling in mice.

    PubMed

    Yu, Ying; Cai, Zhaohua; Cui, Mingli; Nie, Peng; Sun, Zhe; Sun, Shiqun; Chu, Shichun; Wang, Xiaolei; Hu, Liuhua; Yi, Jing; Shen, Linghong; He, Ben

    2015-12-01

    Shear stress, particularly low and oscillatory shear stress, plays a critical pathophysiological role in vascular remodeling-related cardiovascular diseases. Growing evidence suggests that the orphan nuclear receptor Nur77 [also known as TR3 or nuclear receptor subfamily 4, group A, member 1 (NR4A1)] is expressed in diseased human vascular tissue and plays an important role in vascular physiology and pathology. In the present study, we used a mouse model of flow-dependent remodeling by partial ligation of the left common carotid artery (LCCA) to define the exact role of Nur77 in vascular remodeling induced by low shear stress. Following vascular remodeling, Nur77 was highly expressed in neointimal vascular smooth muscle cells (VSMCs) in the ligated carotid arteries. The reactive oxygen species (ROS) levels were elevated in the remodeled arteries in vivo and in primary rat VSMCs in vitro following stimulation with platelet-derived growth factor (PDGF). Further in vitro experiments revealed that Nur77 expression was rapidly increased in the VSMCs following stimulation with PDGF and H2O2, whereas treatment with N-acetyl cysteine (NAC, a ROS scavenger) reversed the increase in the protein level of Nur77 induced by H2O2. Moreover, Nur77 overexpression markedly inhibited the proliferation and migration of VSMCs, induced by PDGF. Finally, to determine the in vivo role of Nur77 in low shear stress-induced vascular remodeling, wild-type (WT) and Nur77-deficient mice were subjected to partial ligation of the LCCA. Four weeks following surgery, in the LCCAs of the Nur77‑deficient mice, a significant increase in the intima-media area and carotid intima-media thickness was noted, as well as more severe elastin disruption and collagen deposition compared to the WT mice. Immunofluorescence staining revealed an increase in VSMC proliferation [determined by the expression of proliferating cell nuclear antigen (PCNA)] and matrix metalloproteinase 9 (MMP-9) production in the Nur77

  13. [Molecular cloning, tissue distribution and expression in engineered cells of human orphan receptor GPR81].

    PubMed

    Wu, Fang-Ming; Huang, Huo-Gao; Hu, Ming; Gao, Yue; Liu, Yong-Xue

    2006-05-01

    The gpr81 was amplified by polymerase chain reaction (PCR) using human fetus kidney cDNA and whole blood genome DNA as template, respectively. The expression profile of gpr81 in human fetus was analyzed by RT-PCR and the result indicated GPR81 mRNA was most abundant in fetus liver and heart. In addition, the deduced amino acid of GPR81 was compared with other related molecules by Clustal w/x software, and a molecular phylogenetic tree was constructed with Treeview software. It was showed that GPR81 had the highest homology with nicotinic acid receptor in amino acids. After sequence identification, gpr81 was inserted into the plasmid pcDNA3. 1 (-)/his-mycA and then transfected into Chinese hamster ovary cell (CHO-K1). With the selection of G418, an engineered cell line which could stably express gpr81 was obtained by the indication of RT-PCR and Western-blot detection. The establishment of the cell line will serve as means for further study of GPR81.

  14. Orphan nuclear receptor Nur77 translocates to mitochondria in the early phase of apoptosis induced by synthetic chenodeoxycholic acid derivatives in human stomach cancer cell line SNU-1.

    PubMed

    Jeong, Jin Hee; Park, Joo-Sung; Moon, Bongkyung; Kim, Min Chan; Kim, Jae-Kon; Lee, Sungeun; Suh, Hongsuk; Kim, Nam Deuk; Kim, Jong-Min; Park, Young Chul; Yoo, Young Hyun

    2003-12-01

    Apoptosis-inducing activity of synthetic CDCA derivatives, HS-1199 and HS-1200, on gastric cancer cell line SNU-1 cells was explored. CDCA derivatives demonstrated various apoptosis hallmarks, such as mitochondrial changes, activation of caspase, DNA fragmentation, and nuclear condensation. Importantly, the orphan receptor Nur77 (TR3) was shown to translocate from the nucleus to mitochondria at the early time points after CDCA derivatives treatment. These data support the theory that CDCA derivatives-induced apoptosis of SNU-1 gastric cancer cell lines is mediated by mitochondria and caspase, and, at least in part, by Nur77.

  15. Orphan nuclear receptor DAX-1 acts as a novel corepressor of liver X receptor alpha and inhibits hepatic lipogenesis.

    PubMed

    Nedumaran, Balachandar; Kim, Gwang Sik; Hong, Sungpyo; Yoon, Young-Sil; Kim, Yong-Hoon; Lee, Chul-Ho; Lee, Young Chul; Koo, Seung-Hoi; Choi, Hueng-Sik

    2010-03-19

    DAX-1 (dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on X chromosome, gene 1) is a member of the nuclear receptor superfamily that can repress diverse nuclear receptors and has a key role in adreno-gonadal development. Our previous report has demonstrated that DAX-1 can inhibit hepatocyte nuclear factor 4alpha transactivity and negatively regulate gluconeogenic gene expression (Nedumaran, B., Hong, S., Xie, Y. B., Kim, Y. H., Seo, W. Y., Lee, M. W., Lee, C. H., Koo, S. H., and Choi, H. S. (2009) J. Biol. Chem. 284, 27511-27523). Here, we further expand the role of DAX-1 in hepatic energy metabolism. Transfection assays have demonstrated that DAX-1 can inhibit the transcriptional activity of nuclear receptor liver X receptor alpha (LXRalpha). Physical interaction between DAX-1 and LXRalpha was confirmed Immunofluorescent staining in mouse liver shows that LXRalpha and DAX-1 are colocalized in the nucleus. Domain mapping analysis shows that the entire region of DAX-1 is involved in the interaction with the ligand binding domain region of LXRalpha. Competition analyses demonstrate that DAX-1 competes with the coactivator SRC-1 for repressing LXRalpha transactivity. Chromatin immunoprecipitation assay showed that endogenous DAX-1 recruitment on the SREBP-1c gene promoter was decreased in the presence of LXRalpha agonist. Overexpression of DAX-1 inhibits T7-induced LXRalpha target gene expression, whereas knockdown of endogenous DAX-1 significantly increases T7-induced LXRalpha target gene expression in HepG2 cells. Finally, overexpression of DAX-1 in mouse liver decreases T7-induced LXRalpha target gene expression, liver triglyceride level, and lipid accumulation. Overall, this study suggests that DAX-1, a novel corepressor of LXRalpha, functions as a negative regulator of lipogenic enzyme gene expression in liver. PMID:20080977

  16. The orphan nuclear receptor DAX-1 functions as a potent corepressor of the constitutive androstane receptor (NR1I3).

    PubMed

    Laurenzana, Elizabeth M; Chen, Tao; Kannuswamy, Malavika; Sell, Brian E; Strom, Stephen C; Li, Yong; Omiecinski, Curtis J

    2012-11-01

    Regulation of gene transcription is controlled in part by nuclear receptors that function coordinately with coregulator proteins. The human constitutive androstane receptor (CAR; NR1I3) is expressed primarily in liver and regulates the expression of genes involved in xenobiotic metabolism as well as hormone, energy, and lipid homeostasis. In this report, DAX-1, a nuclear receptor family member with corepressor properties, was identified as a potent CAR regulator. Results of transaction and mutational studies demonstrated that both DAX-1's downstream LXXLL and its PCFQVLP motifs were critical contributors to DAX-1's corepression activities, although two other LXXM/LL motifs located nearer the N terminus had no impact on the CAR functional interaction. Deletion of DAX-1's C-terminal transcription silencing domain restored CAR1 transactivation activity in reporter assays to approximately 90% of control, demonstrating its critical function in mediating the CAR repression activities. Furthermore, results obtained from mammalian two-hybrid experiments assessing various domain configurations of the respective receptors showed that full-length DAX-1 inhibited the CAR-SRC1 interaction by approximately 50%, whereas the same interaction was restored to 90% of control when the DAX-1 transcription silencing domain was deleted. Direct interaction between CAR and DAX-1 was demonstrated with both alpha-screen and coimmunoprecipitation experiments, and this interaction was enhanced in the presence of the CAR activator 6-(4-chlorophenyl)imidazo[2,1-b]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO). Results obtained in primary human hepatocytes further demonstrated DAX-1 inhibition of CAR-mediated CITCO induction of the CYP2B6 target gene. The results of this investigation identify DAX-1 as a novel and potent CAR corepressor and suggest that DAX-1 functions as a coordinate hepatic regulator of CAR's biological function. PMID:22896671

  17. The Zebrafish Period2 Protein Positively Regulates the Circadian Clock through Mediation of Retinoic Acid Receptor (RAR)-related Orphan Receptor α (Rorα)*

    PubMed Central

    Wang, Mingyong; Zhong, Zhaomin; Zhong, Yingbin; Zhang, Wei; Wang, Han

    2015-01-01

    We report the characterization of a null mutant for zebrafish circadian clock gene period2 (per2) generated by transcription activator-like effector nuclease and a positive role of PER2 in vertebrate circadian regulation. Locomotor experiments showed that per2 mutant zebrafish display reduced activities under light-dark and 2-h phase delay under constant darkness, and quantitative real time PCR analyses showed up-regulation of cry1aa, cry1ba, cry1bb, and aanat2 but down-regulation of per1b, per3, and bmal1b in per2 mutant zebrafish, suggesting that Per2 is essential for the zebrafish circadian clock. Luciferase reporter assays demonstrated that Per2 represses aanat2 expression through E-box and enhances bmal1b expression through the Ror/Rev-erb response element, implicating that Per2 plays dual roles in the zebrafish circadian clock. Cell transfection and co-immunoprecipitation assays revealed that Per2 enhances bmal1b expression through binding to orphan nuclear receptor Rorα. The enhancing effect of mouse PER2 on Bmal1 transcription is also mediated by RORα even though it binds to REV-ERBα. Moreover, zebrafish Per2 also appears to have tissue-specific regulatory roles in numerous peripheral organs. These findings help define the essential functions of Per2 in the zebrafish circadian clock and in particular provide strong evidence for a positive role of PER2 in the vertebrate circadian system. PMID:25544291

  18. Orphan nuclear receptor NR2F6 acts as an essential gatekeeper of Th17 CD4+ T cell effector functions

    PubMed Central

    2014-01-01

    Members of the evolutionarily conserved family of the chicken ovalbumin upstream promoter transcription factor NR2F/COUP-TF orphan receptors have been implicated in lymphocyte biology, ranging from activation to differentiation and elicitation of immune effector functions. In particular, a CD4+ T cell intrinsic and non-redundant function of NR2F6 as a potent and selective repressor of the transcription of the pro-inflammatory cytokines interleukin (Il) 2, interferon y (ifng) and consequently of T helper (Th)17 CD4+ T cell-mediated autoimmune disorders has been discovered. NR2F6 serves as an antigen receptor signaling threshold-regulated barrier against autoimmunity where NR2F6 is part of a negative feedback loop that limits inflammatory tissue damage induced by weakly immunogenic antigens such as self-antigens. Under such low affinity antigen receptor stimulation, NR2F6 appears as a prototypical repressor that functions to “lock out” harmful Th17 lineage effector transcription. Mechanistically, only sustained high affinity antigen receptor-induced protein kinase C (PKC)-mediated phosphorylation has been shown to inactivate NR2F6, thereby displacing pre-bound NR2F6 from the DNA and, subsequently, allowing for robust NFAT/AP-1- and RORγt-mediated cytokine transcription. The NR2F6 target gene repertoire thus identifies a general anti-inflammatory gatekeeper role for this orphan receptor. Investigating these signaling pathway(s) will enable a greater knowledge of the genetic, immune, and environmental mechanisms that lead to chronic inflammation and of certain autoimmune disorders in a given individual. PMID:24919548

  19. Rho-kinase signaling controls nucleocytoplasmic shuttling of class IIa Histone Deacetylase (HDAC7) and transcriptional activation of orphan nuclear receptor NR4A1

    SciTech Connect

    Compagnucci, Claudia; Barresi, Sabina; Petrini, Stefania; Bertini, Enrico; Zanni, Ginevra

    2015-04-03

    Rho-kinase (ROCK) has been well documented to play a key role in RhoA-induced actin remodeling. ROCK activation results in myosin light chain (MLC) phosphorylation either by direct action on MLC kinase (MLCK) or by inhibition of MLC phosphatase (MLCP), modulating actin–myosin contraction. We found that inhibition of the ROCK pathway in induced pluripotent stem cells, leads to nuclear export of HDAC7 and transcriptional activation of the orphan nuclear receptor NR4A1 while in cells with constitutive ROCK hyperactivity due to loss of function of the RhoGTPase activating protein Oligophrenin-1 (OPHN1), the orphan nuclear receptor NR4A1 is downregulated. Our study identify a new target of ROCK signaling via myosin phosphatase subunit (MYPT1) and Histone Deacetylase (HDAC7) at the nuclear level and provide new insights in the cellular functions of ROCK. - Highlights: • ROCK regulates nucleocytoplasmic shuttling of HDAC7 via phosphorylation of MYPT1. • Nuclear export of HDAC7 and upregulation of NR4A1 occurs with low ROCK activity. • High levels of ROCK activity due to OPHN1 loss of function downregulate NR4A1.

  20. GPR139, an Orphan Receptor Highly Enriched in the Habenula and Septum, Is Activated by the Essential Amino Acids L-Tryptophan and L-Phenylalanine.

    PubMed

    Liu, Changlu; Bonaventure, Pascal; Lee, Grace; Nepomuceno, Diane; Kuei, Chester; Wu, Jiejun; Li, Qingqin; Joseph, Victory; Sutton, Steven W; Eckert, William; Yao, Xiang; Yieh, Lynn; Dvorak, Curt; Carruthers, Nicholas; Coate, Heather; Yun, Sujin; Dugovic, Christine; Harrington, Anthony; Lovenberg, Timothy W

    2015-11-01

    GPR139 is an orphan G-protein-coupled receptor expressed in the central nervous system. To identify its physiologic ligand, we measured GPR139 receptor activity from recombinant cells after treatment with amino acids, orphan ligands, serum, and tissue extracts. GPR139 activity was measured using guanosine 5'-O-(3-[(35)S]thio)-triphosphate binding, calcium mobilization, and extracellular signal-regulated kinases phosphorylation assays. Amino acids L-tryptophan (L-Trp) and L-phenylalanine (L-Phe) activated GPR139, with EC50 values in the 30- to 300-μM range, consistent with the physiologic concentrations of L-Trp and L-Phe in tissues. Chromatography of rat brain, rat serum, and human serum extracts revealed two peaks of GPR139 activity, which corresponded to the elution peaks of L-Trp and L-Phe. With the purpose of identifying novel tools to study GPR139 function, a high-throughput screening campaign led to the identification of a selective small-molecule agonist [JNJ-63533054, (S)-3-chloro-N-(2-oxo-2-((1-phenylethyl)amino)ethyl) benzamide]. The tritium-labeled JNJ-63533054 bound to cell membranes expressing GPR139 and could be specifically displaced by L-Trp and L-Phe. Sequence alignment revealed that GPR139 is highly conserved across species, and RNA sequencing studies of rat and human tissues indicated its exclusive expression in the brain and pituitary gland. Immunohistochemical analysis showed specific expression of the receptor in circumventricular regions of the habenula and septum in mice. Together, these findings suggest that L-Trp and L-Phe are candidate physiologic ligands for GPR139, and we hypothesize that this receptor may act as a sensor to detect dynamic changes of L-Trp and L-Phe in the brain.

  1. A genome-wide association study of posttraumatic stress disorder identifies the retinoid-related orphan receptor alpha (RORA) gene as a significant risk locus

    PubMed Central

    Logue, Mark W.; Baldwin, Clinton; Guffanti, Guia; Melista, Efi; Wolf, Erika J.; Reardon, Annemarie F.; Uddin, Monica; Wildman, Derek; Galea, Sandro; Koenen, Karestan C.; Miller, Mark W.

    2012-01-01

    We describe the results of the first genome-wide association study of PTSD performed using trauma-exposed white non-Hispanic participants from a cohort of veterans and their intimate partners (295 cases and 196 controls). Several SNPs yielded evidence of association. One SNP (rs8042149), located in the retinoid-related orphan receptor alpha gene (RORA), reached genome-wide significance. Nominally significant associations were observed for other RORA SNPs in two African American replication samples—one from the veteran cohort (43 cases and 41 controls) and another independent cohort (100 cases and 421 controls). However, only the associated SNP from the veteran African American replication sample survived gene-level multiple testing correction. RORA has been implicated in prior GWAS studies of psychiatric disorders and is known to play an important role in neuroprotection and other behaviorally-relevant processes. This study represents an important step towards identifying the genetic underpinnings of PTSD. PMID:22869035

  2. Association between liver X receptor-α and neuron-derived orphan nuclear receptor-1 in Kupffer cells of C57BL/6 mice during inflammation.

    PubMed

    He, Kun; Dai, Zhuo-Ya; Li, Pei-Zhi; Zhu, Xi-Wen; Gong, Jian-Ping

    2015-10-01

    The liver X receptor (LXR) isoform LXR‑α has a significant role in lipid metabolism and innate immunity. Overexpression of neuron‑derived orphan nuclear receptor‑1 (NOR‑1) in macrophages reduces the synthesis of inflammatory cytokines and chemokines. However, to date, the mechanisms via which NOR‑1 inhibits lipopolysaccharide (LPS)‑induced inflammation in Kupffer cells (KCs) via LXR‑α have not been elucidated. T0901317 is the most potent LXR‑α ligand, leading to its activation. In the present study, KCs were isolated from C57BL/6 mice and randomly divided into five groups: Control, T0901317, LPS, LPS + T0901317 and LPS + T0901317 + NOR‑1 small hairpin (sh)RNA groups. In order to investigate the role of NOR‑1 in inflammation, shRNA targeting NOR‑1 was used to specifically knock down NOR‑1 mRNA in KCs. The expression levels of LXR‑α and NOR‑1 in KCs were determined by reverse transcription quantitative polymerase chain reaction and western blot analyses. The protein levels of tumor necrosis factor (TNF)‑α and interleukin (IL)‑10 in the supernatant of KCs were evaluated by ELISA. The results revealed that LXR‑α expression in the T0901317 group was higher than that in the control group; furthermore, LXR‑α expression was higher in KCs treated with LPS + T0901317 compared with that in KCs treated with LPS only. The expression levels of NOR‑1 in each group showed a similar trend. shRNA targeting of NOR‑1 suppressed the mRNA expression of NOR‑1, but had no influence on LXR‑α mRNA expression. NOR‑1 protein expression was augmented in the LPS + T0901317 group compared with that in the LPS + T09 + shRNA group. In the supernatant of KCs, the TNF‑α levels in the LPS + T0901317 group were lower than those in the LPS group, whereas the IL‑10 levels were higher in the LPS + T0901317 group compared with those in the LPS group. The results of the present study suggested that ligand T0901317 promotes LXR‑α expression

  3. Beyond CTLA-4 and PD-1: Orphan nuclear receptor NR2F6 as T cell signaling switch and emerging target in cancer immunotherapy.

    PubMed

    Klepsch, Victoria; Hermann-Kleiter, Natascha; Baier, Gottfried

    2016-10-01

    Blockade of immune checkpoints has emerged as key strategy in the development of effective cancer therapies. In contrast to cell surface checkpoints like CTLA-4 and PD-1, however, additional cancer therapeutic targets are located inside the effector immune cells. Targeting these alternative checkpoints in cancer immunotherapy with the goal to strengthen the patient's immune system are likely to extend the benefits of cancer immunotherapy in the near future. Along this line, we have defined and validated the orphan nuclear receptor NR2F6 (nuclear receptor subfamily 2 group F member 6, also called Ear-2) as an intracellular immune checkpoint in effector T cells. NR2F6 acts as a novel master switch of antitumor responses against both transplantable and spontaneous tumors in mice relevant for human cancer. NR2F6 directly represses transcription of key cytokine genes in T effector cells relevant for tumor cell rejection, such as IL-2, IFN and TNFα. Thus, in the presence of NR2F6, T cell activation is limited within the tumor microenvironment. This defines NR2F6 as a key checkpoint governing the amplitude of cancer immune surveillance. Based on our study, an approach shall be initiated to identify low molecular weight compounds that selectively interfere with NR2F6 function in the clinic.

  4. Molecular Interactions between NR4A Orphan Nuclear Receptors and NF-κB Are Required for Appropriate Inflammatory Responses and Immune Cell Homeostasis

    PubMed Central

    Murphy, Evelyn P.; Crean, Daniel

    2015-01-01

    Appropriate innate and adaptive immune responses are essential for protection and resolution against chemical, physical or biological insults. Immune cell polarization is fundamental in orchestrating distinct phases of inflammation, specifically acute phase responses followed by resolution and tissue repair. Dysregulation of immune cell and inflammatory responses is a hallmark of multiple diseases encompassing atherosclerosis, rheumatoid arthritis, psoriasis and metabolic syndromes. A master transcriptional mediator of diverse inflammatory signaling and immune cell function is NF-κB, and altered control of this key regulator can lead to an effective switch from acute to chronic inflammatory responses. Members of the nuclear receptor (NR) superfamily of ligand-dependent transcription factors crosstalk with NF-κB to regulate immune cell function(s). Within the NR superfamily the NR4A1-3 orphan receptors have emerged as important regulators of immune cell polarization and NF-κB signaling. NR4A receptors modulate NF-κB activity in a dynamic fashion, either repressing or enhancing target gene expression leading to altered inflammatory outcome. Here we will discuss the pivotal role NR4A’s receptors play in orchestrating immune cell homeostasis through molecular crosstalk with NF-κB. Specifically, we will examine such NR4A/NF-κB interactions within the context of distinct cell phenotypes, including monocyte, macrophage, T cells, endothelial, and mesenchymal cells, which play a role in inflammation-associated disease. Finally, we review the therapeutic potential of altering NR4A/NF-κB interactions to limit hyper-inflammatory responses in vivo. PMID:26131976

  5. Advancements in therapeutically targeting orphan GPCRs

    PubMed Central

    Stockert, Jennifer A.; Devi, Lakshmi A.

    2015-01-01

    G-protein coupled receptors (GPCRs) are popular biological targets for drug discovery and development. To date there are more than 140 orphan GPCRs, i.e., receptors whose endogenous ligands are unknown. Traditionally orphan GPCRs have been difficult to study and the development of therapeutic compounds targeting these receptors has been extremely slow although these GPCRs are considered important targets based on their distribution and behavioral phenotype as revealed by animals lacking the receptor. Recent advances in several methods used to study orphan receptors, including protein crystallography and homology modeling are likely to be useful in the identification of therapeutics targeting these receptors. In the past 13 years, over a dozen different Class A GPCRs have been crystallized; this trend is exciting, since homology modeling of GPCRs has previously been limited by the availability of solved structures. As the number of solved GPCR structures continues to grow so does the number of templates that can be used to generate increasingly accurate models of phylogenetically related orphan GPCRs. The availability of solved structures along with the advances in using multiple templates to build models (in combination with molecular dynamics simulations that reveal structural information not provided by crystallographic data and methods for modeling hard-to-predict flexible loop regions) have improved the quality of GPCR homology models. This, in turn, has improved the success rates of virtual ligand screens that use homology models to identify potential receptor binding compounds. Experimental testing of the predicted hits and validation using traditional GPCR pharmacological approaches can be used to drive ligand-based efforts to probe orphan receptor biology as well as to define the chemotypes and chemical scaffolds important for binding. As a result of these advances, orphan GPCRs are emerging from relative obscurity as a new class of drug targets. PMID

  6. Expression of orphan G-protein coupled receptor GPR174 in CHO cells induced morphological changes and proliferation delay via increasing intracellular cAMP

    SciTech Connect

    Sugita, Kazuya; Yamamura, Chiaki; Tabata, Ken-ichi; Fujita, Norihisa

    2013-01-04

    Highlights: Black-Right-Pointing-Pointer Expression of GPR174 in CHO cells induces morphological changes and proliferation delay. Black-Right-Pointing-Pointer These are due to increase in intracellular cAMP concentration. Black-Right-Pointing-Pointer Lysophosphatidylserine was identified to stimulate GPR174 leading to activate ACase. Black-Right-Pointing-Pointer The potencies of fatty acid moiety on LysoPS were oleoyl Greater-Than-Or-Slanted-Equal-To stearoyl > palmitoyl. Black-Right-Pointing-Pointer We propose that GPR174 is a lysophosphatidylserine receptor. -- Abstract: We established cell lines that stably express orphan GPCR GPR174 using CHO cells, and studied physiological and pharmacological features of the receptor. GPR174-expressing cells showed cell-cell adhesion with localization of actin filaments to cell membrane, and revealed significant delay of cell proliferation. Since the morphological changes of GPR174-cells were very similar to mock CHO cells treated with cholera toxin, we measured the concentration of intracellular cAMP. The results showed the concentration was significantly elevated in GPR174-cells. By measuring intracellular cAMP concentration in GPR174-cells, we screened lipids and nucleotides to identify ligands for GPR174. We found that lysophosphatidylserine (LysoPS) stimulated increase in intracellular cAMP in a dose-dependent manner. Moreover, phosphorylation of Erk was elevated by LysoPS in GPR174 cells. These LysoPS responses were inhibited by NF449, an inhibitor of G{alpha}{sub s} protein. These results suggested that GPR174 was a putative LysoPS receptor conjugating with G{alpha}{sub s}, and its expression induced morphological changes in CHO cells by constitutively activating adenylyl cycles accompanied with cell conjunctions and delay of proliferation.

  7. Feedback induction of a photoreceptor-specific isoform of retinoid-related orphan nuclear receptor β by the rod transcription factor NRL.

    PubMed

    Fu, Yulong; Liu, Hong; Ng, Lily; Kim, Jung-Woong; Hao, Hong; Swaroop, Anand; Forrest, Douglas

    2014-11-21

    Vision requires the generation of cone and rod photoreceptors that function in daylight and dim light, respectively. The neural retina leucine zipper factor (NRL) transcription factor critically controls photoreceptor fates as it stimulates rod differentiation and suppresses cone differentiation. However, the controls over NRL induction that balance rod and cone fates remain unclear. We have reported previously that the retinoid-related orphan receptor β gene (Rorb) is required for Nrl expression and other retinal functions. We show that Rorb differentially expresses two isoforms: RORβ2 in photoreceptors and RORβ1 in photoreceptors, progenitor cells, and other cell types. Deletion of RORβ2 or RORβ1 increased the cone:rod ratio ∼2-fold, whereas deletion of both isoforms in Rorb(-/-) mice produced almost exclusively cone-like cells at the expense of rods, suggesting that both isoforms induce Nrl. Electroporation of either RORβ isoform into retinal explants from Rorb(-/-) neonates reactivated Nrl and rod genes but, in Nrl(-/-) explants, failed to reactivate rod genes, indicating that NRL is the effector for both RORβ isoforms in rod differentiation. Unexpectedly, RORβ2 expression was lost in Nrl(-/-) mice. Moreover, NRL activated the RORβ2-specific promoter of Rorb, indicating that NRL activates Rorb, its own inducer gene. We suggest that feedback activation between Nrl and Rorb genes reinforces the commitment to rod differentiation. PMID:25296752

  8. Adenovirus-mediated expression of orphan nuclear receptor NR4A2 targeting hepatic stellate cell attenuates liver fibrosis in rats

    PubMed Central

    Chen, Pengguo; Li, Jie; Huo, Yan; Lu, Jin; Wan, Lili; Yang, Quanjun; Huang, Jinlu; Gan, Run; Guo, Cheng

    2016-01-01

    Liver fibrosis is a wound-healing response characterized with the accumulation of extracellular matrix (ECM). And hepatic stellate cells (HSCs) are the principal cell source of ECM. NR4A2 (Nurr1) is a member of orphan nuclear receptor NR4A family and acts as transcription factor. It participates in regulating cell differentiation, proliferation and apoptosis. We previously demonstrated that NR4A2 expression in fibrotic liver reduced significantly compared with normal liver and NR4A2 knockout in HSCs promoted ECM production. In the present study we explored the role of NR4A2 on liver fibrosis. Studies in cultured HSCs demonstrated that NR4A2 over-expression suppressed the activation of HSCs, such as ECM production and invasion ability. Moreover cell cycle was arrested, cell apoptosis was promoted and cell signaling pathway was influenced. Adenovirus-mediated delivery of NR4A2 in rats ameliorated significantly dimethylnitrosamine (DMN) induced liver fibrosis. The In vivo experiments produced results consistent with in vitro experiments. Taken together these results demonstrate NR4A2 enhancement attenuates liver fibrosis via suppressing the activation of HSCs and NR4A2 may be an ideal target for anti-fibrotic therapy. PMID:27646469

  9. Adenovirus-mediated expression of orphan nuclear receptor NR4A2 targeting hepatic stellate cell attenuates liver fibrosis in rats.

    PubMed

    Chen, Pengguo; Li, Jie; Huo, Yan; Lu, Jin; Wan, Lili; Yang, Quanjun; Huang, Jinlu; Gan, Run; Guo, Cheng

    2016-01-01

    Liver fibrosis is a wound-healing response characterized with the accumulation of extracellular matrix (ECM). And hepatic stellate cells (HSCs) are the principal cell source of ECM. NR4A2 (Nurr1) is a member of orphan nuclear receptor NR4A family and acts as transcription factor. It participates in regulating cell differentiation, proliferation and apoptosis. We previously demonstrated that NR4A2 expression in fibrotic liver reduced significantly compared with normal liver and NR4A2 knockout in HSCs promoted ECM production. In the present study we explored the role of NR4A2 on liver fibrosis. Studies in cultured HSCs demonstrated that NR4A2 over-expression suppressed the activation of HSCs, such as ECM production and invasion ability. Moreover cell cycle was arrested, cell apoptosis was promoted and cell signaling pathway was influenced. Adenovirus-mediated delivery of NR4A2 in rats ameliorated significantly dimethylnitrosamine (DMN) induced liver fibrosis. The In vivo experiments produced results consistent with in vitro experiments. Taken together these results demonstrate NR4A2 enhancement attenuates liver fibrosis via suppressing the activation of HSCs and NR4A2 may be an ideal target for anti-fibrotic therapy. PMID:27646469

  10. The Orphan Adhesion G Protein-coupled Receptor GPR97 Regulates Migration of Lymphatic Endothelial Cells via the Small GTPases RhoA and Cdc42*

    PubMed Central

    Valtcheva, Nadejda; Primorac, Adriana; Jurisic, Giorgia; Hollmén, Maija; Detmar, Michael

    2013-01-01

    The important role of the lymphatic vascular system in pathological conditions such as inflammation and cancer has been increasingly recognized, but its potential as a pharmacological target is poorly exploited. Our study aimed at the identification and molecular characterization of lymphatic-specific G protein-coupled receptors (GPCRs) to assess new targets for pharmacological manipulation of the lymphatic vascular system. We used a TaqMan quantitative RT-PCR-based low density array to determine the GPCR expression profiles of ex vivo isolated intestinal mouse lymphatic (LECs) and blood vascular endothelial cells (BECs). GPR97, an orphan adhesion GPCR of unknown function, was the most highly and specifically expressed GPCR in mouse lymphatic endothelium. Using siRNA silencing, we found that GPR97-deficient primary human LECs displayed increased adhesion and collective cell migration, whereas single cell migration was decreased as compared with nontargeting siRNA-transfected control LECs. Loss of GPR97 shifted the ratio of active Cdc42 and RhoA and initiated cytoskeletal rearrangements, including F-actin redistribution, paxillin and PAK4 phosphorylation, and β1-integrin activation. Our data suggest a possible role of GPR97 in lymphatic remodeling and furthermore provide the first insights into the biological functions of GPR97. PMID:24178298

  11. The Orphan G Protein-coupled Receptor GPR17 Negatively Regulates Oligodendrocyte Differentiation via Gαi/o and Its Downstream Effector Molecules.

    PubMed

    Simon, Katharina; Hennen, Stephanie; Merten, Nicole; Blättermann, Stefanie; Gillard, Michel; Kostenis, Evi; Gomeza, Jesus

    2016-01-01

    Recent studies have recognized G protein-coupled receptors as important regulators of oligodendrocyte development. GPR17, in particular, is an orphan G protein-coupled receptor that has been identified as oligodendroglial maturation inhibitor because its stimulation arrests primary mouse oligodendrocytes at a less differentiated stage. However, the intracellular signaling effectors transducing its activation remain poorly understood. Here, we use Oli-neu cells, an immortalized cell line derived from primary murine oligodendrocytes, and primary rat oligodendrocyte cultures as model systems to identify molecular targets that link cell surface GPR17 to oligodendrocyte maturation blockade. We demonstrate that stimulation of GPR17 by the small molecule agonist MDL29,951 (2-carboxy-4,6-dichloro-1H-indole-3-propionic acid) decreases myelin basic protein expression levels mainly by triggering the Gαi/o signaling pathway, which in turn leads to reduced activity of the downstream cascade adenylyl cyclase-cAMP-PKA-cAMP response element-binding protein (CREB). In addition, we show that GPR17 activation also diminishes myelin basic protein abundance by lessening stimulation of the exchange protein directly activated by cAMP (EPAC), thus uncovering a previously unrecognized role for EPAC to regulate oligodendrocyte differentiation. Together, our data establish PKA and EPAC as key downstream effectors of GPR17 that inhibit oligodendrocyte maturation. We envisage that treatments augmenting PKA and/or EPAC activity represent a beneficial approach for therapeutic enhancement of remyelination in those demyelinating diseases where GPR17 is highly expressed, such as multiple sclerosis.

  12. Orphan Receptor GPR158 Is an Allosteric Modulator of RGS7 Catalytic Activity with an Essential Role in Dictating Its Expression and Localization in the Brain.

    PubMed

    Orlandi, Cesare; Xie, Keqiang; Masuho, Ikuo; Fajardo-Serrano, Ana; Lujan, Rafael; Martemyanov, Kirill A

    2015-05-29

    Regulators of G protein signaling control the duration and extent of signaling via G protein-coupled receptor (GPCR) pathways by accelerating the GTP hydrolysis on G protein α subunits thereby promoting termination of GPCR signaling. A member of this family, RGS7, plays a critical role in the nervous system where it regulates multiple neurotransmitter GPCRs that mediate vision, memory, and the action of addictive drugs. Previous studies have established that in vivo RGS7 forms mutually exclusive complexes with the membrane protein RGS7-binding protein or the orphan receptor GPR158. In this study, we examine the impact of GPR158 on RGS7 in the brain. We report that knock-out of GPR158 in mice results in marked post-transcriptional destabilization of RGS7 and substantial loss of its association with membranes in several brain regions. We further identified the RGS7-binding site in the C terminus of GPR158 and found that it shares significant homology with the RGS7-binding protein. The proximal portion of the GPR158 C terminus additionally contained a conserved sequence that was capable of enhancing RGS7 GTPase-activating protein activity in solution by an allosteric mechanism acting in conjunction with the regulators of the G protein signaling-binding domain. The distal portion of the GPR158 C terminus contained several phosphodiesterase E γ-like motifs and selectively recruited G proteins in their activated state. The results of this study establish GPR158 as an essential regulator of RGS7 in the native nervous system with a critical role in controlling its expression, membrane localization, and catalytic activity.

  13. Orphan Receptor GPR158 Is an Allosteric Modulator of RGS7 Catalytic Activity with an Essential Role in Dictating Its Expression and Localization in the Brain*♦

    PubMed Central

    Orlandi, Cesare; Xie, Keqiang; Masuho, Ikuo; Fajardo-Serrano, Ana; Lujan, Rafael; Martemyanov, Kirill A.

    2015-01-01

    Regulators of G protein signaling control the duration and extent of signaling via G protein-coupled receptor (GPCR) pathways by accelerating the GTP hydrolysis on G protein α subunits thereby promoting termination of GPCR signaling. A member of this family, RGS7, plays a critical role in the nervous system where it regulates multiple neurotransmitter GPCRs that mediate vision, memory, and the action of addictive drugs. Previous studies have established that in vivo RGS7 forms mutually exclusive complexes with the membrane protein RGS7-binding protein or the orphan receptor GPR158. In this study, we examine the impact of GPR158 on RGS7 in the brain. We report that knock-out of GPR158 in mice results in marked post-transcriptional destabilization of RGS7 and substantial loss of its association with membranes in several brain regions. We further identified the RGS7-binding site in the C terminus of GPR158 and found that it shares significant homology with the RGS7-binding protein. The proximal portion of the GPR158 C terminus additionally contained a conserved sequence that was capable of enhancing RGS7 GTPase-activating protein activity in solution by an allosteric mechanism acting in conjunction with the regulators of the G protein signaling-binding domain. The distal portion of the GPR158 C terminus contained several phosphodiesterase E γ-like motifs and selectively recruited G proteins in their activated state. The results of this study establish GPR158 as an essential regulator of RGS7 in the native nervous system with a critical role in controlling its expression, membrane localization, and catalytic activity. PMID:25792749

  14. Targeting of the orphan receptor GPR35 by pamoic acid: a potent activator of extracellular signal-regulated kinase and β-arrestin2 with antinociceptive activity.

    PubMed

    Zhao, Pingwei; Sharir, Haleli; Kapur, Ankur; Cowan, Alan; Geller, Ellen B; Adler, Martin W; Seltzman, Herbert H; Reggio, Patricia H; Heynen-Genel, Susanne; Sauer, Michelle; Chung, Thomas D Y; Bai, Yushi; Chen, Wei; Caron, Marc G; Barak, Larry S; Abood, Mary E

    2010-10-01

    Known agonists of the orphan receptor GPR35 are kynurenic acid, zaprinast, 5-nitro-2-(3-phenylproplyamino) benzoic acid, and lysophosphatidic acids. Their relatively low affinities for GPR35 and prominent off-target effects at other pathways, however, diminish their utility for understanding GPR35 signaling and for identifying potential therapeutic uses of GPR35. In a screen of the Prestwick Library of drugs and drug-like compounds, we have found that pamoic acid is a potent GPR35 agonist. Pamoic acid is considered by the Food and Drug Administration as an inactive compound that enables long-acting formulations of numerous drugs, such as the antihelminthics oxantel pamoate and pyrantel pamoate; the psychoactive compounds hydroxyzine pamoate (Vistaril) and imipramine pamoate (Tofranil-PM); and the peptide hormones triptorelin pamoate (Trelstar) and octreotide pamoate (OncoLar). We have found that pamoic acid induces a G(i/o)-linked, GPR35-mediated increase in the phosphorylation of extracellular signal-regulated kinase 1/2, recruitment of β-arrestin2 to GPR35, and internalization of GPR35. In mice, it attenuates visceral pain perception, indicating an antinociceptive effect, possibly through GPR35 receptors. We have also identified in collaboration with the Sanford-Burnham Institute Molecular Libraries Probe Production Center new classes of GPR35 antagonist compounds, including the nanomolar potency antagonist methyl-5-[(tert-butylcarbamothioylhydrazinylidene)methyl]-1-(2,4-difluorophenyl)pyrazole-4-carboxylate (CID2745687). Pamoic acid and potent antagonists such as CID2745687 present novel opportunities for expanding the chemical space of GPR35, elucidating GPR35 pharmacology, and stimulating GPR35-associated drug development. Our results indicate that the unexpected biological functions of pamoic acid may yield potential new uses for a common drug constituent. PMID:20826425

  15. Genome analysis of quorum sensing Cedecea neteri SSMD04 leads to identification of its novel signaling synthase (cneI), cognate receptor (cneR) and an orphan receptor

    PubMed Central

    Tan, Kian-Hin; Tan, Jia-Yi; Yin, Wai-Fong

    2015-01-01

    Cedecea neteri is a very rare human pathogen. We have isolated a strain of C. neteri SSMD04 from pickled mackerel sashimi identified using molecular and phenotypics approaches. Using the biosensor Chromobacterium violaceum CV026, we have demonstrated the presence of short chain N-acyl-homoserine lactone (AHL) type quorum sensing (QS) activity in C. neteri SSMD04. Triple quadrupole LC/MS analysis revealed that C. neteri SSMD04 produced short chain N-butyryl-homoserine lactone (C4-HSL). With the available genome information of C. neteri SSMD04, we went on to analyse and identified a pair of luxI/R homologues in this genome that share the highest similarity with croI/R homologues from Citrobacter rodentium. The AHL synthase, which we named cneI(636 bp), was found in the genome sequences of C. neteri SSMD04. At a distance of 8bp from cneI is a sequence encoding a hypothetical protein, potentially the cognate receptor, a luxR homologue which we named it as cneR. Analysis of this protein amino acid sequence reveals two signature domains, the autoinducer-binding domain and the C-terminal effector which is typical characteristic of luxR. In addition, we found that this genome harboured an orphan luxR that is most closely related to easR in Enterobacter asburiae. To our knowledge, this is the first report on the AHL production activity in C. neteri, and the discovery of its luxI/R homologues, the orphan receptor and its whole genome sequence. PMID:26355540

  16. The orphan nuclear receptor Nr5a2 is essential for luteinization in the female mouse ovary.

    PubMed

    Bertolin, Kalyne; Gossen, Jan; Schoonjans, Kristina; Murphy, Bruce D

    2014-05-01

    In the ovary, the follicular granulosa cells express the nuclear receptor Nr5a2 (nuclear receptor subfamily 5 group A member 2), also known as liver receptor homolog-1, and after ovulation, Nr5a2 expression persists in the corpus luteum. Previous studies demonstrated that Nr5a2 is required for both ovulation and luteal steroid synthesis. Our objectives were to analyze the temporal sequence in the regulatory effects of Nr5a2 in the ovary, with focus on its contribution to luteal function. We developed a female mouse model of granulosa-specific targeted disruption from the formation of the antral follicles forward (genotype Nr5a2(Cyp19-/-)). Mice lacking Nr5a2 in granulosa cells of antral follicles are infertile. Although their cumulus cells undergo expansion after gonadotropin stimulation, ovulation is disrupted in those mice, at least in part, due to the down-regulation of the progesterone receptor (Pgr) gene. The depletion of Nr5a2 in antral follicles permits formation of luteal-like structures but not functional corpora lutea, as evidenced by reduced progesterone levels and failure to support pseudopregnancy. Progesterone synthesis is affected by depletion of Nr5a2 due to, among others, defects in the transport of cholesterol, evidenced by down-regulation of Scarb1, Ldlr, and Star. Comparison of this mouse line with the models in which Nr5a2 is depleted from the primary follicle forward (genotype Nr5a2(Amhr2-/-)) and after the ovulatory signal (genotype Nr5a2(Pgr-/-)) demonstrates that Nr5a2 differentially regulates female fertility across the trajectory of follicular development.

  17. The orphan nuclear receptor, steroidogenic factor 1, regulates neuronal nitric oxide synthase gene expression in pituitary gonadotropes.

    PubMed

    Wei, Xueying; Sasaki, Masayuki; Huang, Hui; Dawson, Valina L; Dawson, Ted M

    2002-12-01

    Steroidogenic factor 1 (SF-1), an essential nuclear receptor, plays key roles in steroidogenic cell function within the adrenal cortex and gonads. It also contributes to reproductive function at all three levels of the hypothalamic-pituitary-gonadal axis. SF-1 regulates genes in the steroidogenic pathway, such as LHbeta, FSHbeta, and steroid hydroxylase. Abundant evidence suggests that nitric oxide (NO) has an important role in the control of reproduction due to its ability to control GnRH secretion from the hypothalamus and the preovulatory LH surge in pituitary gonadotropes. Recently, we cloned and characterized the promoter of mouse neuronal NO synthase (nNOS). nNOS is localized at all three levels of the hypothalamic-pituitary-gonadal axis to generate NO. We find that its major promoter resides at exon 2 in the pituitary gonadotrope alphaT3-1 cell line and that there is a nuclear hormone receptor binding site in this region, to which SF-1 can bind and regulate nNOS transcription. Mutation of the nuclear hormone receptor binding site dramatically decreases basal promoter activity and abolishes SF-1 responsiveness. A dominant negative of SF-1, in which the transactivation (AF-2) domain of SF-1 was deleted, inhibits nNOS exon 2 promoter activity. Dosage-sensitive reversal- adrenal hypoplasia congenita critical region on the X chromosome, gene 1 (DAX-1), which colocalizes and interferes with SF-1 actions in multiple cell lineages, negatively modulates SF-1 regulation of nNOS transcription. These findings demonstrate that mouse nNOS gene expression is regulated by the SF-1 gene family in pituitary gonadotropes. nNOS, a member of the cytochrome p450 gene family, could be one of the downstream effector genes, which mediates SF-1's reproductive function and developmental patterning.

  18. Profiling the orphan enzymes.

    PubMed

    Sorokina, Maria; Stam, Mark; Médigue, Claudine; Lespinet, Olivier; Vallenet, David

    2014-06-06

    The emergence of Next Generation Sequencing generates an incredible amount of sequence and great potential for new enzyme discovery. Despite this huge amount of data and the profusion of bioinformatic methods for function prediction, a large part of known enzyme activities is still lacking an associated protein sequence. These particular activities are called "orphan enzymes". The present review proposes an update of previous surveys on orphan enzymes by mining the current content of public databases. While the percentage of orphan enzyme activities has decreased from 38% to 22% in ten years, there are still more than 1,000 orphans among the 5,000 entries of the Enzyme Commission (EC) classification. Taking into account all the reactions present in metabolic databases, this proportion dramatically increases to reach nearly 50% of orphans and many of them are not associated to a known pathway. We extended our survey to "local orphan enzymes" that are activities which have no representative sequence in a given clade, but have at least one in organisms belonging to other clades. We observe an important bias in Archaea and find that in general more than 30% of the EC activities have incomplete sequence information in at least one superkingdom. To estimate if candidate proteins for local orphans could be retrieved by homology search, we applied a simple strategy based on the PRIAM software and noticed that candidates may be proposed for an important fraction of local orphan enzymes. Finally, by studying relation between protein domains and catalyzed activities, it appears that newly discovered enzymes are mostly associated with already known enzyme domains. Thus, the exploration of the promiscuity and the multifunctional aspect of known enzyme families may solve part of the orphan enzyme issue. We conclude this review with a presentation of recent initiatives in finding proteins for orphan enzymes and in extending the enzyme world by the discovery of new activities.

  19. miR-34a Inhibits Proliferation and Invasion of Bladder Cancer Cells by Targeting Orphan Nuclear Receptor HNF4G

    PubMed Central

    Sun, Huaibin; Tian, Jun; Xian, Wanhua; Xie, Tingting; Yang, Xiangdong

    2015-01-01

    miR-34a is a member of the miR-34 family and acts as a tumor suppressor in bladder cancer. This study explored the regulative role of miR-34a on an orphan nuclear receptor HNF4G, which has a well-confirmed role in bladder tumor growth and invasion. qRT-PCR analysis was applied to measure miR-34a expression in two tumorigenic bladder cancer cell lines 5637 and T24 and one normal human urothelial cell line SV-HUC-1. Luciferase assay was performed to verify the putative binding between miR-34a and HNF4G. The influence of miR-34a-HNF4G axis on cell viability, colony formation, and invasion was assessed with loss- and gain-of-function analysis. This study observed that the miR-34a expressions in 5637 and T24 cells were significantly lower than in SV-HUC-1, while the muscle invasive cell sublines 5637-M and T24-M had even lower miR-34a expression than in the nonmuscle invasive sublines. HNF4G has a 3′-UTR binding site with miR-34a and is a direct downstream target of miR-34a. miR-34a can directly downregulate the expression of HNF4G and thus inhibit tumor cell viability, colony formation, and invasion. Therefore, miR-34a-HNF4G axis is an important pathway modulating cell viability, proliferation, and invasion of bladder cancer cells. PMID:25878394

  20. Differential transactivation by orphan nuclear receptor NOR1 and its fusion gene product EWS/NOR1: possible involvement of poly(ADP-ribose) polymerase I, PARP-1.

    PubMed

    Ohkura, Naganari; Nagamura, Yuko; Tsukada, Toshihiko

    2008-10-15

    In extraskeletal myxoid chondrosarcoma, a chromosomal translocation creates a gene fusion between EWS and an orphan nuclear receptor, NOR1. The resulting fusion protein EWS/NOR1 has been believed to lead to malignant transformation by functioning as a transactivator for NOR1-target genes. By comparing the gene expression profiles of NOR1- and EWS/NOR1-overexpressing cells, we found that they largely shared up-regulated genes, but no significant correlation was observed with respect to the transactivation levels of each gene. In addition, the proteins associated with NOR1 and EWS/NOR1 were mostly the same in these cells. The results suggest that these proteins differentially transactivate overlapping target genes through a similar transcriptional machinery. To clarify the mechanisms underlying the transcriptional divergence between NOR1 and EWS/NOR1, we searched for alternatively associated proteins, and identified poly(ADP-ribose) polymerase I (PARP-1) as an NOR1-specific binding protein. Consistent with its binding properties, PARP-1 acted as a transcriptional repressor of NOR1, but not EWS/NOR1, in a luciferase reporter assay employing PARP-1(-/-) fibroblasts. Interestingly, suppressive activity of PARP-1 was observed in a DNA response element-specific manner, and in a subtype-specific manner toward the NR4A family (Nur77, Nurr1, and NOR1), suggesting that PARP-1 plays a role in the diversity of transcriptional regulation mediated by the NR4A family in normal cells. Altogether, our findings suggest that NOR1 and EWS/NOR1 regulate overlapping target genes differently by utilizing associated proteins, including PARP-1; and that EWS/NOR1 may acquire oncogenic activities by avoiding (or gaining) transcription factor-specific modulation by the associated proteins.

  1. miR-34a inhibits proliferation and invasion of bladder cancer cells by targeting orphan nuclear receptor HNF4G.

    PubMed

    Sun, Huaibin; Tian, Jun; Xian, Wanhua; Xie, Tingting; Yang, Xiangdong

    2015-01-01

    miR-34a is a member of the miR-34 family and acts as a tumor suppressor in bladder cancer. This study explored the regulative role of miR-34a on an orphan nuclear receptor HNF4G, which has a well-confirmed role in bladder tumor growth and invasion. qRT-PCR analysis was applied to measure miR-34a expression in two tumorigenic bladder cancer cell lines 5637 and T24 and one normal human urothelial cell line SV-HUC-1. Luciferase assay was performed to verify the putative binding between miR-34a and HNF4G. The influence of miR-34a-HNF4G axis on cell viability, colony formation, and invasion was assessed with loss- and gain-of-function analysis. This study observed that the miR-34a expressions in 5637 and T24 cells were significantly lower than in SV-HUC-1, while the muscle invasive cell sublines 5637-M and T24-M had even lower miR-34a expression than in the nonmuscle invasive sublines. HNF4G has a 3'-UTR binding site with miR-34a and is a direct downstream target of miR-34a. miR-34a can directly downregulate the expression of HNF4G and thus inhibit tumor cell viability, colony formation, and invasion. Therefore, miR-34a-HNF4G axis is an important pathway modulating cell viability, proliferation, and invasion of bladder cancer cells.

  2. Glucocorticoids antagonize cAMP-induced Star transcription in Leydig cells through the orphan nuclear receptor NR4A1.

    PubMed

    Martin, Luc J; Tremblay, Jacques J

    2008-09-01

    It is well established that stress, either physical or psychosocial, causes a decrease in testosterone production by Leydig cells. Glucocorticoids (Gc) are the main mediators of stress response and they convey their repressive effect on Leydig cells through the glucocorticoid receptor (GR). So far, various mechanisms have been proposed to explain the mechanism of action of Gc on Leydig cell steroidogenesis including repression of genes involved in testosterone biosynthesis. Several steroidogenic genes, including steroidogenic acute regulatory (STAR) protein, have been shown to be repressed by Gc in a GR-dependent manner but the underlying mechanisms remain to be fully elucidated. Here, we found that dexamethasone (Dex), a potent synthetic Gc, partly antagonizes the cAMP-dependent stimulation of the mouse Star promoter in MA-10 Leydig cells as revealed by transient transfection assays. This repression requires an element located at -95 bp previously implicated in the activation of the Star promoter by the nuclear receptors, NR4A1 and NR5A1. Dex was found to inhibit NR4A1-dependent transactivation of the Star promoter in Leydig cells by decreasing NR4A1, but not NR5A1, recruitment to the proximal Star promoter as determined by chromatin immunoprecipitation assay. Western blots revealed that Dex did not affect NR4A1 or NR5A1 expression in response to cAMP. These data suggest that NR4A1 would be associated with the GR in a transcriptionally inactive complex as previously demonstrated in pituitary corticotrope cells. Thus, our data provide new molecular insights into the stress-mediated suppression of testosterone production in testicular Leydig cells.

  3. Orphan nuclear receptor NR4A2 inhibits hepatic stellate cell proliferation through MAPK pathway in liver fibrosis

    PubMed Central

    Chen, Pengguo; Li, Jie; Huo, Yan; Lu, Jin; Wan, Lili; Li, Bin; Gan, Run

    2015-01-01

    Hepatic stellate cells (HSCs) play a crucial role in liver fibrosis, which is a pathological process characterized by extracellular matrix accumulation. NR4A2 is a nuclear receptor belonging to the NR4A subfamily and vital in regulating cell growth, metabolism, inflammation and other biological functions. However, its role in HSCs is unclear. We analyzed NR4A2 expression in fibrotic liver and stimulated HSCs compared with control group and studied the influence on cell proliferation, cell cycle, cell apoptosis and MAPK pathway after NR4A2 knockdown. NR4A2 expression was examined by real-time polymerase chain reaction, Western blotting, immunohistochemistry and immunofluorescence analyses. NR4A2 expression was significantly lower in fibrotic liver tissues and PDGF BB or TGF-β stimulated HSCs compared with control group. After NR4A2 knockdown α-smooth muscle actin and Col1 expression increased. In addition, NR4A2 silencing led to the promotion of cell proliferation, increase of cell percentage in S phase and reduced phosphorylation of ERK1/2, P38 and JNK in HSCs. These results indicate that NR4A2 can inhibit HSC proliferation through MAPK pathway and decrease extracellular matrix in liver fibrogenesis. NR4A2 may be a promising therapeutic target for liver fibrosis. PMID:26713258

  4. Orphan nuclear receptor NR4A2 inhibits hepatic stellate cell proliferation through MAPK pathway in liver fibrosis.

    PubMed

    Chen, Pengguo; Li, Jie; Huo, Yan; Lu, Jin; Wan, Lili; Li, Bin; Gan, Run; Guo, Cheng

    2015-01-01

    Hepatic stellate cells (HSCs) play a crucial role in liver fibrosis, which is a pathological process characterized by extracellular matrix accumulation. NR4A2 is a nuclear receptor belonging to the NR4A subfamily and vital in regulating cell growth, metabolism, inflammation and other biological functions. However, its role in HSCs is unclear. We analyzed NR4A2 expression in fibrotic liver and stimulated HSCs compared with control group and studied the influence on cell proliferation, cell cycle, cell apoptosis and MAPK pathway after NR4A2 knockdown. NR4A2 expression was examined by real-time polymerase chain reaction, Western blotting, immunohistochemistry and immunofluorescence analyses. NR4A2 expression was significantly lower in fibrotic liver tissues and PDGF BB or TGF-β stimulated HSCs compared with control group. After NR4A2 knockdown α-smooth muscle actin and Col1 expression increased. In addition, NR4A2 silencing led to the promotion of cell proliferation, increase of cell percentage in S phase and reduced phosphorylation of ERK1/2, P38 and JNK in HSCs. These results indicate that NR4A2 can inhibit HSC proliferation through MAPK pathway and decrease extracellular matrix in liver fibrogenesis. NR4A2 may be a promising therapeutic target for liver fibrosis.

  5. Endocrine and neurogenic regulation of the orphan nuclear receptors Nur77 and Nurr-1 in the adrenal glands.

    PubMed Central

    Davis, I J; Lau, L F

    1994-01-01

    nurr77 and nurr-1 are growth factor-inducible members of the steroid/thyroid hormone receptor gene superfamily. In order to gain insight into the potential roles of nur77 in the living organism, we used pharmacologic treatments to examine the expression of nur77 in the mouse adrenal gland. We found that nur77 and nurr-1 are induced in the adrenal gland upon treatment with pentylene tetrazole (Ptz; Metrazole). This induction is separable into distinct endocrine and neurogenic mechanisms. In situ hybridization analysis demonstrates that nur77 expression upon Ptz treatment in the adrenal cortex is localized primarily to the inner cortical region, the zona fasciculata-reticularis, with minimal induction in the zona glomerulosa. This induction is inhibitable by pretreatment with dexamethasone, indicating involvement of the hypothalamic-pituitary-adrenal axis in the activation of adrenal cortical expression. When mice were injected with adrenocorticotrophic hormone (ACTH), nur77 expression in the adrenal gland spanned all cortical layers including the zona glomerulosa, but medullary expression was not induced. Ptz also induces expression of both nur77 and nurr-1 in the adrenal medulla. Medullary induction is likely to have a neurogenic origin, as nur77 expression was not inhibitable by dexamethasone pretreatment and induction was seen after treatment with the cholinergic neurotransmitter nicotine. nur77 is also inducible by ACTH, forskolin, and the second messenger analog dibutyryl cyclic AMP in the ACTH-responsive adrenal cortical cell line Y-1. Significantly, Nur77 isolated from ACTH-stimulated Y-1 cells bound to its response element whereas Nur77 present in unstimulated cells did not. Moreover, Nur77 in ACTH-treated Y-1 cells was hypophosphorylated at serine 354 compared with that in untreated cells. These results, taken together with the previous observation that dephosphorylation of serine 354 affects DNA binding affinity in vitro, show for the first time that

  6. Convergence of linkage, gene expression and association data demonstrates the influence of the RAR-related orphan receptor alpha (RORA) gene on neovascular AMD: A systems biology based approach

    PubMed Central

    Silveira, Alexandra C.; Morrison, Margaux A.; Ji, Fei; Xu, Haiyan; Reinecke, James B.; Adams, Scott M.; Arneberg, Trevor M.; Janssian, Maria; Lee, Joo-Eun; Yuan, Yang; Schaumberg, Debra A.; Kotoula, Maria G.; Tsironi, Evangeline E.; Tsiloulis, Aristoteles N.; Chatzoulis, Dimitrios Z.; Miller, Joan W.; Kim, Ivana K.; Hageman, Gregory H.; Farrer, Lindsay A.; Haider, Neena B.; DeAngelis, Margaret M.

    2009-01-01

    To identify novel genes and pathways associated with AMD, we performed microarray gene expression and linkage analysis which implicated the candidate gene, retinoic acid receptor-related orphan receptor alpha (RORA, 15q). Subsequent genotyping of 159 RORA single nucleotide polymorphisms (SNPs) in a family-based cohort, followed by replication in an unrelated case-control cohort, demonstrated that SNPs and haplotypes located in intron 1 were significantly associated with neovascular AMD risk in both cohorts. This is the first report demonstrating a possible role for RORA, a receptor for cholesterol, in the pathophysiology of AMD. Moreover, we found a significant interaction between RORA and the ARMS2/HTRA1 locus suggesting a novel pathway underlying AMD pathophysiology. PMID:19786043

  7. The effect of vitamin A supplementation on retinoic acid-related orphan receptor γt (RORγt) and interleukin-17 (IL-17) gene expression in Avonex-treated multiple sclerotic patients.

    PubMed

    Mohammadzadeh Honarvar, Niyaz; Harirchian, Mohammad Hossein; Koohdani, Fariba; Siassi, Feridoun; Abdolahi, Mina; Bitarafan, Sama; Salehi, Eisa; Sahraian, Mohammad Ali; Eshraghian, Mohammad Reza; Saboor-Yarghi, Ali Akbar

    2013-11-01

    The aim of this study was to investigate the role of vitamin A on RORγt and IL-17 gene expression in multiple sclerotic patients. Patients in the vitamin A group received 25,000 IU retinyl palmitate per day, while patients in the placebo group took one capsule of placebo per day for 6 months. Gene expression was measured by real-time PCR at the first and end of the study. The results of this study show that vitamin A downregulates IL-17 and RORγt gene expression. No changes in gene expression occurred in the placebo group. PMID:23868508

  8. Fomepizole (orphan medical).

    PubMed

    Hantson, P

    2001-06-01

    Orphan Medical has developed fomepizole as a potential treatment for both ethylene glycol and methanol poisoning. The drug was launched as Antizol in January 1998 for the treatment of ethylene glycol poisoning [273949] after US marketing approval was grantedin December 1997 [271563]. It has also received US approval for methanol poisoning [393217] and UK approval for ethylene glycol poisoning [329495]. In 1999, Orphan Medical's partner, Cambridge Laboratories, intended to pursue European approval under the mutual recognition procedure [329495]. However, by September 2000, Cambridge Laboratories had discontinued their involvement with fomepizole and IDIS World Medicines had licensed the rights to distribute the drug in the UK [412142]. In February 2000, the Canadian Therapeutic Products Programme (TPP) granted fomepizole Priority Review, provided that an NDA was submitted by March 14, 2000 [354665]. In August 2000, the TPP accepted this NDA and set a target date for approval in the fourth quarter of 2000 [379474]. The TPP granted fomepizole a Notice of Compliance permitting the sale of fomepizole in Canada in December 2000. The company's marketing partner in Canada, Paladin Labs had launched fomepizole by January 2001 [396953]. In June 2000, Tucker Anthony Cleary Gull stated that the Orphan Drug status which Orphan Medical had obtained for fomepizole would provide marketing exclusivity through December 2004. The analysts also stated that fomepizole had accounted for 40% of Orphan Medical's revenue in financial year 1999, although +/- 30% of sales were estimated to be due to stockpiling [409606].

  9. Fomepizole (orphan medical).

    PubMed

    Hantson, P

    2001-06-01

    Orphan Medical has developed fomepizole as a potential treatment for both ethylene glycol and methanol poisoning. The drug was launched as Antizol in January 1998 for the treatment of ethylene glycol poisoning [273949] after US marketing approval was grantedin December 1997 [271563]. It has also received US approval for methanol poisoning [393217] and UK approval for ethylene glycol poisoning [329495]. In 1999, Orphan Medical's partner, Cambridge Laboratories, intended to pursue European approval under the mutual recognition procedure [329495]. However, by September 2000, Cambridge Laboratories had discontinued their involvement with fomepizole and IDIS World Medicines had licensed the rights to distribute the drug in the UK [412142]. In February 2000, the Canadian Therapeutic Products Programme (TPP) granted fomepizole Priority Review, provided that an NDA was submitted by March 14, 2000 [354665]. In August 2000, the TPP accepted this NDA and set a target date for approval in the fourth quarter of 2000 [379474]. The TPP granted fomepizole a Notice of Compliance permitting the sale of fomepizole in Canada in December 2000. The company's marketing partner in Canada, Paladin Labs had launched fomepizole by January 2001 [396953]. In June 2000, Tucker Anthony Cleary Gull stated that the Orphan Drug status which Orphan Medical had obtained for fomepizole would provide marketing exclusivity through December 2004. The analysts also stated that fomepizole had accounted for 40% of Orphan Medical's revenue in financial year 1999, although +/- 30% of sales were estimated to be due to stockpiling [409606]. PMID:16001315

  10. FMRFamide related peptide ligands activate the Caenorhabditis elegans orphan GPCR Y59H11AL.1

    Technology Transfer Automated Retrieval System (TEKTRAN)

    G-protein coupled receptors (GPCRs) are ancient molecules that sense environmental and physiological signals. Currently, the majority of the predicted Caenorhabditis elegans GPCRs are orphan. Here, we describe the characterization of such an orphan C. elegans GPCR, which is categorized in the tachyk...

  11. [Orphan diseases and orphan medicines: a Belgian and European study].

    PubMed

    Denis, Alain; Mergaert, Lut; Fostier, Christel; Cleemput, Irina; Simoens, Steven

    2009-12-01

    The objective of this study is to analyze policies concerning orphan medicines, used to treat patients suffering from a rare disease. The decisions about orphan designation and marketing authorization of orphan medicines are taken at European level, but each Member State is responsible for decisions regarding reimbursement. The European measures to encourage the development of orphan medicines, such as market exclusivity for a period of ten years, seem to be successful. However, this market exclusivity should be revised once the profitability of such medicines has clearly been demonstrated. Our study recommends the implementation of patient registries at the European level in order to describe the natural evolution of rare diseases and the efficacy of orphan medicines, the majority of which are relatively expensive. In 2008, Belgian social security services reimbursed orphan medicines for an amount of 66 million euro, accounting for more than 5% of the hospital pharmaceutical budget. The reimbursement of an orphan medicine to an individual patient is subject to multiple conditions. Our study recommends that a unique counter within the NIHDI is created which centralizes all reimbursement requests. The reimbursement of an orphan medicine must be linked to the provision of standardized information needed for a patient register. The NIHDI administration could then, in collaboration with external experts, evaluate reimbursement requests and ensure a coherent application of reimbursement criteria. PMID:20183989

  12. Transcriptional repression by the orphan steroid receptor RVR/Rev-erb beta is dependent on the signature motif and helix 5 in the E region: functional evidence for a biological role of RVR in myogenesis.

    PubMed Central

    Burke, L; Downes, M; Carozzi, A; Giguère, V; Muscat, G E

    1996-01-01

    RVR/Rev-erb beta/BD73 is an orphan steroid receptor that has no known ligand in the "classical' sense. RVR binds as a monomer to an element which consists of an A/T-rich sequence upstream of the consensus hexameric half-site. However, RVR does not activate transcription and blocks transactivation of this element by ROR/RZR. The mechanism of RVR action remains obscure, hence we used the GAL4 hybrid system to identify and characterize an active transcriptional silencer in the ligand binding domain (LBD) of RVR. Rigorous deletion and mutational analysis demonstrated that this repressor domain is encoded by amino acids 416-449 of RVR. Furthermore, we demonstrated that efficient repression is dependent on the so-called LBD-specific signature motif, (F/W)AKxxxxFxxLxxxDQxxLL (which spans loop3-4 and helix 4) and helix 5 (H5; identified in the crystal structures of the steroid receptor LBDs). Although RVR is expressed in many adult tissues, including skeletal muscle, and during embryogenesis, its physiological function in differentiation and mammalian development remains unknown. Since other 'orphans', e.g. COUP-TF II and Rev-erbA alpha, have been demonstrated to regulate muscle and adipocyte differentiation, we investigated the expression and functional role of RVR during mouse myogenesis. In C2C12 myogenic cells, RVR mRNA was detected in proliferating myoblasts and was suppressed when the cells were induced to differentiate into post-mitotic, multinucleated myotubes by serum withdrawal. This decrease in RVR mRNA correlated with the appearance of muscle-specific markers (e.g. myogenin mRNA). RVR 'loss of function' studies by constitutive over-expression of a dominant negative RVR delta E resulted in increased levels of p21Cip1/Waf1 and myogenin mRNAs after serum withdrawal. Time course studies indicated that expression of RVR delta E mRNA results in the precocious induction and accumulation of myogenin and p21 mRNAs after serum withdrawal. In addition, we demonstrated

  13. Isolation of a Novel Family of C2H2 Zinc Finger Proteins Implicated in Transcriptional Repression Mediated by Chicken Ovalbumin Upstream Promoter Transcription Factor (COUP-TF) Orphan Nuclear Receptors*

    PubMed Central

    Avram, Dorina; Fields, Andrew; Top, Karen Pretty On; Nevrivy, Daniel J.; Ishmael, Jane E.; Leid, Mark

    2010-01-01

    Two novel and related C2H2 zinc finger proteins that are highly expressed in the brain, CTIP1 and CTIP2 (COUP TF-interacting proteins 1 and 2, respectively), were isolated and shown to interact with all members of the chicken ovalbumin upstream promoter transcription factor (COUP-TF) subfamily of orphan nuclear receptors. The interaction of CTIP1 with ARP1 was studied in detail, and CTIP1 was found to harbor two independent ARP1 interaction domains, ID1 and ID2, whereas the putative AF-2 of ARP1 was required for interaction with CTIP1. CTIP1, which exhibited a punctate staining pattern within the nucleus of transfected cells, recruited cotransfected ARP1 to these foci and potentiated ARP1-mediated transcriptional repression of a reporter construct. However, transcriptional repression mediated by ARP1 acting through CTIP1 did not appear to involve recruitment of a trichostatin A-sensitive histone deacetylase(s) to the template, suggesting that this repression pathway may be distinct from that utilized by several other nuclear receptors. PMID:10744719

  14. Animal behavior: the orphan rebellion.

    PubMed

    Nieh, James C

    2012-04-24

    After their queen has left with a swarm, orphaned larvae exhibiting rebel traits emerge in honeybee colonies. As adults, these orphans have reduced food glands to feed the colony's larvae and more developed ovaries to selfishly reproduce their own offspring. PMID:22537633

  15. Orphan drugs: the regulatory environment.

    PubMed

    Franco, Pedro

    2013-02-01

    The definition of a rare disease is not universal and depends on the legislation and policies adopted by each region or country. The main objective of this article is to describe and discuss the legal framework and the regulatory environment of orphan drugs worldwide. Some reflections and discussions on the need for specific orphan drug legislation or policies are described at length. Furthermore, some aspects of the history of each region in respect of the orphan drug legislation evolution are outlined. This article describes and compares the orphan drug legislation or policies of the following countries or regions: United Sates of America (US), European Union (EU), Japan, Australia, Singapore, Taiwan and Canada. The incentives described in the orphan drug legislations or policies, the criteria for designation of orphan status and the authorisation process of an orphan drug are also described and compared. The legislations and policies are to some extent similar but not the same. It is important to understand the main differences among all available legislative systems to improve the international collaboration in the field of orphan drugs and rare diseases.

  16. Orphan penumbrae: Submerging horizontal fields

    NASA Astrophysics Data System (ADS)

    Jurčák, J.; Bellot Rubio, L. R.; Sobotka, M.

    2014-04-01

    Aims: We investigate the properties of orphan penumbrae, which are photospheric filamentary structures observed in active regions near polarity inversion lines that resemble the penumbra of regular sunspots but are not connected to any umbra. Methods: We use Hinode data from the Solar Optical Telescope to determine the properties of orphan penumbrae. Spectropolarimetric data are employed to obtain the vector magnetic field and line-of-sight velocities in the photosphere. Magnetograms are used to study the overall evolution of these structures, and G-band and Ca ii H filtergrams are to investigate their brightness and apparent horizontal motions. Results: Orphan penumbrae form between regions of opposite polarity in places with horizontal magnetic fields. Their magnetic configuration is that of Ω-shaped flux ropes. In the two cases studied here, the opposite-polarity regions approach each other with time and the whole structure submerges as the penumbral filaments disappear. Orphan penumbrae are very similar to regular penumbrae, including the existence of strong gas flows. Therefore, they could have a similar origin. The main difference between them is the absence of a "background" magnetic field in orphan penumbrae. This could explain most of the observed differences. Conclusions: The fast flows we detect in orphan penumbrae may be caused by the siphon flow mechanism. Based on the similarities between orphan and regular penumbrae, we propose that the Evershed flow is also a manifestation of siphon flows. A movie attached to Fig. 11 is available in electronic form at http://www.aanda.org

  17. Chromosomal mapping of the human and murine orphan receptors ERRalpha (ESRRA) and ERRbeta (ESRRB) and identification of a novel human ERRalpha-related pseudogene.

    PubMed

    Sladek, R; Beatty, B; Squire, J; Copeland, N G; Gilbert, D J; Jenkins, N A; Giguère, V

    1997-10-15

    The estrogen-related receptors ERRalpha and ERRbeta (formerly ERR1 and ERR2) form a subgroup of the steroid/thyroid/retinoid receptor family. ERRalpha and ERRbeta are homologous to the estrogen receptor and bind similar DNA targets; however, they are unable to activate gene transcription in response to estrogens. We have used interspecific backcross analysis to map the murine Estrra locus to chromosome 19 and Estrrb to mouse chromosome 12. Using fluorescence in situ hybridization, we have mapped the human ESRRA gene to chromosome 11q12-q13 and the human ESRRB gene to chromosome 14q24.3. In addition, we report the isolation of a processed human ERRalpha pseudogene mapping to chromosome 13q12.1. To our knowledge, this represents the first report of a pseudogene associated with a member of the nuclear receptor superfamily.

  18. The Benzenesulfoamide T0901317 [N-(2,2,2-Trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide] Is a Novel Retinoic Acid Receptor-Related Orphan Receptor-α/γ Inverse Agonist

    PubMed Central

    Kumar, Naresh; Solt, Laura A.; Conkright, Juliana J.; Wang, Yongjun; Istrate, Monica A.; Busby, Scott A.; Garcia-Ordonez, Ruben D.; Burris, Thomas P.

    2010-01-01

    Retinoic acid receptor-related orphan receptors (RORs) regulate a variety of physiological processes including hepatic gluconeogenesis, lipid metabolism, circadian rhythm, and immune function. Here we present the first high-affinity synthetic ligand for both RORα and RORγ. In a screen against all 48 human nuclear receptors, the benzenesulfonamide liver X receptor (LXR) agonist N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide (T0901317) inhibited transactivation activity of RORα and RORγ but not RORβ. T0901317 was found to directly bind to RORα and RORγ with high affinity (Ki = 132 and 51 nM, respectively), resulting in the modulation of the receptor's ability to interact with transcriptional cofactor proteins. T0901317 repressed RORα/γ-dependent transactivation of ROR-responsive reporter genes and in HepG2 cells reduced recruitment of steroid receptor coactivator-2 by RORα at an endogenous ROR target gene (G6Pase). Using small interference RNA, we demonstrate that repression of the gluconeogenic enzyme glucose-6-phosphatase in HepG2 cells by T0901317 is ROR-dependent and is not due to the compound's LXR activity. In summary, T0901317 represents a novel chemical probe to examine RORα/γ function and an excellent starting point for the development of ROR selective modulators. More importantly, our results demonstrate that small molecules can be used to target the RORs for therapeutic intervention in metabolic and immune disorders. PMID:19887649

  19. Drug repositioning for orphan diseases.

    PubMed

    Sardana, Divya; Zhu, Cheng; Zhang, Minlu; Gudivada, Ranga C; Yang, Lun; Jegga, Anil G

    2011-07-01

    The need and opportunity to discover therapeutics for rare or orphan diseases are enormous. Due to limited prevalence and/or commercial potential, of the approximately 6000 orphan diseases (defined by the FDA Orphan Drug Act as <200 000 US prevalence), only a small fraction (5%) is of interest to the biopharmaceutical industry. The fact that drug development is complicated, time-consuming and expensive with extremely low success rates only adds to the low rate of therapeutics available for orphan diseases. An alternative and efficient strategy to boost the discovery of orphan disease therapeutics is to find connections between an existing drug product and orphan disease. Drug Repositioning or Drug Repurposing--finding a new indication for a drug--is one way to maximize the potential of a drug. The advantages of this approach are manifold, but rational drug repositioning for orphan diseases is not trivial and poses several formidable challenges--pharmacologically and computationally. Most of the repositioned drugs currently in the market are the result of serendipity. One reason the connection between drug candidates and their potential new applications are not identified in an earlier or more systematic fashion is that the underlying mechanism 'connecting' them is either very intricate and unknown or indirect or dispersed and buried in an ever-increasing sea of information, much of which is emerging only recently and therefore is not well organized. In this study, we will review some of these issues and the current methodologies adopted or proposed to overcome them and translate chemical and biological discoveries into safe and effective orphan disease therapeutics.

  20. The Detectability of Orphan Afterglows

    NASA Astrophysics Data System (ADS)

    Nakar, Ehud; Piran, Tsvi; Granot, Jonathan

    2002-11-01

    The realization that gamma-ray bursts (GRBs) release a constant amount of energy implies that post-jet-break afterglow evolution is 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 (mlim=25), orphan afterglows will typically be detected from small (~10°) angles away from the GRB jet axis. A detected orphan afterglow generally corresponds to a ``near miss'' of a GRB whose jet is pointing just slightly away from us. With our most optimistic parameters, we expect that 15 orphan afterglows will be recorded in the Sloan Digital Sky Survey, and 35 transients will be recorded in a dedicated 2 m 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 a larger area, rather than deeper. The limiting magnitude should not be, however, lower than ~23, 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 mlim=23, 25, and 27, respectively.

  1. Apolipoprotein M regulates the orphan nuclear receptor LRH-1 gene expression through binding to its promoter region in HepG2 cells

    PubMed Central

    Pan, Yi; Zhou, Hou-gang; Zhou, Hui; Hu, Min; Tang, Li-jun

    2015-01-01

    Apolipoprotein M (ApoM) is predominantly located in the high-density lipoprotein in human plasma. It has been demonstrated that ApoM expression could be regulated by several crucial nuclear receptors that are involved in the bile acid metabolism. In the present study, by combining gene-silencing experiments, overexpression studies, and chromatin immunoprecipitation assays, we showed that ApoM positively regulated liver receptor homolog-1 (LRH-1) gene expression via direct binding to an LRH-1 promoter region (nucleotides −406/ −197). In addition, we investigated the effects of farnesoid X receptor agonist GW4064 on hepatic ApoM expression in vitro. In HepG2 cell cultures, both mRNA and protein levels of ApoM and LRH-1 were decreased in a time-dependent manner in the presence of 1 μM GW4064, and the inhibition effect was gradually attenuated after 24 hours. In conclusion, our findings present supportive evidence that ApoM is a regulator of human LRH-1 transcription, and further reveal the importance of ApoM as a critical regulator of bile acids metabolism. PMID:25987835

  2. Apolipoprotein M regulates the orphan nuclear receptor LRH-1 gene expression through binding to its promoter region in HepG2 cells.

    PubMed

    Pan, Yi; Zhou, Hou-gang; Zhou, Hui; Hu, Min; Tang, Li-jun

    2015-01-01

    Apolipoprotein M (ApoM) is predominantly located in the high-density lipoprotein in human plasma. It has been demonstrated that ApoM expression could be regulated by several crucial nuclear receptors that are involved in the bile acid metabolism. In the present study, by combining gene-silencing experiments, overexpression studies, and chromatin immunoprecipitation assays, we showed that ApoM positively regulated liver receptor homolog-1 (LRH-1) gene expression via direct binding to an LRH-1 promoter region (nucleotides -406/ -197). In addition, we investigated the effects of farnesoid X receptor agonist GW4064 on hepatic ApoM expression in vitro. In HepG2 cell cultures, both mRNA and protein levels of ApoM and LRH-1 were decreased in a time-dependent manner in the presence of 1 μM GW4064, and the inhibition effect was gradually attenuated after 24 hours. In conclusion, our findings present supportive evidence that ApoM is a regulator of human LRH-1 transcription, and further reveal the importance of ApoM as a critical regulator of bile acids metabolism.

  3. Discovery of 1-{4-[3-fluoro-4-((3s,6r)-3-methyl-1,1-dioxo-6-phenyl-[1,2]thiazinan-2-ylmethyl)-phenyl]-piperazin-1-yl}-ethanone (GNE-3500): a potent, selective, and orally bioavailable retinoic acid receptor-related orphan receptor C (RORc or RORγ) inverse agonist.

    PubMed

    Fauber, Benjamin P; René, Olivier; Deng, Yuzhong; DeVoss, Jason; Eidenschenk, Céline; Everett, Christine; Ganguli, Arunima; Gobbi, Alberto; Hawkins, Julie; Johnson, Adam R; La, Hank; Lesch, Justin; Lockey, Peter; Norman, Maxine; Ouyang, Wenjun; Summerhill, Susan; Wong, Harvey

    2015-07-01

    Retinoic acid receptor-related orphan receptor C (RORc, RORγ, or NR1F3) is a nuclear receptor that plays a major role in the production of interleukin (IL)-17. Considerable efforts have been directed toward the discovery of selective RORc inverse agonists as potential treatments of inflammatory diseases such as psoriasis and rheumatoid arthritis. Using the previously reported tertiary sulfonamide 1 as a starting point, we engineered structural modifications that significantly improved human and rat metabolic stabilities while maintaining a potent and highly selective RORc inverse agonist profile. The most advanced δ-sultam compound, GNE-3500 (27, 1-{4-[3-fluoro-4-((3S,6R)-3-methyl-1,1-dioxo-6-phenyl-[1,2]thiazinan-2-ylmethyl)-phenyl]-piperazin-1-yl}-ethanone), possessed favorable RORc cellular potency with 75-fold selectivity for RORc over other ROR family members and >200-fold selectivity over 25 additional nuclear receptors in a cell assay panel. The favorable potency, selectivity, in vitro ADME properties, in vivo PK, and dose-dependent inhibition of IL-17 in a PK/PD model support the evaluation of 27 in preclinical studies. PMID:26061388

  4. Angiotensin II Triggers Expression of the Adrenal Gland Zona Glomerulosa-Specific 3β-Hydroxysteroid Dehydrogenase Isoenzyme through De Novo Protein Synthesis of the Orphan Nuclear Receptors NGFIB and NURR1

    PubMed Central

    Ota, Takumi; Yamazaki, Fumiyoshi; Yarimizu, Daisuke; Okada, Kazuki; Murai, Iori; Hayashi, Hida; Kunisue, Sumihiro; Nakagawa, Yuuki; Okamura, Hitoshi

    2014-01-01

    The 3β-hydroxysteroid dehydrogenase (3β-HSD) is an enzyme crucial for steroid synthesis. Two different 3β-HSD isoforms exist in humans. Classically, HSD3B2 was considered the principal isoform present in the adrenal. However, we recently showed that the alternative isoform, HSD3B1, is expressed specifically within the adrenal zona glomerulosa (ZG), where aldosterone is produced, raising the question of why this isozyme needs to be expressed in this cell type. Here we show that in both human and mouse, expression of the ZG isoform 3β-HSD is rapidly induced upon angiotensin II (AngII) stimulation. AngII is the key peptide hormone regulating the capacity of aldosterone synthesis. Using the human adrenocortical H295R cells as a model system, we show that the ZG isoform HSD3B1 differs from HSD3B2 in the ability to respond to AngII. Mechanistically, the induction of HSD3B1 involves de novo protein synthesis of the nuclear orphan receptors NGFIB and NURR1. The HSD3B1 promoter contains a functional NGFIB/NURR1-responsive element to which these proteins bind in response to AngII. Knockdown of these proteins and overexpression of a dominant negative NGFIB both reduce the AngII responsiveness of HSD3B1. Thus, the AngII-NGFIB/NURR1 pathway controls HSD3B1. Our work reveals HSD3B1 as a new regulatory target of AngII. PMID:25092869

  5. ERα/E2 signaling suppresses the expression of steroidogenic enzyme genes via cross-talk with orphan nuclear receptor Nur77 in the testes.

    PubMed

    Lee, Seung-Yon; Park, Eunsook; Kim, Seung-Chang; Ahn, Ryun-Sup; Ko, CheMyong; Lee, Keesook

    2012-10-15

    Estrogen receptor alpha (ERα) has been reported to affect steroidogenesis in testicular Leydig cells, but its molecular mechanism remains unclear. Here, we investigate the effect of estrogen and ERα on Nur77, a major transcription factor that regulates the expression of steroidogenic enzyme genes. In MA-10 Leydig cells, estradiol (E2) treatment, and interestingly ERα overexpression, suppressed the cAMP-induced and Nur77-activated promoter activity of steroidogenic enzyme genes via the suppression of Nur77 transactivation. ERα physically interacted with Nur77 and inhibited its DNA binding activity. In addition, ERα/E2 signaling decreased Nur77 protein levels. Consistent with the above results, the testicular testosterone level was higher in Leydig cell-specific ERα knock-out mice (ERα(flox/flox)Cyp17iCre) than in wild-type mice (ERα(flox/flox)). Taken together, these results suggest that ERα/E2 signaling controls the Nur77-mediated expression of steroidogenic enzyme genes in Leydig cells. These findings may provide a mechanistic explanation for the local regulation of testicular steroidogenesis by estrogenic compounds and ERα.

  6. Novel reciprocal regulation of cAMP signaling and apoptosis by orphan G-protein-coupled receptor GPRC5A gene expression

    SciTech Connect

    Hirano, Minoru; Zang, Liqing; Oka, Takehiko; Ito, Yoshiyuki; Shimada, Yasuhito; Nishimura, Yuhei; Tanaka, Toshio . E-mail: tanaka@doc.medic.mie-u.ac.jp

    2006-12-08

    GPRC5A is a member of G-protein-coupled receptors, which was originally identified as an all-trans-retinoic acid-induced gene. Although recent studies reported that this gene was highly expressed in the cancer cell lines and that GPRC5A might positively regulate cell proliferation, its mechanism remains unknown. We investigated the upstream and downstream signaling of GPRC5A and its biological function, and found that cAMP signaling is the novel GPRC5A induction pathway. When GPRC5A gene was overexpressed, intracellular cAMP concentration was decreased, and Gs{alpha} gene expression was downregulated. On the other hand, RNA interference of GPRC5A increased mRNA levels of Gs{alpha} and intracellular cAMP, reduced cell number, and induced apoptosis. Conversely, cell number was increased by GPRC5A overexpression. We first report the novel negative feedback model of cAMP signaling through GPRC5A gene expression. This evidence explains one of the mechanisms of the GPRC5A-regulated cell growth in some cancer cell lines.

  7. The orphan nuclear receptor NUR77 regulates hormone-induced StAR transcription in Leydig cells through cooperation with Ca2+/calmodulin-dependent protein kinase I.

    PubMed

    Martin, Luc J; Boucher, Nicolas; Brousseau, Catherine; Tremblay, Jacques J

    2008-09-01

    Cholesterol transport in the mitochondrial membrane, an essential step of steroid biosynthesis, is mediated by a protein complex containing the steroidogenic acute regulatory (StAR) protein. The importance of this transporter is underscored by mutations in the human StAR gene that cause lipoid congenital adrenal hyperplasia, male pseudohermaphroditism, and adrenal insufficiency. StAR transcription in steroidogenic cells is hormonally regulated and involves several transcription factors. The nuclear receptor NUR77 is present in steroidogenic cells, and its expression is induced by hormones known to activate StAR expression. We have now established that StAR transcription in cAMP-stimulated Leydig cells requires de novo protein synthesis and involves NUR77. We found that cAMP-induced NUR77 expression precedes that of StAR both at the mRNA and protein levels in Leydig cells. In these cells, small interfering RNA-mediated NUR77 knockdown reduces cAMP-induced StAR expression. Chromatin immunoprecipitation assays revealed a cAMP-dependent increase in NUR77 recruitment to the proximal StAR promoter, whereas transient transfections in MA-10 Leydig cells confirmed that NUR77 can activate the StAR promoter and that this requires an element located at -95 bp. cAMP-induced StAR and NUR77 expression in Leydig cells was found to require a Ca2+/calmodulin-dependent protein kinase (CaMK)-dependent signaling pathway. Consistent with this, we show that within the testis, CaMKI is specifically expressed in Leydig cells. Finally, we report that CaMKI transcriptionally cooperates with NUR77, but not steroidogenic factor 1, to further enhance StAR promoter activity in Leydig cells. All together, our results implicate NUR77 as a mediator of cAMP action on StAR transcription in steroidogenic Leydig cells and identify a role for CaMKI in this process.

  8. Orphan Trains in Iowa History.

    ERIC Educational Resources Information Center

    Frese, Millie K., Ed.

    2000-01-01

    The "Goldfinch" is a magazine that introduces children to different aspects of Iowa history. Each issue contains articles that provide in-depth knowledge of a topic about Iowa. The focus of this issue is orphan trains in Iowa it introduces readers to some of the people heroes of modern history who rode the trains west between 1854 and 1929 in…

  9. Orphan drugs: expensive yet necessary.

    PubMed

    Hyry, H I; Roos, J C P; Cox, T M

    2015-04-01

    Whether the prices of certain orphan treatments are justified is highly controversial. One argument is that such therapies should not be funded through the public purse or private health plans because a patient with a rare disease requires more than their 'fair share' of a limited health care budget. Orphan medications can also be denied because they fare poorly in the cost-effectiveness assessments of drugs. This paper takes the unusual line that life-saving treatments should be provided regardless of their cost. This contention is based on the Harvard philosopher John Rawls' theory of justice. We offer three rules to limit the use of cost-effectiveness approaches: efficiency assessments should not be deployed (i) when the choice is between an only treatment and no treatment, or to (ii) prioritise between different patients and patient groups. However a well considered cost efficiency calculation may have its place (iii) where a patient has a choice between two or more equally safe and effective treatments. We rebut potential objections to this analysis, and conclude that there has been a tendency to classify appeals for orphan treatments as a minority interest and in conflict with the aims of public health and society at large. Rawls' concept of societal justice shows that a distinction between the individual and society in this context is bogus. The funding of orphan therapies is as much a matter for public health as the funding of treatments for other conditions. Treatment must not be withheld on economic grounds. PMID:25434052

  10. Orphan drugs: expensive yet necessary.

    PubMed

    Hyry, H I; Roos, J C P; Cox, T M

    2015-04-01

    Whether the prices of certain orphan treatments are justified is highly controversial. One argument is that such therapies should not be funded through the public purse or private health plans because a patient with a rare disease requires more than their 'fair share' of a limited health care budget. Orphan medications can also be denied because they fare poorly in the cost-effectiveness assessments of drugs. This paper takes the unusual line that life-saving treatments should be provided regardless of their cost. This contention is based on the Harvard philosopher John Rawls' theory of justice. We offer three rules to limit the use of cost-effectiveness approaches: efficiency assessments should not be deployed (i) when the choice is between an only treatment and no treatment, or to (ii) prioritise between different patients and patient groups. However a well considered cost efficiency calculation may have its place (iii) where a patient has a choice between two or more equally safe and effective treatments. We rebut potential objections to this analysis, and conclude that there has been a tendency to classify appeals for orphan treatments as a minority interest and in conflict with the aims of public health and society at large. Rawls' concept of societal justice shows that a distinction between the individual and society in this context is bogus. The funding of orphan therapies is as much a matter for public health as the funding of treatments for other conditions. Treatment must not be withheld on economic grounds.

  11. Hunting for the function of orphan GPCRs – beyond the search for the endogenous ligand

    PubMed Central

    Ahmad, Raise; Wojciech, Stefanie; Jockers, Ralf

    2015-01-01

    Seven transmembrane-spanning proteins (7TM), also called GPCRs, are among the most versatile and evolutionary successful protein families. Out of the 400 non-odourant members identified in the human genome, approximately 100 remain orphans that have not been matched with an endogenous ligand. Apart from the classical deorphanization strategies, several alternative strategies provided recent new insights into the function of these proteins, which hold promise for high therapeutic potential. These alternative strategies consist of the phenotypical characterization of organisms silenced or overexpressing orphan 7TM proteins, the search for constitutive receptor activity and formation of protein complexes including 7TM proteins as well as the development of synthetic, surrogate ligands. Taken together, a variety of ligand-independent functions can be attributed to orphan 7TM proteins that range from constitutive activity to complex formation with other proteins and include ‘true’ orphans for which no ligand exist and ‘conditional’ orphans that behave like orphans in the absence of ligand and as non-orphans in the presence of ligand. PMID:25231237

  12. Saving orphan drug legislations: misconceptions and clarifications.

    PubMed

    Hyry, Hanna I; Cox, Timothy M; Roos, Jonathan C P

    2016-01-01

    Orphan-drug sales are rocketing, with revenue expected to total $176 billion annually by 2020. As a share of the industry, orphan drugs now account for close to 15% of all prescription revenue globally (excluding generics) and the sector is set to grow at more than twice the rate (10.5%) of the overall prescription market (4.3%). But this success also equates to costs--borne by individual patients and cash-strapped health systems. Prices for orphan drugs can be 19 times higher than for other medications, hampering access for patients, many of whom are children. With ever more such expensive drugs reaching the market, the situation is becoming unsustainable and putting the survival of the orphan drug legislation itself at risk. Here the authors consider why there has been an increase in orphan drug designations, how orphan drug prices are set and regulated, before discussing proposals for how changes which could save the legislation.

  13. Orphan neuropeptides. Novel neuropeptides modulating sleep or feeding.

    PubMed

    Chung, Shinjae; Civelli, Olivier

    2006-08-01

    Neuropeptides form the largest family of modulators of synaptic transmission. Until 1995 some 60 different neuropeptides had been found. With the recognition that all neuropeptides act by binding to G protein coupled receptors (GPCRs), a new approach relying on the use of orphan GPCRs as targets was designed to identify novel neuropeptides. Thirteen new neuropeptide families have since been discovered. In this review we will describe the orphan GPCR-based approach that led to these discoveries and present its impact on two specific physiological responses, feeding and sleep. In particular, we will discuss the modulatory roles of the hypocretins/orexins and of neuropeptide S in sleep and awakening and those of ghrelin and melanin concentrating hormone in food intake.

  14. C2-domain abscisic acid-related proteins mediate the interaction of PYR/PYL/RCAR abscisic acid receptors with the plasma membrane and regulate abscisic acid sensitivity in Arabidopsis.

    PubMed

    Rodriguez, Lesia; Gonzalez-Guzman, Miguel; Diaz, Maira; Rodrigues, Americo; Izquierdo-Garcia, Ana C; Peirats-Llobet, Marta; Fernandez, Maria A; Antoni, Regina; Fernandez, Daniel; Marquez, Jose A; Mulet, Jose M; Albert, Armando; Rodriguez, Pedro L

    2014-12-01

    Membrane-delimited abscisic acid (ABA) signal transduction plays a critical role in early ABA signaling, but the molecular mechanisms linking core signaling components to the plasma membrane are unclear. We show that transient calcium-dependent interactions of PYR/PYL ABA receptors with membranes are mediated through a 10-member family of C2-domain ABA-related (CAR) proteins in Arabidopsis thaliana. Specifically, we found that PYL4 interacted in an ABA-independent manner with CAR1 in both the plasma membrane and nucleus of plant cells. CAR1 belongs to a plant-specific gene family encoding CAR1 to CAR10 proteins, and bimolecular fluorescence complementation and coimmunoprecipitation assays showed that PYL4-CAR1 as well as other PYR/PYL-CAR pairs interacted in plant cells. The crystal structure of CAR4 was solved, which revealed that, in addition to a classical calcium-dependent lipid binding C2 domain, a specific CAR signature is likely responsible for the interaction with PYR/PYL receptors and their recruitment to phospholipid vesicles. This interaction is relevant for PYR/PYL function and ABA signaling, since different car triple mutants affected in CAR1, CAR4, CAR5, and CAR9 genes showed reduced sensitivity to ABA in seedling establishment and root growth assays. In summary, we identified PYR/PYL-interacting partners that mediate a transient Ca(2+)-dependent interaction with phospholipid vesicles, which affects PYR/PYL subcellular localization and positively regulates ABA signaling. PMID:25465408

  15. C2-domain abscisic acid-related proteins mediate the interaction of PYR/PYL/RCAR abscisic acid receptors with the plasma membrane and regulate abscisic acid sensitivity in Arabidopsis.

    PubMed

    Rodriguez, Lesia; Gonzalez-Guzman, Miguel; Diaz, Maira; Rodrigues, Americo; Izquierdo-Garcia, Ana C; Peirats-Llobet, Marta; Fernandez, Maria A; Antoni, Regina; Fernandez, Daniel; Marquez, Jose A; Mulet, Jose M; Albert, Armando; Rodriguez, Pedro L

    2014-12-01

    Membrane-delimited abscisic acid (ABA) signal transduction plays a critical role in early ABA signaling, but the molecular mechanisms linking core signaling components to the plasma membrane are unclear. We show that transient calcium-dependent interactions of PYR/PYL ABA receptors with membranes are mediated through a 10-member family of C2-domain ABA-related (CAR) proteins in Arabidopsis thaliana. Specifically, we found that PYL4 interacted in an ABA-independent manner with CAR1 in both the plasma membrane and nucleus of plant cells. CAR1 belongs to a plant-specific gene family encoding CAR1 to CAR10 proteins, and bimolecular fluorescence complementation and coimmunoprecipitation assays showed that PYL4-CAR1 as well as other PYR/PYL-CAR pairs interacted in plant cells. The crystal structure of CAR4 was solved, which revealed that, in addition to a classical calcium-dependent lipid binding C2 domain, a specific CAR signature is likely responsible for the interaction with PYR/PYL receptors and their recruitment to phospholipid vesicles. This interaction is relevant for PYR/PYL function and ABA signaling, since different car triple mutants affected in CAR1, CAR4, CAR5, and CAR9 genes showed reduced sensitivity to ABA in seedling establishment and root growth assays. In summary, we identified PYR/PYL-interacting partners that mediate a transient Ca(2+)-dependent interaction with phospholipid vesicles, which affects PYR/PYL subcellular localization and positively regulates ABA signaling.

  16. C2-Domain Abscisic Acid-Related Proteins Mediate the Interaction of PYR/PYL/RCAR Abscisic Acid Receptors with the Plasma Membrane and Regulate Abscisic Acid Sensitivity in Arabidopsis[C][W

    PubMed Central

    Rodriguez, Lesia; Diaz, Maira; Rodrigues, Americo; Izquierdo-Garcia, Ana C.; Peirats-Llobet, Marta; Fernandez, Maria A.; Antoni, Regina; Fernandez, Daniel; Marquez, Jose A.; Mulet, Jose M.; Albert, Armando; Rodriguez, Pedro L.

    2014-01-01

    Membrane-delimited abscisic acid (ABA) signal transduction plays a critical role in early ABA signaling, but the molecular mechanisms linking core signaling components to the plasma membrane are unclear. We show that transient calcium-dependent interactions of PYR/PYL ABA receptors with membranes are mediated through a 10-member family of C2-domain ABA-related (CAR) proteins in Arabidopsis thaliana. Specifically, we found that PYL4 interacted in an ABA-independent manner with CAR1 in both the plasma membrane and nucleus of plant cells. CAR1 belongs to a plant-specific gene family encoding CAR1 to CAR10 proteins, and bimolecular fluorescence complementation and coimmunoprecipitation assays showed that PYL4-CAR1 as well as other PYR/PYL-CAR pairs interacted in plant cells. The crystal structure of CAR4 was solved, which revealed that, in addition to a classical calcium-dependent lipid binding C2 domain, a specific CAR signature is likely responsible for the interaction with PYR/PYL receptors and their recruitment to phospholipid vesicles. This interaction is relevant for PYR/PYL function and ABA signaling, since different car triple mutants affected in CAR1, CAR4, CAR5, and CAR9 genes showed reduced sensitivity to ABA in seedling establishment and root growth assays. In summary, we identified PYR/PYL-interacting partners that mediate a transient Ca2+-dependent interaction with phospholipid vesicles, which affects PYR/PYL subcellular localization and positively regulates ABA signaling. PMID:25465408

  17. Current status of orphan disease drug development.

    PubMed

    Thoene, J G

    1994-04-01

    The Orphan Drug Act has successfully stimulated the production of many orphan products for a number of orphan diseases. The success of its exclusive marketing provision in bringing otherwise unprofitable products to market has attracted the attention of manufacturers who use this provision to gain a monopoly for products with much larger annual sales than were contemplated by the original legislation. Corrective legislation to close this loophole is being prepared for introduction to Congress.

  18. Orphan drug: Development trends and strategies

    PubMed Central

    Sharma, Aarti; Jacob, Abraham; Tandon, Manas; Kumar, Dushyant

    2010-01-01

    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. PMID:21180460

  19. Historical overview of nuclear receptors.

    PubMed

    Gustafsson, Jan-Ake

    2016-03-01

    This review summarizes the birth of the field of nuclear receptors, from Jensen's discovery of estrogen receptor alpha, Gustafsson's discovery of the three-domain structure of the glucocorticoid receptor, the discovery of the glucocorticoid response element and the first partial cloning of the glucocorticoid receptor. Furthermore the discovery of the novel receptors called orphan receptors is described.

  20. World health dilemmas: Orphan and rare diseases, orphan drugs and orphan patients

    PubMed Central

    Kontoghiorghe, Christina N; Andreou, Nicholas; Constantinou, Katerina; Kontoghiorghes, George J

    2014-01-01

    According to global annual estimates hunger/malnutrition is the major cause of death (36 of 62 million). Cardiovascular diseases and cancer (5.44 of 13.43 million) are the major causes of death in developed countries, while lower respiratory tract infections, human immunodeficiency virus infection/acquired immunodeficiency syndrome, diarrhoeal disease, malaria and tuberculosis (10.88 of 27.12 million) are the major causes of death in developing countries with more than 70% of deaths occurring in children. The majority of approximately 800 million people with other rare diseases, including 100000 children born with thalassaemia annually receive no treatment. There are major ethical dilemmas in dealing with global health issues such as poverty and the treatment of orphan and rare diseases. Of approximately 50000 drugs about 10% are orphan drugs, with annual sales of the latter approaching 100 billion USD. In comparison, the annual revenue in 2009 from the top 12 pharmaceutical companies in Western countries was 445 billion USD and the top drug, atorvastatin, reached 100 billion USD. In the same year, the total government expenditure for health in the developing countries was 410 billion USD with only 6%-7% having been received as aid from developed countries. Drugs cost the National Health Service in the United Kingdom more than 20 billion USD or 10% of the annual health budget. Uncontrollable drug prices and marketing policies affect global health budgets, clinical practice, patient safety and survival. Fines of 5.3 billion USD were imposed on two pharmaceutical companies in the United States, the regulatory authority in France was replaced and clinicians were charged with bribery in order to overcome recent illegal practises affecting patient care. High expenditure for drug development is mainly related to marketing costs. However, only 2 million USD was spent developing the drug deferiprone (L1) for thalassaemia up to the stage of multicentre clinical trials. The

  1. World health dilemmas: Orphan and rare diseases, orphan drugs and orphan patients.

    PubMed

    Kontoghiorghe, Christina N; Andreou, Nicholas; Constantinou, Katerina; Kontoghiorghes, George J

    2014-09-26

    According to global annual estimates hunger/malnutrition is the major cause of death (36 of 62 million). Cardiovascular diseases and cancer (5.44 of 13.43 million) are the major causes of death in developed countries, while lower respiratory tract infections, human immunodeficiency virus infection/acquired immunodeficiency syndrome, diarrhoeal disease, malaria and tuberculosis (10.88 of 27.12 million) are the major causes of death in developing countries with more than 70% of deaths occurring in children. The majority of approximately 800 million people with other rare diseases, including 100000 children born with thalassaemia annually receive no treatment. There are major ethical dilemmas in dealing with global health issues such as poverty and the treatment of orphan and rare diseases. Of approximately 50000 drugs about 10% are orphan drugs, with annual sales of the latter approaching 100 billion USD. In comparison, the annual revenue in 2009 from the top 12 pharmaceutical companies in Western countries was 445 billion USD and the top drug, atorvastatin, reached 100 billion USD. In the same year, the total government expenditure for health in the developing countries was 410 billion USD with only 6%-7% having been received as aid from developed countries. Drugs cost the National Health Service in the United Kingdom more than 20 billion USD or 10% of the annual health budget. Uncontrollable drug prices and marketing policies affect global health budgets, clinical practice, patient safety and survival. Fines of 5.3 billion USD were imposed on two pharmaceutical companies in the United States, the regulatory authority in France was replaced and clinicians were charged with bribery in order to overcome recent illegal practises affecting patient care. High expenditure for drug development is mainly related to marketing costs. However, only 2 million USD was spent developing the drug deferiprone (L1) for thalassaemia up to the stage of multicentre clinical trials. The

  2. 21 CFR 316.24 - Granting orphan-drug designation.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Granting orphan-drug designation. 316.24 Section 316.24 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Designation of an Orphan Drug § 316.24 Granting orphan-drug...

  3. 21 CFR 316.24 - Granting orphan-drug designation.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 5 2012-04-01 2012-04-01 false Granting orphan-drug designation. 316.24 Section 316.24 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Designation of an Orphan Drug § 316.24 Granting orphan-drug...

  4. 21 CFR 316.24 - Granting orphan-drug designation.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 5 2011-04-01 2011-04-01 false Granting orphan-drug designation. 316.24 Section 316.24 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Designation of an Orphan Drug § 316.24 Granting orphan-drug...

  5. 21 CFR 316.24 - Granting orphan-drug designation.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 5 2013-04-01 2013-04-01 false Granting orphan-drug designation. 316.24 Section 316.24 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Designation of an Orphan Drug § 316.24 Granting orphan-drug...

  6. 21 CFR 316.36 - Insufficient quantities of orphan drugs.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Insufficient quantities of orphan drugs. 316.36... (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Orphan-drug Exclusive Approval § 316.36 Insufficient quantities of orphan drugs. (a) Under section 527 of the act, whenever the Director has reason to believe...

  7. The Orphan among Us: An Examination of Orphans in Newbery Award Winning Literature

    ERIC Educational Resources Information Center

    Mattix, April A.

    2012-01-01

    Orphan stories in children's literature are rich and complex, and they have historically permeated the pages of children's books. The purpose of this study was to explore the use of orphans as protagonists in children's award-winning literature through content analysis. This study utilizes all the Newbery Award winning books…

  8. Detail view of headframe, from within the Orphan Mine Site, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Detail view of headframe, from within the Orphan Mine Site, view to east-southeast - Orphan Lode Mine, Headframe, North of West Rim Road between Powell Point and Maricopa Point, South Rim, Grand Canyon Village, Coconino County, AZ

  9. Detail view of headframe, from within the Orphan Mine Site, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Detail view of headframe, from within the Orphan Mine Site, view to the north - Orphan Lode Mine, Headframe, North of West Rim Road between Powell Point and Maricopa Point, South Rim, Grand Canyon Village, Coconino County, AZ

  10. Detail view of headframe, from within the Orphan Mine Site, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Detail view of headframe, from within the Orphan Mine Site, view to the northwest - Orphan Lode Mine, Headframe, North of West Rim Road between Powell Point and Maricopa Point, South Rim, Grand Canyon Village, Coconino County, AZ

  11. View of headframe, from within the Orphan Mine Site, view ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    View of headframe, from within the Orphan Mine Site, view to the east - Orphan Lode Mine, Headframe, North of West Rim Road between Powell Point and Maricopa Point, South Rim, Grand Canyon Village, Coconino County, AZ

  12. Financing drug discovery for orphan diseases.

    PubMed

    Fagnan, David E; Gromatzky, Austin A; Stein, Roger M; Fernandez, Jose-Maria; Lo, Andrew W

    2014-05-01

    Recently proposed 'megafund' financing methods for funding translational medicine and drug development require billions of dollars in capital per megafund to de-risk the drug discovery process enough to issue long-term bonds. Here, we demonstrate that the same financing methods can be applied to orphan drug development but, because of the unique nature of orphan diseases and therapeutics (lower development costs, faster FDA approval times, lower failure rates and lower correlation of failures among disease targets) the amount of capital needed to de-risk such portfolios is much lower in this field. Numerical simulations suggest that an orphan disease megafund of only US$575 million can yield double-digit expected rates of return with only 10-20 projects in the portfolio. PMID:24269746

  13. Financing drug discovery for orphan diseases.

    PubMed

    Fagnan, David E; Gromatzky, Austin A; Stein, Roger M; Fernandez, Jose-Maria; Lo, Andrew W

    2014-05-01

    Recently proposed 'megafund' financing methods for funding translational medicine and drug development require billions of dollars in capital per megafund to de-risk the drug discovery process enough to issue long-term bonds. Here, we demonstrate that the same financing methods can be applied to orphan drug development but, because of the unique nature of orphan diseases and therapeutics (lower development costs, faster FDA approval times, lower failure rates and lower correlation of failures among disease targets) the amount of capital needed to de-risk such portfolios is much lower in this field. Numerical simulations suggest that an orphan disease megafund of only US$575 million can yield double-digit expected rates of return with only 10-20 projects in the portfolio.

  14. Enriching Orphans' Potentials through Interpersonal and Intrapersonal Intelligence Enrichment Activities

    ERIC Educational Resources Information Center

    Azid, Nurulwahida Hj; Yaacob, Aizan

    2016-01-01

    Orphans are considered a minority and they should be given a greater emphasis so that they do not feel left out and can build their own lives without a sense of humility. This does not mean that the orphans should be pampered instead they should be given the confidence and motivation to strive for success in later life. Humility among orphans can…

  15. Exploring the Relationship between Caregiving and Health: Perceptions among Orphaned and Non-Orphaned Adolescents in Tanzania

    ERIC Educational Resources Information Center

    Mmari, Kristin

    2011-01-01

    The objectives of this study were to (1) explore the nature of caregiving for orphaned and non-orphaned adolescents; and (2), examine how changes in the caretaking roles, as a result of a parental loss, impact on an orphan's sexual behaviors. A total of 52 in-depth interviews and 11 focus group discussions (n = 83) were conducted among adolescent…

  16. 78 FR 35117 - Orphan Drug Regulations

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-12

    ... previous factors, FDA currently considers pneumonia in cystic fibrosis patients to be a different ``disease...,000, sponsors seeking orphan-drug designation for a drug for pneumonia in cystic fibrosis patients... other words, provide a rationale for why only cystic fibrosis patients with pneumonia (and not...

  17. The African Orphan Crisis and International Adoption

    ERIC Educational Resources Information Center

    Roby, Jini L.; Shaw, Stacey A.

    2006-01-01

    The plight of Africa's AIDS orphans has reached crisis proportions, and the international community is beginning to mobilize at the family, community, national, and international levels. Despite these encouraging efforts, the response is inadequate, and increased attention and action are needed. The authors suggest that international adoption,…

  18. Nuclear Receptors, RXR, and the Big Bang.

    PubMed

    Evans, Ronald M; Mangelsdorf, David J

    2014-03-27

    Isolation of genes encoding the receptors for steroids, retinoids, vitamin D, and thyroid hormone and their structural and functional analysis revealed an evolutionarily conserved template for nuclear hormone receptors. This discovery sparked identification of numerous genes encoding related proteins, termed orphan receptors. Characterization of these orphan receptors and, in particular, of the retinoid X receptor (RXR) positioned nuclear receptors at the epicenter of the "Big Bang" of molecular endocrinology. This Review provides a personal perspective on nuclear receptors and explores their integrated and coordinated signaling networks that are essential for multicellular life, highlighting the RXR heterodimer and its associated ligands and transcriptional mechanism.

  19. Nuclear Receptors, RXR & the Big Bang

    PubMed Central

    Evans, Ronald M.; Mangelsdorf, David J.

    2014-01-01

    Summary Isolation of genes encoding the receptors for steroids, retinoids, vitamin D and thyroid hormone, and their structural and functional analysis revealed an evolutionarily conserved template for nuclear hormone receptors. This discovery sparked identification of numerous genes encoding related proteins, termed orphan receptors. Characterization of these orphan receptors, and in particular of the retinoid X receptor (RXR), positioned nuclear receptors at the epicenter of the “Big Bang” of molecular endocrinology. This review provides a personal perspective on nuclear receptors and explores their integrated and coordinated signaling networks that are essential for multi-cellular life, highlighting the RXR heterodimer and its associated ligands and transcriptional mechanism. PMID:24679540

  20. Nuclear Receptors, RXR, and the Big Bang.

    PubMed

    Evans, Ronald M; Mangelsdorf, David J

    2014-03-27

    Isolation of genes encoding the receptors for steroids, retinoids, vitamin D, and thyroid hormone and their structural and functional analysis revealed an evolutionarily conserved template for nuclear hormone receptors. This discovery sparked identification of numerous genes encoding related proteins, termed orphan receptors. Characterization of these orphan receptors and, in particular, of the retinoid X receptor (RXR) positioned nuclear receptors at the epicenter of the "Big Bang" of molecular endocrinology. This Review provides a personal perspective on nuclear receptors and explores their integrated and coordinated signaling networks that are essential for multicellular life, highlighting the RXR heterodimer and its associated ligands and transcriptional mechanism. PMID:24679540

  1. An evolutionary analysis of orphan genes in Drosophila.

    PubMed

    Domazet-Loso, Tomislav; Tautz, Diethard

    2003-10-01

    Orphan genes are protein-coding regions that have no recognizable homolog in distantly related species. A substantial fraction of coding regions in any genome sequenced consists of orphan genes, but the evolutionary and functional significance of orphan genes is not understood. We present a reanalysis of the Drosophila melanogaster proteome that shows that there are still between 26% and 29% of all proteins without a significant match with noninsect sequences, and that these orphans are underrepresented in genetic screens. To analyze the characteristics of orphan genes in Drosophila, we used sequence comparisons between cDNAs retrieved from two Drosophila yakuba libraries and their corresponding D. melanogaster orthologs. We find that a cDNA library from adults yields twice as many orphan genes as such a library from embryos. The orphan genes evolve on average more than three times faster than nonorphan genes, although the width of the evolutionary rate distribution is similar for the two classes. In particular, some orphan genes show very low substitution rates that are comparable to otherwise highly conserved genes. We propose a model suggesting that orphans may be involved in the evolution of adaptive traits, and that slow-evolving orphan genes may be particularly interesting candidate genes for identifying lineage-specific adaptations.

  2. Orphan enzymes in ether lipid metabolism.

    PubMed

    Watschinger, Katrin; Werner, Ernst R

    2013-01-01

    Ether lipids are an emerging class of lipids which have so far not been investigated and understood in every detail. They have important roles as membrane components of e.g. lens, brain and testis, and as mediators such as platelet-activating factor. The metabolic enzymes for biosynthesis and degradation have been investigated to some extent. As most involved enzymes are integral membrane proteins they are tricky to handle in biochemical protocols. The sequence of some ether lipid metabolising enzymes has only recently been reported and other sequences still remain obscure. Defined enzymes without assigned sequence are known as orphan enzymes. One of these enzymes with uncharacterised sequence is plasmanylethanolamine desaturase, a key enzyme for the biosynthesis of one of the most abundant phospholipids in our body, the plasmalogens. This review aims to briefly summarise known functions of ether lipids, give an overview on their metabolism including the most prominent members, platelet-activating factor and the plasmalogens. A special focus is set on the description of orphan enzymes in ether lipid metabolism and on the successful strategies how four previous orphans have recently been assigned a sequence. Only one of these four was characterised by classical protein purification and sequencing, whereas the other three required alternative strategies such as bioinformatic candidate gene selection and recombinant expression or development of an inhibitor and multidimensional metabolic profiling.

  3. Orphan radon daughters at Denver Radium site

    SciTech Connect

    Holub, R.F.; Droullard, R.F.; Davis, T.H.

    1992-12-31

    During 18 mo of sampling airborne radioactively at a National Priority List ({open_quotes}Superfund{close_quotes}) site in metroPOlitan Denver, Bureau of mines personnel discovered radon daughters that are not supported by the parent radon gas. We refer to them as {open_quotes}orphan{close_quotes} daughters because the parent, radon, is not present in sufficient concentration to support the measured daughter products. Measurements of the {open_quotes}orphan{close_quotes} daughters were made continuously, using the Bureau-developed radon and working-level (radon-daughter) monitors. The data showed high equilibrium ratios, ranging from 0.7 to 3.5, for long periods of time. Repeated, high-volume, 15-min grab samples were made, using the modified Tsivoglou method, to measure radon daughters, to which thoron daughters contributed 26 {+-} 12%. On average 28 {+-} 6% of the particulate activity was contributed by thoron daughters. Most samples were mixtures in which the {sup 218}Po concentration was lower than that of {sup 214}Pb and {sup 214}Bi, in agreement with the high-equilibrium factors obtained from the continuous sampling data. In view of the short half-life of radon progeny, we conclude that the source of the orphan daughters is not far from the Superfund sites. The mechanism of this phenomenon is not understood at this time, but we will discuss its possible significance in evaluating population doses.

  4. Development of orphan vaccines: an industry perspective.

    PubMed Central

    Lang, J.; Wood, S. C.

    1999-01-01

    The development of vaccines against rare emerging infectious diseases is hampered by many disincentives. In the face of growing in-house expenditures associated with research and development projects in a complex legal and regulatory environment, most pharmaceutical companies prioritize their projects and streamline their product portfolio. Nevertheless, for humanitarian reasons, there is a need to develop niche vaccines for rare diseases not preventable or curable by other means. The U.S. Orphan Drug Act of 1983 and a similar proposal from the European Commission (currently under legislative approval) provide financial and practical incentives for the research and development of drugs to treat rare diseases. In addition, updated epidemiologic information from experts in the field of emerging diseases; increased disease awareness among health professionals, patients, and the general public; a list of priority vaccines; emergence of a dedicated organization with strong leadership; and the long-term pharmacoeconomic viability of orphan products will be key factors in overcoming the complexity of orphan status and the limited need for vaccine. PMID:10603207

  5. An Orphan No Longer? Detection of the Southern Orphan Stream and a Candidate Progenitor

    NASA Astrophysics Data System (ADS)

    Grillmair, Carl J.; Hetherington, Lauren; Carlberg, Raymond G.; Willman, Beth

    2015-10-01

    Using a shallow, two-color survey carried out with the Dark Energy Camera, we detect the southern, possibly trailing arm of the Orphan Stream. The stream is reliably detected to a decl. of ‑38°, bringing the total known length of the Orphan Stream to 108°. We find a slight offset or “S” shape in the stream at δ ≃ ‑14° that would be consistent with the transition from leading to trailing arms. This coincides with a moderate concentration of 137 ± 25 stars (to g = 21.6) that we consider a possible remnant of the Orphan progenitor. The position of this feature is in agreement with previous predictions.

  6. Access to orphan drugs despite poor quality of clinical evidence

    PubMed Central

    Dupont, Alain G; Van Wilder, Philippe B

    2011-01-01

    AIM We analysed the Belgian reimbursement decisions of orphan drugs as compared with those of innovative drugs for more common but equally severe diseases, with special emphasis on the quality of clinical evidence. METHODS Using the National Health Insurance Agency administrative database, we evaluated all submitted orphan drug files between 2002 and 2007. A quality analysis of the clinical evidence in the orphan reimbursement files was performed. The evaluation reports of the French ‘Haute Autorité de Santé’, including the five-point scale parameter ‘Service Médical Rendu (SMR), were examined to compare disease severity. Chi-squared tests (at P < 0.05 significance level) were used to compare the outcome of the reimbursement decisions between orphan and non-orphan innovative medicines. RESULTS Twenty-five files of orphan drugs and 117 files of non-orphan drugs were evaluated. Twenty-two of 25 (88%) submissions of orphan drugs were granted reimbursement as opposed to 74 of the 117 (63%) non-orphan innovative medicines (P = 0.02). Only 52% of the 25 orphan drug files included a randomized controlled trial as opposed to 84% in a random control sample of 25 non-orphan innovative submissions (P < 0.01). The duration of drug exposure was in most cases far too short in relation to the natural history of the disease. CONCLUSIONS Orphan drug designation predicts reimbursement despite poor quality of clinical evidence. The evidence gap at market authorization should be reduced by post-marketing programmes, in which the centralized regulatory and the local reimbursement authorities collaborate in an efficient way across the European Union member states. PMID:21395641

  7. The Orbit of the Orphan Stream

    SciTech Connect

    Newberg, Heidi Jo; Willett, Benjamin A.; Yanny, Brian; Xu, Yan

    2010-01-01

    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 e = 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{sup o}; 49{sup o}), 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){sub 0} = 0.22. The BHB stars have a low metallicity of [Fe/H]{sub WBG} = -2.1. The orbit is best fit to a halo potential with a halo plus disk mass of about 2.6 x 10{sup 11} M{sub {circle_dot}}, integrated to 60 kpc from the Galactic center. Our fits are done to orbits rather than full N-body simulations; we show that if N-body simulations are used, the inferred mass of the galaxy would be slightly smaller. Our best fit is found with a logarithmic halo speed of v{sub halo} = 73 {+-} 24 km s{sup -1}, a disk+bulge mass of M(R < 60 kpc) = 1.3 x 10{sup 11} M{sub {circle_dot}}, and a halo mass of M(R < 60 kpc) = 1.4 x 10{sup 11} M{sub {circle_dot}}. However, we can find similar fits to the data that use an NFW halo profile, or that have smaller disk masses and

  8. The US orphan drug programme 1983-1995.

    PubMed

    Shulman, S R; Manocchia, M

    1997-09-01

    The Orphan Drug Act has become a staple of food and drug law in the US. The experience with the US programme continues to serve as a useful reference point as interest in orphan drug incentive programmes expands globally. This article first reviews details of the legislation and orphan drug regulations, and then provides a 13-year overview (1983-1995) of orphan drug activity in the US, including descriptive data on the designated and approved orphan drugs, their indications and sponsors. In light of a recent challenge to the Food and Drug Administration's (FDA's) authority under the Act, we also examine the interplay between the exclusivity provision of the Act and the orphan drug regulations that define when 2 drugs will be considered the 'same' for the purposes of the Act. A recent court decision affirming the FDA's interpretation of the clinical superiority provisions of the regulations suggests that orphan exclusivity may be less predictable and less certain than it has been in the past. Finally, we consider the usefulness to orphan drug sponsors of other initiatives such as FDA's early access and fast-track approval programmes, and the extent to which the FDA's discretion to waive, defer and reduce prescription drug user fees has worked to the benefit of orphan drug sponsors. Over the 13-year analysis period, the FDA granted 631 orphan designations involving 450 different drugs, for which 121 FDA marketing approvals have been granted. Those with both treatment investigational drug designation and fast-track approval status appeared to benefit substantially from shorter development times. The indications targeted by the orphan drugs fall into 8 categories, with 40% of all orphan indications involving cancer and genetic diseases. Evident in the latter part of the analysis period is the increasing share of orphan activity attributable to biotechnology firms. Even though the Prescription Drug User Fee Act of 1992 did not recognise orphan status for the purpose of

  9. Factors Associated with Substance Use among Orphaned and Non-Orphaned Youth in South Africa

    ERIC Educational Resources Information Center

    Meghdadpour, Susanne; Curtis, Sian; Pettifor, Audrey; MacPhail, Catherine

    2012-01-01

    Substance use is increasing among youth in South Africa, and may be contributing to transmission of HIV. As parental death often leaves youth with altered emotional and physical resources, substance use may be greater among orphaned adolescents. Utilizing data from a household survey of 15-24 year old South Africans (n = 11,904), multivariable…

  10. Orphan flavonoids and dihydrochalcones from Primula exudates.

    PubMed

    Bhutia, Tshering Doma; Valant-Vetschera, Karin M; Brecker, Lothar

    2013-08-01

    Two orphan flavonoids containing an oxepin structure in ring A and named as Primcortusin (1) and 3'-OH-Primcortusin (2) were isolated from leaf exudates of Primula cortusoides, while P. glutinosa exudates yielded two dihydrochalcone derivatives (3,4). These novel structures have not been detected in other species of Primula so far. Chemical structures were elucidated by 2D NMR and mas spectrometry. The nature of compounds 1 and 2 is discussed, and ideas about their possible origin and that of unsubstituted flavone and other irregular substituted Primula flavones are presented.

  11. Nonblocking and orphan free message logging protocols

    NASA Technical Reports Server (NTRS)

    Alvisi, Lorenzo; Hoppe, Bruce; Marzullo, Keith

    1992-01-01

    Currently existing message logging protocols demonstrate a classic pessimistic vs. optimistic tradeoff. We show that the optimistic-pessimistic tradeoff is not inherent to the problem of message logging. We construct a message-logging protocol that has the positive features of both optimistic and pessimistic protocol: our protocol prevents orphans and allows simple failure recovery; however, it requires no blocking in failure-free runs. Furthermore, this protocol does not introduce any additional message overhead as compared to one implemented for a system in which messages may be lost but processes do not crash.

  12. Orphan Children: Adjusting to Life after the Boarding Institution

    ERIC Educational Resources Information Center

    Prisiazhnaia, N. V.

    2008-01-01

    According to official statistics, in Russia there are over 800,000 orphans and children who are deprived of parental care; 260,000 are living and being taught in more than 4,000 state boarding institutions. The category "orphan child" consists of children up to the age of eighteen, one or both of whose parents have died. The term "social…

  13. Care and Education of Orphaned Children in Poland

    ERIC Educational Resources Information Center

    Nowak-Fabrykowski, Krystyna

    2004-01-01

    Poland is going through tremendous changes in its educational and health-care systems. These changes may bring reforms in the care of orphaned children, because the new politics and economy are forcing educators to look for new solutions and forms of care. There are many problems with the care of orphan children in Poland in both Children's Homes…

  14. Orphan strontium-87 in abyssal peridotites: daddy was a granite.

    PubMed

    Snow, J E; Hart, S R; Dick, H J

    1993-12-17

    The (87)Sr/(86)Sr ratios in some bulk abyssal and alpine peridotites are too high to be binary mixtures of depleted mantle and seawater components. The apparent excess, or "orphan," (87)Sr appears to be separated from its radioactive parent. Such observations were widely held to be analytical artifacts. Study of several occurrences of orphan (87)Sr shows that the orphan component in abyssal peridotite is located in the alteration products of olivine and enstatite in the peridotite. The orphan (87)Sr is most likely introduced by infiltration of low-temperature (<200 degrees C) seawater bearing suspended detrital particulates. These particulates include grains of detrital clay that are partly derived from continental (that is, granitic) sources and thus are highly radiogenic. Orphan (87)Sr and other radiogenic isotopes may provide a tracer for low-temperature seawater penetrating into the oceanic crust. PMID:17829634

  15. The Orphan Drug Act: Restoring the Mission to Rare Diseases.

    PubMed

    Daniel, Michael G; Pawlik, Timothy M; Fader, Amanda N; Esnaola, Nestor F; Makary, Martin A

    2016-04-01

    The Orphan Drug Act has fostered drug development for patients with rare cancers and other diseases; however, current data suggest that companies are gaming the system to use the law for mainstream drugs. We identify a pattern of pharmaceutical companies submitting drugs to the Food and Drug Administration (FDA) as orphan drugs but once approved, the drugs are used broadly off-label with the lucrative orphan drug protections and exclusivity benefits. Since the law was passed, the proportion of new FDA-approved drugs that were submitted as orphan drugs has increased with a peak last year of 41% of all FDA-approved drugs approved as orphan drugs. On the basis of the current data, we suggest that patients with rare cancers and other diseases may suffer due to dilution of the incentives and benefits. We propose reform to increase submission scrutiny, decrease benefits based on off-label use, and increase price transparency. PMID:26580246

  16. Orphan strontium-87 in abyssal peridotites: daddy was a granite.

    PubMed

    Snow, J E; Hart, S R; Dick, H J

    1993-12-17

    The (87)Sr/(86)Sr ratios in some bulk abyssal and alpine peridotites are too high to be binary mixtures of depleted mantle and seawater components. The apparent excess, or "orphan," (87)Sr appears to be separated from its radioactive parent. Such observations were widely held to be analytical artifacts. Study of several occurrences of orphan (87)Sr shows that the orphan component in abyssal peridotite is located in the alteration products of olivine and enstatite in the peridotite. The orphan (87)Sr is most likely introduced by infiltration of low-temperature (<200 degrees C) seawater bearing suspended detrital particulates. These particulates include grains of detrital clay that are partly derived from continental (that is, granitic) sources and thus are highly radiogenic. Orphan (87)Sr and other radiogenic isotopes may provide a tracer for low-temperature seawater penetrating into the oceanic crust.

  17. Mechanisms and Dynamics of Orphan Gene Emergence in Insect Genomes

    PubMed Central

    Wissler, Lothar; Gadau, Jürgen; Simola, Daniel F.; Helmkampf, Martin; Bornberg-Bauer, Erich

    2013-01-01

    Orphan genes are defined as genes that lack detectable similarity to genes in other species and therefore no clear signals of common descent (i.e., homology) can be inferred. Orphans are an enigmatic portion of the genome because their origin and function are mostly unknown and they typically make up 10% to 30% of all genes in a genome. Several case studies demonstrated that orphans can contribute to lineage-specific adaptation. Here, we study orphan genes by comparing 30 arthropod genomes, focusing in particular on seven recently sequenced ant genomes. This setup allows analyzing a major metazoan taxon and a comparison between social Hymenoptera (ants and bees) and nonsocial Diptera (flies and mosquitoes). First, we find that recently split lineages undergo accelerated genomic reorganization, including the rapid gain of many orphan genes. Second, between the two insect orders Hymenoptera and Diptera, orphan genes are more abundant and emerge more rapidly in Hymenoptera, in particular, in leaf-cutter ants. With respect to intragenomic localization, we find that ant orphan genes show little clustering, which suggests that orphan genes in ants are scattered uniformly over the genome and between nonorphan genes. Finally, our results indicate that the genetic mechanisms creating orphan genes—such as gene duplication, frame-shift fixation, creation of overlapping genes, horizontal gene transfer, and exaptation of transposable elements—act at different rates in insects, primates, and plants. In Formicidae, the majority of orphan genes has their origin in intergenic regions, pointing to a high rate of de novo gene formation or generalized gene loss, and support a recently proposed dynamic model of frequent gene birth and death. PMID:23348040

  18. Exploring Responses to Transformative Group Therapy for Orphaned Children in the Context of Mass Orphaning in Botswana

    ERIC Educational Resources Information Center

    Thamuku, Masego; Daniel, Marguerite

    2013-01-01

    In the context of AIDS, the Botswana Government has adopted a group therapy program to help large numbers of orphaned children cope with bereavement. This study explores the effectiveness of the therapy and examines how it interacts with cultural attitudes and practices concerning death. Ten orphaned children were involved in five rounds of data…

  19. Family Contexts and Schooling Disruption among Orphans in Post-Genocide Rwanda

    PubMed Central

    2014-01-01

    This study examines the relationship between orphan status and schooling disruption in post-genocide Rwanda. The results indicate that while non-orphans have more favorable schooling outcomes in two-parent than in single-parent families, the reverse is true among Rwandan orphans. In single-mother households, paternal orphans, i.e. orphans with only a living mother, have better outcomes than their orphan and non-orphan counterparts. In contrast, paternal orphans have worse outcomes than other children in two-parent households, especially in households headed by males. Maternal orphans are more likely to experience schooling disruptions than non-orphans regardless of family structure. The maternal-orphan disadvantage is nevertheless greater in female-headed than in male-headed households. As expected, non-related orphans are more disadvantaged than orphans related to their household heads. However, non-related orphans have a greater disadvantage in two-parent than in single-parent households. The results also suggest that within households, the provision of childcare to children below schooling age is an impediment to orphan’s schooling. These impediments are, however, greater for double-orphans than paternal or maternal orphans. PMID:25035526

  20. 21 CFR 316.27 - Change in ownership of orphan-drug designation.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Change in ownership of orphan-drug designation... SERVICES (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Designation of an Orphan Drug § 316.27 Change in ownership of orphan-drug designation. (a) A sponsor may transfer ownership of or any beneficial interest...

  1. 21 CFR 316.40 - Treatment use of a designated orphan drug.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Treatment use of a designated orphan drug. 316.40... (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Open Protocols for Investigations § 316.40 Treatment use of a designated orphan drug. Prospective investigators seeking to obtain treatment use of designated orphan...

  2. 21 CFR 316.31 - Scope of orphan-drug exclusive approval.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Scope of orphan-drug exclusive approval. 316.31... (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Orphan-drug Exclusive Approval § 316.31 Scope of orphan-drug exclusive approval. (a) After approval of a sponsor's marketing application for a designated...

  3. Identifying and quantifying orphan protein sequences in fungi.

    PubMed

    Ekman, Diana; Elofsson, Arne

    2010-02-19

    For large regions of many proteins, and even entire proteins, no homology to known domains or proteins can be detected. These sequences are often referred to as orphans. Surprisingly, it has been reported that the large number of orphans is sustained in spite of a rapid increase of available genomic sequences. However, it is believed that de novo creation of coding sequences is rare in comparison to mechanisms such as domain shuffling and gene duplication; hence, most sequences should have homologs in other genomes. To investigate this, the sequences of 19 complete fungi genomes were compared. By using the phylogenetic relationship between these genomes, we could identify potentially de novo created orphans in Saccharomyces cerevisiae. We found that only a small fraction, <2%, of the S. cerevisiae proteome is orphan, which confirms that de novo creation of coding sequences is indeed rare. Furthermore, we found it necessary to compare the most closely related species to distinguish between de novo created sequences and rapidly evolving sequences where homologs are present but cannot be detected. Next, the orphan proteins (OPs) and orphan domains (ODs) were characterized. First, it was observed that both OPs and ODs are short. In addition, at least some of the OPs have been shown to be functional in experimental assays, showing that they are not pseudogenes. Furthermore, in contrast to what has been reported before and what is seen for older orphans, S. cerevisiae specific ODs and proteins are not more disordered than other proteins. This might indicate that many of the older, and earlier classified, orphans indeed are fast-evolving sequences. Finally, >90% of the detected ODs are located at the protein termini, which suggests that these orphans could have been created by mutations that have affected the start or stop codons.

  4. The African orphan crisis and international adoption.

    PubMed

    Roby, Jini L; Shaw, Stacey A

    2006-07-01

    The plight of Africa's AIDS orphans has reached crisis proportions, and the international community is beginning to mobilize at the family, community, national, and international levels. Despite these encouraging efforts, the response is inadequate, and increased attention and action are needed. The authors suggest that international adoption, although a small and temporary solution, may fit within the framework being used as a global working model. Issues surrounding adoption, such as racism, racial and cultural identity development, waiting children in the U.S. public child welfare system, and the potential legal risks, are delineated. The African perspective toward adoption is presented, although the response varies and is not collectively defined. The authors conclude that although international adoptions should be used as a last-resort solution, and with tight regulations, the potential benefits to some children merit the opening of a dialogue on the topic.

  5. Flexible kinship: caring for AIDS orphans in rural Lesotho

    PubMed Central

    Block, Ellen

    2015-01-01

    HIV/AIDS has devastated families in rural Lesotho, leaving many children orphaned. Families have adapted to the increase in the number of orphans and HIV-positive children in ways that provide children with the best possible care. Though local ideas about kinship and care are firmly rooted in patrilineal social organization, in practice, maternal caregivers, often grandmothers, are increasingly caring for orphaned children. Negotiations between affinal kin capitalize on flexible kinship practices in order to legitimate new patterns of care, which have shifted towards a model that often favours matrilocal practices of care in the context of idealized patrilineality. PMID:25866467

  6. Elucidation of signaling and functional activities of an orphan GPCR, GPR81.

    PubMed

    Ge, Hongfei; Weiszmann, Jennifer; Reagan, Jeff D; Gupte, Jamila; Baribault, Helene; Gyuris, Tibor; Chen, Jin-Long; Tian, Hui; Li, Yang

    2008-04-01

    GPR81 is an orphan G protein-coupled receptor (GPCR) that has a high degree of homology to the nicotinic acid receptor GPR109A. GPR81 expression is highly enriched and specific in adipocytes. However, the function and signaling properties of GPR81 are unknown because of the lack of natural or synthetic ligands. Using chimeric G proteins that convert Gi-coupled receptors to Gq-mediated inositol phosphate (IP) accumulation, we show that GPR81 can constitutively increase IP accumulation in HEK293 cells and suggest that GPR81 couples to the Gi signaling pathway. We also constructed a chimeric receptor that expresses the extracellular domains of cysteinyl leukotriene 2 receptor (CysLT2R) and the intracellular domains of GPR81. We show that the CysLT2R ligand, leukotriene D(4) (LTD4), is able to activate this chimeric receptor through activation of the Gi pathway. In addition, LTD4 is able to inhibit lipolysis in adipocytes expressing this chimeric receptor. These results suggest that GPR81 couples to the Gi signaling pathway and that activation of the receptor may regulate adipocyte function and metabolism. Hence, targeting GPR81 may lead to the development of a novel and effective therapy for dyslipidemia and a better side effect profile than nicotinic acid.

  7. From novice to expert: agroecological competences of children orphaned by AIDS compared to non-orphans in Benin

    PubMed Central

    2011-01-01

    Background AIDS has created new vulnerabilities for rural African households due to prime-age adult mortality and is assumed to lead to impairment of the intergenerational transfer of farming knowledge. There has been scant research to date, however, on the impacts of parental death on farming knowledge of children made orphans by AIDS. The question we investigate is if there is a difference in agricultural expertise between AIDS affected and non-affected adults and children. Methods The research was carried out in rural Benin with 77 informants randomly selected according to their AIDS status: 13 affected and 13 non-affected adults; 13 paternal, 13 maternal and 13 double orphans; and 12 non-orphan children. Informants descriptions from pile sorting exercises of maize and cowpea pests were categorized and then aggregated into descriptions based form (morphology) and function (utility) and used to determine whether the moving from novice to expert is impaired by children orphaned by AIDS. Differences and similarities in responses were determined using the Fischer exact test and the Cochran-Mantzel-Haenszel test. Results No significant differences were found between AIDS affected and non-affected adults. Results of the study do reveal differences in the use of form and function descriptors among the children. There is a statistically significant difference in the use of form descriptors between one-parent orphans and non-orphans and in descriptors of specific damages to maize. One-parent paternal orphans were exactly like non-affected adults in their 50/50 balanced expertise in the use of both form and function descriptors. One-parent orphans also had the highest number of descriptors used by children overall and these descriptors are spread across the various aspects of the knowledge domain relative to non-orphans. Conclusions Rather than a knowledge loss for one-parent orphans, particularly paternal orphans, we believe we are witnessing acceleration into adult

  8. Orphan Products: Hope for People with Rare Diseases

    MedlinePlus

    ... drug manufacturers rarely could make a profit from marketing drugs to such small groups. Consequently, the prescription ... research, and a seven-year period of exclusive marketing given to the first sponsor of an orphan- ...

  9. View of headframe, looking southeast from Powell Memorial Orphan ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    View of headframe, looking southeast from Powell Memorial - Orphan Lode Mine, Headframe, North of West Rim Road between Powell Point and Maricopa Point, South Rim, Grand Canyon Village, Coconino County, AZ

  10. View of headframe, looking west from Powell Memorial Orphan ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    View of headframe, looking west from Powell Memorial - Orphan Lode Mine, Headframe, North of West Rim Road between Powell Point and Maricopa Point, South Rim, Grand Canyon Village, Coconino County, AZ

  11. View of headframe, looking southwest from Powell Memorial Orphan ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    View of headframe, looking southwest from Powell Memorial - Orphan Lode Mine, Headframe, North of West Rim Road between Powell Point and Maricopa Point, South Rim, Grand Canyon Village, Coconino County, AZ

  12. View of headframe, looking southsoutheast from Powell Memorial Orphan ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    View of headframe, looking south-southeast from Powell Memorial - Orphan Lode Mine, Headframe, North of West Rim Road between Powell Point and Maricopa Point, South Rim, Grand Canyon Village, Coconino County, AZ

  13. Synthesis, pharmacological characterization, and molecular modeling of heterobicyclic amino acids related to (+)-2-aminobicyclo[3.1.0] hexane-2,6-dicarboxylic acid (LY354740): identification of two new potent, selective, and systemically active agonists for group II metabotropic glutamate receptors.

    PubMed

    Monn, J A; Valli, M J; Massey, S M; Hansen, M M; Kress, T J; Wepsiec, J P; Harkness, A R; Grutsch, J L; Wright, R A; Johnson, B G; Andis, S L; Kingston, A; Tomlinson, R; Lewis, R; Griffey, K R; Tizzano, J P; Schoepp, D D

    1999-03-25

    As part of our ongoing research program aimed at the identification of highly potent, selective, and systemically active agonists for group II metabotropic glutamate (mGlu) receptors, we have prepared novel heterobicyclic amino acids (-)-2-oxa-4-aminobicyclo[3.1. 0]hexane-4,6-dicarboxylate (LY379268, (-)-9) and (-)-2-thia-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY389795, (-)-10). Compounds (-)-9 and (-)-10 are structurally related to our previously described nanomolar potency group II mGlu receptor agonist, (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate (LY354740 monohydrate, 5), with the C4-methylene unit of 5 being replaced with either an oxygen atom (as in (-)-9) or a sulfur atom (as in (-)-10). Compounds (-)-9 and (-)-10 potently and stereospecifically displaced specific binding of the mGlu2/3 receptor antagonist ([3H]LY341495) in rat cerebral cortical homogenates, displaying IC50 values of 15 +/- 4 and 8.4 +/- 0.8 nM, respectively, while having no effect up to 100 000 nM on radioligand binding to the glutamate recognition site on NMDA, AMPA, or kainate receptors. Compounds (-)-9 and (-)-10 also potently displaced [3H]LY341495 binding from membranes expressing recombinant human group II mGlu receptor subtypes: (-)-9, Ki = 14.1 +/- 1.4 nM at mGlu2 and 5.8 +/- 0.64 nM at mGlu3; (-)-10, Ki = 40.6 +/- 3.7 nM at mGlu2 and 4.7 +/- 1.2 nM at mGlu3. Evaluation of the functional effects of (-)-9 and (-)-10 on second-messenger responses in nonneuronal cells expressing human mGlu receptor subtypes demonstrated each to be a highly potent agonist for group II mGlu receptors: (-)-9, EC50 = 2.69 +/- 0.26 nM at mGlu2 and 4.58 +/- 0.04 nM at mGlu3; (-)-10, EC50 = 3.91 +/- 0.81 nM at mGlu2 and 7.63 +/- 2. 08 nM at mGlu3. In contrast, neither compound (up to 10 000 nM) displayed either agonist or antagonist activity in cells expressing recombinant human mGlu1a, mGlu5a, mGlu4a, or mGlu7a receptors. The agonist effects of (-)-9 and (-)-10 at group II m

  14. [Orphan drugs: some legal, ethical and economics aspects].

    PubMed

    Pabst, J Y

    2001-09-01

    Besides well-known diseases, about 5,000 identified are classed as "orphan" because of the lack of any response in terms of diagnosis, prevention and treatment. The development of drugs for these diseases, intended for a limited number of patients, often requires considerable research, and subsequently, cost. The aim of the present article is to discuss the ethical, political and economic problems relevant to the development and disposal of drugs specifically designed for these diseases, now commonly called "orphan" drugs. These questions have been raised at discussions and dialogues at the European Parliament where European regulations on orphan drugs were adopted on December 15, 1999. These regulations (141/2000/EEC) came into effect in the European Union on January 22, 2000, and are widely inspired from the American model. The regulations stipulate that the criterion for designation of the drug is based on a disease prevalence of 5/10000). Advantages commonly recognized for the orphan drug status concern: community registration (centralized marketing approval), eligibility for grants and national or community fiscal support, lower or canceled registration fees, technical contribution via the European drug agency (EMEA), and exclusive rights for a 10-year period. On May 12, 2000, the European Commission completed the status by adopting rules establishing the criteria used for designating a drug as an orphan drug. This document implements the dispositions available to pharmaceutical firms inciting them to invest in the development of orphan drugs. PMID:11567205

  15. The therapeutic potential of orphan GPCRs, GPR35 and GPR55

    PubMed Central

    Shore, Derek M.; Reggio, Patricia H.

    2015-01-01

    The G protein-coupled receptor (GPCR) superfamily of integral proteins is the largest family of signal transducers, comprised of ∼1000 members. Considering their prevalence and functional importance, it’s not surprising that ∼60% of drugs target GPCRs. Regardless, there exists a subset of the GPCR superfamily that is largely uncharacterized and poorly understood; specifically, more than 140 GPCRs have unknown endogenous ligands—the so-called orphan GPCRs. Orphan GPCRs offer tremendous promise, as they may provide novel therapeutic targets that may be more selective than currently known receptors, resulting in the potential reduction in side effects. In addition, they may provide access to signal transduction pathways currently unknown, allowing for new strategies in drug design. Regardless, orphan GPCRs are an important area of inquiry, as they represent a large gap in our understanding of signal transduction at the cellular level. Here, we focus on the therapeutic potential of two recently deorphanized GPCRs: GPR35/CXCR8 and GPR55. First, GPR35/CXCR8 has been observed in numerous tissues/organ systems, including the gastrointestinal tract, liver, immune system, central nervous system, and cardiovascular system. Not surprisingly, GPR35/CXCR8 has been implicated in numerous pathologies involving these tissues/systems. While several endogenous ligands have been identified, GPR35/CXCR8 has recently been observed to bind the chemokine CXCL17. Second, GPR55 has been observed to be expressed in the central nervous system, adrenal glands, gastrointestinal tract, lung, liver, uterus, bladder, kidney, and bone, as well as, other tissues/organ systems. Likewise, it is not surprising that GPR55 has been implicated in pathologies involving these tissues/systems. GPR55 was initially deorphanized as a cannabinoid receptor and this receptor does bind many cannabinoid compounds. However, the GPR55 endogenous ligand has been found to be a non

  16. AIDS and orphans: legal and ethical issues.

    PubMed

    Siamwiza, R

    1998-03-01

    This article explores the ethical and human rights issues surrounding AIDS and those orphaned by the epidemic in Zambia. A major area of controversy is on the rights of parents and children in adoptive or fostering relationships; civil law is unclear, and customary law treats children as the property of parents and selected kin. HIV/AIDS adds to the controversy concerning the following rights for adoptive and foster parents and children: 1) the right of prospective parents to know the health status of the child, and the child to know the prospective parent's status; 2) the rights, responsibilities, and obligations of the foster child's biological family after the placement; 3) the rights of adoptive or foster parents to public welfare assistance, health care, educational grants, particularly if the child has HIV; 4) property rights of adopted or foster children within their new families; and 5) the legal and civil rights of abandoned children. In conclusion, the ethical issues surrounding adoption and fostering require extensive research and public debate, taking into account the impact of broad socioeconomic changes affecting the extended family, as well as the impact of AIDS. PMID:12222354

  17. AIDS and orphans: legal and ethical issues.

    PubMed

    Siamwiza, R

    1998-03-01

    This article explores the ethical and human rights issues surrounding AIDS and those orphaned by the epidemic in Zambia. A major area of controversy is on the rights of parents and children in adoptive or fostering relationships; civil law is unclear, and customary law treats children as the property of parents and selected kin. HIV/AIDS adds to the controversy concerning the following rights for adoptive and foster parents and children: 1) the right of prospective parents to know the health status of the child, and the child to know the prospective parent's status; 2) the rights, responsibilities, and obligations of the foster child's biological family after the placement; 3) the rights of adoptive or foster parents to public welfare assistance, health care, educational grants, particularly if the child has HIV; 4) property rights of adopted or foster children within their new families; and 5) the legal and civil rights of abandoned children. In conclusion, the ethical issues surrounding adoption and fostering require extensive research and public debate, taking into account the impact of broad socioeconomic changes affecting the extended family, as well as the impact of AIDS.

  18. The Orphan Gene dauerless Regulates Dauer Development and Intraspecific Competition in Nematodes by Copy Number Variation.

    PubMed

    Mayer, Melanie G; Rödelsperger, Christian; Witte, Hanh; Riebesell, Metta; Sommer, Ralf J

    2015-06-01

    Many nematodes form dauer larvae when exposed to unfavorable conditions, representing an example of phenotypic plasticity and a major survival and dispersal strategy. In Caenorhabditis elegans, the regulation of dauer induction is a model for pheromone, insulin, and steroid-hormone signaling. Recent studies in Pristionchus pacificus revealed substantial natural variation in various aspects of dauer development, i.e. pheromone production and sensing and dauer longevity and fitness. One intriguing example is a strain from Ohio, having extremely long-lived dauers associated with very high fitness and often forming the most dauers in response to other strains' pheromones, including the reference strain from California. While such examples have been suggested to represent intraspecific competition among strains, the molecular mechanisms underlying these dauer-associated patterns are currently unknown. We generated recombinant-inbred-lines between the Californian and Ohioan strains and used quantitative-trait-loci analysis to investigate the molecular mechanism determining natural variation in dauer development. Surprisingly, we discovered that the orphan gene dauerless controls dauer formation by copy number variation. The Ohioan strain has one dauerless copy causing high dauer formation, whereas the Californian strain has two copies, resulting in strongly reduced dauer formation. Transgenic animals expressing multiple copies do not form dauers. dauerless is exclusively expressed in CAN neurons, and both CAN ablation and dauerless mutations increase dauer formation. Strikingly, dauerless underwent several duplications and acts in parallel or downstream of steroid-hormone signaling but upstream of the nuclear-hormone-receptor daf-12. We identified the novel or fast-evolving gene dauerless as inhibitor of dauer development. Our findings reveal the importance of gene duplications and copy number variations for orphan gene function and suggest daf-12 as major target for

  19. Unintended Effects of Orphan Product Designation for Rare Neurological Diseases

    PubMed Central

    Murphy, Sinéad M; Puwanant, Araya; Griggs, Robert C.

    2012-01-01

    Since the introduction of the Orphan Drug Act in 1983, designed to promote development of treatments for rare diseases, at least 378 orphan drugs have been approved. Incentives include financial support, tax credits and, perhaps most importantly, extended market exclusivity. These incentives have encouraged industry interest and accelerated research on rare diseases, allowing patients with orphan diseases access to treatments. However, extended market exclusivity has been associated with unacceptably high drug costs; both for newly developed drugs and even for drugs which were previously widely available. We suggest that a paradoxical effect of orphan product exclusivity can be reduced patient access to existing drugs. In addition, the costs of each new drug are arguably unsustainable for patients and for the American health care system. Of all the specialties, neurology has the third highest number of orphan product designations, and neurological diseases account for at least one fifth of rare diseases. Citing the use of tetrabenazine for chorea in Huntington’s disease, adrenocorticotropic hormone for infantile spasms and enzyme replacement therapy with alglucosidase alpha for Pompe’s disease we highlight these paradoxical effects. PMID:23109143

  20. Unintended effects of orphan product designation for rare neurological diseases.

    PubMed

    Murphy, Sinéad M; Puwanant, Araya; Griggs, Robert C

    2012-10-01

    Since the introduction of the Orphan Drug Act in 1983, designed to promote development of treatments for rare diseases, at least 378 orphan drugs have been approved. Incentives include financial support, tax credits, and perhaps most importantly, extended market exclusivity. These incentives have encouraged industry interest and accelerated research on rare diseases, allowing patients with orphan diseases access to treatments. However, extended market exclusivity has been associated with unacceptably high drug costs, both for newly developed drugs and for drugs that were previously widely available. We suggest that a paradoxical effect of orphan product exclusivity can be reduced patient access to existing drugs. In addition, the costs of each new drug are arguably unsustainable for patients and for the American health care system. Of all the specialties, neurology has the third highest number of orphan product designations, and neurological diseases account for at least one-fifth of rare diseases. Citing the use of tetrabenazine for chorea in Huntington disease, adrenocorticotropic hormone for infantile spasms, and enzyme replacement therapy with alglucosidase alpha for Pompe disease, we highlight these paradoxical effects.

  1. Is Ursa Major II the Progenitor of the Orphan Stream?

    SciTech Connect

    Fellhauer, M.; Evans, N.W.; Belokurov, V.; Zucker, D.B.; Yanny, B.; Wilkinson, M.I.; Gilmore, G.; Irwin, M.J.; Bramich, D.M.; Vidrih, S.; Hewett, Paul C.; /Cambridge U., Inst. of Astron. /Michigan State U.

    2006-11-01

    Prominent in the ''Field of Streams''--the Sloan Digital Sky Survey map of substructure in the Galactic halo--is an ''Orphan Stream'' without obvious progenitor. In this numerical study, we show a possible connection between the newly found dwarf satellite Ursa Major II (UMa II) and the Orphan Stream. We provide numerical simulations of the disruption of UMa II that match the observational data on the position, distance and morphology of the Orphan Stream. We predict the radial velocity of UMa II as -100kms{sup -1}, as well as the existence of strong velocity gradients along the Orphan Stream. The velocity dispersion of UMa II is expected to be high, though this can be caused both by a high dark matter content or by the presence of unbound stars in a disrupted remnant. However, the existence of a gradient in the mean radial velocity across UMa II provides a clear-cut distinction between these possibilities. The simulations support the idea that some of the anomalous, young halo globular clusters like Palomar 1 or Arp 2 or Ruprecht 106 may be physically associated with the Orphan Stream.

  2. The Guanine-Based Purinergic System: The Tale of An Orphan Neuromodulation

    PubMed Central

    Garozzo, Roberta; Frinchi, Monica; Fernandez-Dueñas, Víctor; Di Iorio, Patrizia; Ciccarelli, Renata; Caciagli, Francesco; Condorelli, Daniele F.; Ciruela, Francisco; Belluardo, Natale

    2016-01-01

    Guanine-based purines (GBPs) have been recently proposed to be not only metabolic agents but also extracellular signaling molecules that regulate important functions in the central nervous system. In such way, GBPs-mediated neuroprotection, behavioral responses and neuronal plasticity have been broadly described in the literature. However, while a number of these functions (i.e., GBPs neurothophic effects) have been well-established, the molecular mechanisms behind these GBPs-dependent effects are still unknown. Furthermore, no plasma membrane receptors for GBPs have been described so far, thus GBPs are still considered orphan neuromodulators. Interestingly, an intricate and controversial functional interplay between GBPs effects and adenosine receptors activity has been recently described, thus triggering the hypothesis that GBPs mechanism of action might somehow involve adenosine receptors. Here, we review recent data describing the GBPs role in the brain. We focus on the involvement of GBPs regulating neuronal plasticity, and on the new hypothesis based on putative GBPs receptors. Overall, we expect to shed some light on the GBPs world since although these molecules might represent excellent candidates for certain neurological diseases management, the lack of putative GBPs receptors precludes any high throughput screening intent for the search of effective GBPs-based drugs. PMID:27378923

  3. EU marketing authorization review of orphan and non-orphan drugs does not differ.

    PubMed

    Putzeist, M; Mantel-Teeuwisse, A K; Llinares, J; Gispen-De Wied, C C; Hoes, A W; Leufkens, H G M

    2013-10-01

    Marketing authorization application dossiers of 17 orphan drugs (ODs) and 51 non-ODs evaluated by the European Medicines Agency (EMA) in the period 2009-2010 were compared. We aimed to identify whether any differences existed between ODs and non-ODs in number and type of deficits brought forward during the EMA review, regarding the clinical development plan, clinical outcome and medical need and studied whether these deficits were similarly associated with marketing approval in the EU. In 71% of the ODs dossiers and 65% of the non-ODs dossiers marketing approval was granted. Differences in deficits were found, but similarities in the way ODs and non-ODs were reviewed and marketing approval decisions were taken, underline that regulatory standards are equally high.

  4. Orphan caribou, Rangifer tarandus, calves: A re-evaluation of overwinter survival data

    USGS Publications Warehouse

    Joly, Kyle

    2000-01-01

    Low sample size and high variation within populations reduce power of statistical tests. These aspects of statistical power appear to have affected an analysis comparing overwinter survival rates of non-orphan and orphan Caribou (Rangifer tarandus) calves by an earlier study for the Porcupine Caribou Herd. A re-evaluation of the data revealed that conclusions about a lack of significant difference in the overwinter survival rates between orphan and non-orphan calves were premature.

  5. Accessing Social Grants to Meet Orphan Children School Needs: Namibia and South Africa Perspective

    ERIC Educational Resources Information Center

    Taukeni, Simon; Matshidiso, Taole

    2013-01-01

    In this comparative paper we interrogate the access of social grants to meet orphan children school needs in Namibia and South Africa. We noted that the two governments are committed to provide orphan children with social grants to enable them to meet the school needs. However, accessing social grant to benefit most vulnerable orphan children…

  6. 76 FR 29183 - Exclusion of Orphan Drugs for Certain Covered Entities Under 340B Program

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-20

    ... services for HIV disease); (4) A state-operated AIDS drug purchasing assistance program receiving financial... Affordable Care Act, orphan drugs, when used for the rare condition or disease for which that orphan drug was... an orphan drug when used for a rare disease or condition. The entity types added to the list...

  7. Orphan Drug Expenditures In The United States: A Historical And Prospective Analysis, 2007-18.

    PubMed

    Divino, Victoria; DeKoven, Mitch; Kleinrock, Michael; Wade, Rolin L; Kaura, Satyin

    2016-09-01

    The Orphan Drug Act of 1983 established incentives for the development of drugs that treat rare, or orphan, diseases. We used the IMS Health MIDAS database of audited biopharmaceutical sales to measure US annual spending on orphan drugs in the period 2007-13, and we estimated spending on the drugs for the period 2014-18. We identified 356 brand-name orphan drugs that were approved by the Food and Drug Administration in the period 1983-2013. While we included orphan drugs with both orphan and other indications, we adjusted spending to include only spending for orphan indications. In 2014 dollars, expenditures on orphan drugs totaled $15 billion in 2007 and $30 billion in 2013-representing 4.8 percent and 8.9 percent of total pharmaceutical expenditures, respectively. Our future trend analysis for the period 2014-18 suggests a slowing in the growth of orphan drug expenditures. The overall impact of orphan drugs on payers' drug budgets is relatively small, and spending on orphan drugs as a percentage of total pharmaceutical expenditures has remained fairly stable. Concerns that growth in orphan drug expenditures may lead to unsustainable drug expenditures do not appear to be justified. PMID:27605637

  8. 21 CFR 316.21 - Verification of orphan-drug status.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 5 2014-04-01 2014-04-01 false Verification of orphan-drug status. 316.21 Section 316.21 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Designation of an Orphan Drug § 316.21 Verification of...

  9. 21 CFR 316.21 - Verification of orphan-drug status.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 5 2013-04-01 2013-04-01 false Verification of orphan-drug status. 316.21 Section 316.21 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Designation of an Orphan Drug § 316.21 Verification of...

  10. 21 CFR 316.21 - Verification of orphan-drug status.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 5 2012-04-01 2012-04-01 false Verification of orphan-drug status. 316.21 Section 316.21 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Designation of an Orphan Drug § 316.21 Verification of...

  11. 21 CFR 316.21 - Verification of orphan-drug status.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 5 2011-04-01 2011-04-01 false Verification of orphan-drug status. 316.21 Section 316.21 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Designation of an Orphan Drug § 316.21 Verification of...

  12. Plant insecticide L-canavanine repels Drosophila via the insect orphan GPCR DmX.

    PubMed

    Mitri, Christian; Soustelle, Laurent; Framery, Bérénice; Bockaert, Joël; Parmentier, Marie-Laure; Grau, Yves

    2009-06-30

    For all animals, the taste sense is crucial to detect and avoid ingesting toxic molecules. Many toxins are synthesized by plants as a defense mechanism against insect predation. One example of such a natural toxic molecule is L-canavanine, a nonprotein amino acid found in the seeds of many legumes. Whether and how insects are informed that some plants contain L-canavanine remains to be elucidated. In insects, the taste sense relies on gustatory receptors forming the gustatory receptor (Gr) family. Gr proteins display highly divergent sequences, suggesting that they could cover the entire range of tastants. However, one cannot exclude the possibility of evolutionarily independent taste receptors. Here, we show that L-canavanine is not only toxic, but is also a repellent for Drosophila. Using a pharmacogenetic approach, we find that flies sense food containing this poison by the DmX receptor. DmXR is an insect orphan G-protein-coupled receptor that has partially diverged in its ligand binding pocket from the metabotropic glutamate receptor family. Blockade of DmXR function with an antagonist lowers the repulsive effect of L-canavanine. In addition, disruption of the DmXR encoding gene, called mangetout (mtt), suppresses the L-canavanine repellent effect. To avoid the ingestion of L-canavanine, DmXR expression is required in bitter-sensitive gustatory receptor neurons, where it triggers the premature retraction of the proboscis, thus leading to the end of food searching. These findings show that the DmX receptor, which does not belong to the Gr family, fulfills a gustatory function necessary to avoid eating a natural toxin. PMID:19564899

  13. The Social and Pedagogical Protection of Orphans in Russia

    ERIC Educational Resources Information Center

    Pantiukhina, E. N.

    2009-01-01

    This article discusses the history of the provision of children's care ("prizrenie") in Russia which provides evidence that the desire to help those close to one, especially orphans and the poor, was a traditional trait of the Russian national character. The system of children's welfare as it took shape over many centuries is unique in its own…

  14. Family and Nation: Cherokee Orphan Care, 1835-1903

    ERIC Educational Resources Information Center

    Reed, Julie L.

    2010-01-01

    On November 17, 1903, fifteen miles from the nearest railway station and fifty miles northwest of the capital of the Cherokee Nation in Tahlequah, a fire engulfed the Cherokee Orphan Asylum. After the fire the Cherokee Nation relocated the homeless children to the nation's Insane Asylum in Tahlequah, where Sequoyah School stands today. The…

  15. An Analysis of How Multicultural Adult Orphans Achieve Economic Success

    ERIC Educational Resources Information Center

    Simonee, Saundra W.

    2014-01-01

    Successful multicultural adult orphans who were not adopted pose an interesting challenge in their history, their physical, psychological, social emotional and personal identity development. One must understand their journey from orphanhood to adulthood and their current prominent status in life to build a contextualized personal story (Banks,…

  16. 77 FR 64555 - Orphan Works and Mass Digitization

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-10-22

    ... ability to control the digital commercialization of millions of books as it would require authors and... plan to digitize and make available orphan works to faculty, students, and library patrons (the... Copyright Office and Private Registries In October 2011, the Register of Copyrights released a two-year...

  17. In whose care and custody? Orphans of the HIV epidemic.

    PubMed

    Levine, C

    1995-10-01

    Skip generation parenting occurs in two directions: grandparents, who assume major burdens and primary caregiving responsibilities; and the younger adults, who may care for younger siblings or the ailing parents. These adolescents may benefit from learning to assume responsibility, acquiring coping skills, and developing the ability to nurture. However, the situation can be overwhelming and may backfire. It may therefore be necessary to establish a system of care for children orphaned by the HIV epidemic. In the past, most children in orphanages were not orphans but had come from families where one parent was dead or ill, where the parents could not afford to support their children, or where the children were abused or neglected. Recently, transitional homes for HIV-infected babies have successfully provided health care and emotional nurturing in a non-hospital setting. However, it is easier to place infants and young children in families than it is to place older children. Institutional care will probably serve orphaned adolescents. There have been mixed results with group homes for teens, where little attention is paid to the special needs of orphaned adolescents placed in such care. The needs of these children may be addressed through HIV-specific programs, and systemic reform may be necessary to adequately address the needs of this population. PMID:11362834

  18. Therapeutic Art Practices with Orphan Children in Bulgaria

    ERIC Educational Resources Information Center

    Ivanova, Alexandra S.

    2004-01-01

    This paper presents therapeutic art practices carried out with 60 orphan children in the small town of Ugarchin in northern Bulgaria. In 1999, a group of artists and teachers developed a varied program of art activities for these children. These activities included two 1-week visits and the opening of five art workshops--Art History, Ceramics,…

  19. Motives for Taking Orphan Children into a Foster (Guardian) Family

    ERIC Educational Resources Information Center

    Kozlova, T. Z.

    2013-01-01

    Research in Russia on the opinions of guardians and experts of the department of guardianship examines the motives that people have for taking orphan children into their homes. The data indicate that about 80 percent of the guardians are grandmothers taking care of their grandchildren, whose parents have been stripped of their parental rights.…

  20. Gender differences in maladaptive cognitive schema in orphans in Dakahlia, Egypt.

    PubMed

    El-Gilany, Abdel-Hady; El-Bilsha, Mona A; Ibrahim, Azza

    2013-01-01

    The objective of this study was to assess the gender differences of maladaptive cognitive schema among orphans in Dakahlia governorate orphanages. A cross-sectional comparative study included 152 orphan boys and 48 orphan girls in all orphanages homes in Dakahlia governorate, Egypt. Data collection tools included a structured interview questionnaire for personal data; early maladaptive schema questionnaire-short form (EMSQ-SF). The mean score of the total YSQ and all the subscales, except self-sacrifice and unrelenting standards, are significantly higher among females than males. Attention should be given to the psychological care of the orphans especially security, trust, confidence, and autonomy with more attention to orphan girls.

  1. Children’s psychosocial wellbeing in the context of HIV/AIDS and poverty: a comparative investigation of orphaned and non-orphaned children living in South Africa

    PubMed Central

    2014-01-01

    Background Recent studies have questioned whether orphanhood is primarily associated with key dimensions of psycho-social wellbeing in children living in circumstances of material deprivation and high prevalence of HIV and AIDS. Methods This study uses cross-sectional data from a longitudinal study conducted between 2004-2007 to examine the psychosocial well-being of orphans and non-orphans in the Amajuba District of KwaZulu-Natal, South Africa. Psychosocial wellbeing included an assessment of orphans’ and non orphans’ level of anxiety and depression, affability and resilience. Stratified cluster sampling, based on both school and age, was used to construct a cohort of recent orphans and non-orphans and their households, randomly selected from schools. Results Levels of anxiety and depression, affability and resilience did not differ significantly between orphans and non-orphans, nor did salient household, poverty and caregiver characteristics vary substantially amongst orphans and non-orphans. Multivariate analyses indicated that children’s psychosocial outcomes, when controlling for orphan status and related demographic variables were more strongly influenced by household composition/size, living above or below the poverty threshold and factors associated with the caregiver-child relationship and caregiver health. Conclusions The results muster additional evidence for moving beyond narrow definitions of vulnerability associated exclusively with orphanhood to consider the multitude of material, social and relational factors affecting the psycho-social well-being of children in general who are living in circumstances of poverty and HIV and AIDS. PMID:24938864

  2. 76 FR 53912 - FDA's Public Database of Products With Orphan-Drug Designation: Replacing Non-Informative Code...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-30

    ... HUMAN SERVICES Food and Drug Administration FDA's Public Database of Products With Orphan-Drug... its public database of products that have received orphan-drug designation. The Orphan Drug Act... received orphan designation were published on our public database with non-informative code names....

  3. 21 CFR 316.23 - Timing of requests for orphan-drug designation; designation of already approved drugs.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Timing of requests for orphan-drug designation..., DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Designation of an Orphan Drug § 316.23 Timing of requests for orphan-drug designation; designation of already approved drugs....

  4. Pricing and reimbursement of orphan drugs: the need for more transparency.

    PubMed

    Simoens, Steven

    2011-01-01

    Pricing and reimbursement of orphan drugs are an issue of high priority for policy makers, legislators, health care professionals, industry leaders, academics and patients. This study aims to conduct a literature review to provide insight into the drivers of orphan drug pricing and reimbursement. Although orphan drug pricing follows the same economic logic as drug pricing in general, the monopolistic power of orphan drugs results in high prices: a) orphan drugs benefit from a period of marketing exclusivity; b) few alternative health technologies are available; c) third-party payers and patients have limited negotiating power; d) manufacturers attempt to maximise orphan drug prices within the constraints of domestic pricing and reimbursement policies; and e) substantial R&D costs need to be recouped from a small number of patients. Although these conditions apply to some orphan drugs, they do not apply to all orphan drugs. Indeed, the small number of patients treated with an orphan drug and the limited economic viability of orphan drugs can be questioned in a number of cases. Additionally, manufacturers have an incentive to game the system by artificially creating monopolistic market conditions. Given their high price for an often modest effectiveness, orphan drugs are unlikely to provide value for money. However, additional criteria are used to inform reimbursement decisions in some countries. These criteria may include: the seriousness of the disease; the availability of other therapies to treat the disease; and the cost to the patient if the medicine is not reimbursed. Therefore, the maximum cost per unit of outcome that a health care payer is willing to pay for a drug could be set higher for orphan drugs to which society attaches a high social value. There is a need for a transparent and evidence-based approach towards orphan drug pricing and reimbursement. Such an approach should be targeted at demonstrating the relative effectiveness, cost-effectiveness and

  5. Pricing and reimbursement of orphan drugs: the need for more transparency

    PubMed Central

    2011-01-01

    Pricing and reimbursement of orphan drugs are an issue of high priority for policy makers, legislators, health care professionals, industry leaders, academics and patients. This study aims to conduct a literature review to provide insight into the drivers of orphan drug pricing and reimbursement. Although orphan drug pricing follows the same economic logic as drug pricing in general, the monopolistic power of orphan drugs results in high prices: a) orphan drugs benefit from a period of marketing exclusivity; b) few alternative health technologies are available; c) third-party payers and patients have limited negotiating power; d) manufacturers attempt to maximise orphan drug prices within the constraints of domestic pricing and reimbursement policies; and e) substantial R&D costs need to be recouped from a small number of patients. Although these conditions apply to some orphan drugs, they do not apply to all orphan drugs. Indeed, the small number of patients treated with an orphan drug and the limited economic viability of orphan drugs can be questioned in a number of cases. Additionally, manufacturers have an incentive to game the system by artificially creating monopolistic market conditions. Given their high price for an often modest effectiveness, orphan drugs are unlikely to provide value for money. However, additional criteria are used to inform reimbursement decisions in some countries. These criteria may include: the seriousness of the disease; the availability of other therapies to treat the disease; and the cost to the patient if the medicine is not reimbursed. Therefore, the maximum cost per unit of outcome that a health care payer is willing to pay for a drug could be set higher for orphan drugs to which society attaches a high social value. There is a need for a transparent and evidence-based approach towards orphan drug pricing and reimbursement. Such an approach should be targeted at demonstrating the relative effectiveness, cost-effectiveness and

  6. Elucidation of primary metabolic pathways in Aspergillus species: orphaned research in characterizing orphan genes.

    PubMed

    Andersen, Mikael Rørdam

    2014-11-01

    Primary metabolism affects all phenotypical traits of filamentous fungi. Particular examples include reacting to extracellular stimuli, producing precursor molecules required for cell division and morphological changes as well as providing monomer building blocks for production of secondary metabolites and extracellular enzymes. In this review, all annotated genes from four Aspergillus species have been examined. In this process, it becomes evident that 80-96% of the genes (depending on the species) are still without verified function. A significant proportion of the genes with verified metabolic functions are assigned to secondary or extracellular metabolism, leaving only 2-4% of the annotated genes within primary metabolism. It is clear that primary metabolism has not received the same attention in the post-genomic area as many other research areas--despite its role at the very centre of cellular function. However, several methods can be employed to use the metabolic networks in tandem with comparative genomics to accelerate functional assignment of genes in primary metabolism. In particular, gaps in metabolic pathways can be used to assign functions to orphan genes. In this review, applications of this from the Aspergillus genes will be examined, and it is proposed that, where feasible, this should be a standard part of functional annotation of fungal genomes.

  7. Insurance Companies’ Perspectives on the Orphan Drug Pipeline

    PubMed Central

    Handfield, Robert; Feldstein, Josh

    2013-01-01

    Background Rare diseases are of increasing concern to private and public healthcare insurance plans. Largely neglected by manufacturers before the 1983 passing of the Orphan Drug Act (ODA), orphan drugs have become a commercialization target of steadily increasing importance to the healthcare industry. The ODA mandates the coverage of rare diseases, which are defined in research communities as diseases that are so infrequent that there is no reasonable expectation of a drugmaker recovering the cost of developing that drug. Objectives To determine the views of leading commercial US payers regarding providing access to and coverage for orphan drugs; to assess whether and to what degree cost-effectiveness analysis (CEA) is viewed by payers as relevant to rare disease coverage. Methods The study sample was identified through a call for action sent by America's Health Insurance Plans to its members, resulting in 4 interviews conducted and 3 completed surveys from a total of 7 companies. These 7 US health insurance companies represent approximately 75% of the US private insurance market by revenue and include approximately 157 million covered lives (using self-reported data from insurance companies). Representatives of 3 companies responded to the survey, and representatives of 4 companies were interviewed via the phone. The interviews were conducted with subject matter experts at each company and included 2 senior vice presidents of a pharmacy program, 1 chief medical director, and 1 head of pharmacoeconomics. The surveys were completed by 1 vice president of clinical pharmacy strategy, 1 chief pharmacy director, and 1 medical director. Results Based on the responses in this study, approximately 67% of US private insurance companies are concerned about orphan drugs, but only approximately 17% have developed meaningful strategies for addressing the cost of orphan drugs. Of the companies who do have such a strategy, 100% are unsure how to determine the best economic

  8. Cultural practices and sexual risk behaviour among adolescent orphans and non-orphans: a qualitative study on perceptions from a community in western Kenya

    PubMed Central

    2014-01-01

    Background This study explored community perceptions of cultural beliefs and practices that may increase sexual risk behaviour of adolescents, to understand more about meaning they hold within the culture and how they expose adolescent orphans and non-orphans to higher risks in a high HIV and teenage pregnancy prevalence context. Methods Using a qualitative descriptive cross-sectional design 14 focus group discussions were conducted with 78 adolescents and 68 parents/guardians purposively selected to represent their communities. Thirteen key informant interviews were also conducted with community leaders, health care and child welfare workers, and adolescents who were also selected purposively. The two methods were used to explore how cultural beliefs and practices predispose adolescent orphans and non- orphans to risky sexual behaviours. Data were analysed through line-by-line coding, grouped into families and retrieved as themes and sub-themes. Results Identified cultural practices that predisposed adolescents orphans and non-orphans to risky sexual behaviours included: adolescent sleeping arrangements, funeral ceremonies, replacing a deceased married daughter with her younger sister in marriage, widow inheritance among boys, early marriage among girls, and preference for boys/sons. Cultural risks perceived to equally affect both orphans and non-orphans were sleeping arrangements, funeral ceremonies, and sister replacement. Factors associated more with orphans than non-orphans were widow inheritance among boys and a preference for boy over girl children. Conclusions Adolescent sexual risk reduction programs should be developed considering the specific cultural context, using strategies that empower communities to challenge the widely accepted cultural norms that may predispose young people in general to sexual risks while targeting those that unequally influence orphans. PMID:24467940

  9. Access to Orphan Drugs: A Comprehensive Review of Legislations, Regulations and Policies in 35 Countries

    PubMed Central

    Gammie, Todd

    2015-01-01

    Objective To review existing regulations and policies utilised by countries to enable patient access to orphan drugs. Methods A review of the literature (1998 to 2014) was performed to identify relevant, peer-reviewed articles. Using content analysis, we synthesised regulations and policies for access to orphan drugs by type and by country. Results Fifty seven articles and 35 countries were included in this review. Six broad categories of regulation and policy instruments were identified: national orphan drug policies, orphan drug designation, marketing authorization, incentives, marketing exclusivity, and pricing and reimbursement. The availability of orphan drugs depends on individual country’s legislation and regulations including national orphan drug policies, orphan drug designation, marketing authorization, marketing exclusivity and incentives such as tax credits to ensure research, development and marketing. The majority of countries (27/35) had in place orphan drug legislation. Access to orphan drugs depends on individual country’s pricing and reimbursement policies, which varied widely between countries. High prices and insufficient evidence often limit orphan drugs from meeting the traditional health technology assessment criteria, especially cost-effectiveness, which may influence access. Conclusions Overall many countries have implemented a combination of legislations, regulations and policies for orphan drugs in the last two decades. While these may enable the availability and access to orphan drugs, there are critical differences between countries in terms of range and types of legislations, regulations and policies implemented. Importantly, China and India, two of the largest countries by population size, both lack national legislation for orphan medicines and rare diseases, which could have substantial negative impacts on their patient populations with rare diseases. PMID:26451948

  10. GPR55: from orphan to metabolic regulator?

    PubMed

    Liu, Bo; Song, Shuang; Jones, Peter M; Persaud, Shanta J

    2015-01-01

    GPR55 belongs to the class A family of G-protein coupled receptor (GPCRs) and its activity is regulated by a range of synthetic and endogenous cannabinoids, and by lipid-derived ligands. Cannabinoids are known to be important in controlling appetite and metabolic balance, and it is now emerging that GPR55 may have a role to play in energy homeostasis through the regulation of food intake, fuel storage in adipocytes, gut motility and insulin secretion. This review summarises our current knowledge of expression and function of GPR55 in tissues involved in metabolic regulation, the signalling cascades through which GPR55 is reported to act to exert its effects, and it comments on the difficulties in reaching firm conclusions when using GPR55 ligands of poor specificity. Understanding the role of GPR55 in energy homeostasis may provide a novel target for therapeutic intervention in obesity and type 2 diabetes mellitus. PMID:24972076

  11. Evolving pharmacology of orphan GPCRs: IUPHAR Commentary

    PubMed Central

    Davenport, Anthony P; Harmar, Anthony J

    2013-01-01

    The award of the 2012 Nobel Prize in Chemistry to Robert Lefkowitz and Brian Kobilka for their work on the structure and function of GPCRs, spanning a period of more than 20 years from the cloning of the human β2-adrenoceptor to determining the crystal structure of the same protein, has earned both researchers a much deserved place in the pantheon of major scientific discoveries. GPCRs comprise one of the largest families of proteins, controlling many major physiological processes and have been a major focus of the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR) since its inception in 1987. We report here recent efforts by the British Pharmacological Society and NC-IUPHAR to define the endogenous ligands of ‘orphan’ GPCRs and to place authoritative and accessible information about these crucial therapeutic targets online. PMID:23957221

  12. A nuclear-receptor-dependent phosphatidylcholine pathway with antidiabetic effects

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Nuclear hormone receptors regulate diverse metabolic pathways and the orphan nuclear receptor LRH-1 (also known as NR5A2) regulates bile acid biosynthesis. Structural studies have identified phospholipids as potential LRH-1 ligands, but their functional relevance is unclear. Here we show that an unu...

  13. [Role of Human Orphan Esterases in Drug-induced Toxicity].

    PubMed

    Fukami, Tatsuki

    2015-01-01

    Esterases hydrolyze compounds containing ester, amide, and thioester bonds, causing prodrug activation or detoxification. Among esterases, carboxylesterases have been studied in depth due to their ability to hydrolyze a variety of drugs. However, there are several drugs for which the involved esterase(s) is unknown. We found that flutamide, phenacetin, rifamycins (rifampicin, rifabutin, and rifapentine), and indiplon are hydrolyzed by arylacetamide deacetylase (AADAC), which is highly expressed in human liver and gastrointestinal tissues. Flutamide hydrolysis is considered associated with hepatotoxicity. Phenacetin, a prodrug of acetaminophen, was withdrawn due to side effects such as methemoglobinemia and renal failure. It was demonstrated in vitro and in vivo using mice that AADAC is responsible for phenacetin hydrolysis, which leads to methemoglobinemia. In addition, it was shown that AADAC-mediated hydrolysis attenuates the cytotoxicity of rifamycins. Thus AADAC plays critical roles in drug-induced toxicity. Another orphan esterase, α/β hydrolase domain containing 10 (ABHD10), was found responsible for deglucuronidation of acyl-glucuronides including mycophenolic acid acyl-glucuronide and probenecid acyl-glucuronide. Because acyl-glucuronides appear associated with toxicity, ABHD10 would function as a detoxification enzyme. The roles of orphan esterases are becoming increasingly understood. Further studies will facilitate our knowledge of the pharmacologic and toxicological significance of orphan esterases in drug therapy. PMID:26521872

  14. Extending stellar density maps of the Orphan Tidal Stream

    NASA Astrophysics Data System (ADS)

    Varilly, Taylor; Carlin, J. L.; Newberg, H. J.; Beaton, R.; Majewski, S. R.

    2014-01-01

    This project involves analyzing data directly off the footprint of the Sloan Digital Sky Survey in order to find the progenitor of the Orphan tidal stream. This stream of stellar debris, known to span distances 20 to 47 kpc from the Sun, is believed to be the remnants of a small dwarf galaxy that is largely disrupted. Images were obtained in the vicinity of this stream from the MOSAIC1.1 camera on the 4-meter Mayall telescope at the Kitt Peak National Observatory. The region observed covers 11 square degrees of sky, approximately 7 square degrees of which have no SDSS data. The area outside the SDSS was selected to explore the increase in density of Orphan stars in this location, discussed in Newberg et al. 2010. The positions and magnitudes of stars outside of the SDSS were calculated and calibrated with both data from the SDSS itself, as well as the USNOB-1 catalog. The resulting Orphan candidates selected from this catalog were used to explore the stellar densities along this stream, providing insight into the nature of its progenitor. This research was supported by NSF grant AST 09-37523.

  15. Molecular mechanisms in therapy of acid-related diseases

    PubMed Central

    Shin, J. M.; Vagin, O.; Munson, K.; Kidd, M.; Modlin, I. M.; Sachs, G.

    2011-01-01

    Inhibition of gastric acid secretion is the mainstay of the treatment of gastroesophageal reflux disease and peptic ulceration; therapies to inhibit acid are among the best-selling drugs worldwide. Highly effective agents targeting the histamine H2 receptor were first identified in the 1970s. These were followed by the development of irreversible inhibitors of the parietal cell hydrogen-potassium ATPase (the proton pump inhibitors) that inhibit acid secretion much more effectively. Reviewed here are the chemistry, biological targets and pharmacology of these drugs, with reference to their current and evolving clinical utilities. Future directions in the development of acid inhibitory drugs include modifications of current agents and the emergence of a novel class of agents, the acid pump antagonists. PMID:17928953

  16. Nematode orphan genes are adopted by conserved regulatory networks and find a home in ecology.

    PubMed

    Mayer, Melanie G; Sommer, Ralf J

    2015-01-01

    Nematode dauer formation represents an essential survival and dispersal strategy and is one of a few ecologically relevant traits that can be studied in laboratory approaches. Under harsh environmental conditions, the nematode model organisms Caenorhabditis elegans and Pristionchus pacificus arrest their development and induce the formation of stress-resistant dauer larvae in response to dauer pheromones, representing a key example of phenotypic plasticity. Previous studies have indicated that in P. pacificus, many wild isolates show cross-preference of dauer pheromones and compete for access to a limited food source. When investigating the genetic mechanisms underlying this intraspecific competition, we recently discovered that the orphan gene dauerless (dau-1) controls dauer formation by copy number variation. Our results show that dau-1 acts in parallel to or downstream of steroid hormone signaling but upstream of the nuclear hormone receptor daf-12, suggesting that DAU-1 represents a novel inhibitor of DAF-12. Phylogenetic analysis reveals that the observed copy number variation is part of a complex series of gene duplication events that occurred over short evolutionary time scales. Here, we comment on the incorporation of novel or fast-evolving genes into conserved genetic networks as a common principle for the evolution of phenotypic plasticity and intraspecific competition. We discuss the possibility that orphan genes might often function in the regulation and execution of ecologically relevant traits. Given that only few ecological processes can be studied in model organisms, the function of such genes might often go unnoticed, explaining the large number of uncharacterized genes in model system genomes. PMID:27123366

  17. Exploring responses to transformative group therapy for orphaned children in the context of mass orphaning in Botswana.

    PubMed

    Thamuku, Masego; Daniel, Marguerite

    2013-01-01

    In the context of AIDS, the Botswana Government has adopted a group therapy program to help large numbers of orphaned children cope with bereavement. This study explores the effectiveness of the therapy and examines how it interacts with cultural attitudes and practices concerning death. Ten orphaned children were involved in five rounds of data collection during a therapeutic retreat; eight social workers completed questionnaires concerning the effectiveness of the therapy. Most children were able to come to terms with their loss, face problems in their home and school environments, and envision ways of solving problems. All the children described benefits of group formation and the support it would provide when they returned to their home situations.

  18. Exploring responses to transformative group therapy for orphaned children in the context of mass orphaning in Botswana.

    PubMed

    Thamuku, Masego; Daniel, Marguerite

    2013-01-01

    In the context of AIDS, the Botswana Government has adopted a group therapy program to help large numbers of orphaned children cope with bereavement. This study explores the effectiveness of the therapy and examines how it interacts with cultural attitudes and practices concerning death. Ten orphaned children were involved in five rounds of data collection during a therapeutic retreat; eight social workers completed questionnaires concerning the effectiveness of the therapy. Most children were able to come to terms with their loss, face problems in their home and school environments, and envision ways of solving problems. All the children described benefits of group formation and the support it would provide when they returned to their home situations. PMID:24517564

  19. Formation of a solar Hα filament from orphan penumbrae

    NASA Astrophysics Data System (ADS)

    Buehler, D.; Lagg, A.; van Noort, M.; Solanki, S. K.

    2016-05-01

    Aims: The formation and evolution of an Hα filament in active region (AR) 10953 is described. Methods: Observations from the Solar Optical Telescope (SOT) aboard the Hinode satellite starting from UT 18:09 on 27th April 2007 until UT 06:08 on 1st May 2007 were analysed. 20 scans of the 6302 Å Fe I line pair recorded by SOT/SP were inverted using the spatially coupled version of the SPINOR code. The inversions were analysed together with co-spatial SOT/BFI G-band and Ca II H and SOT/NFI Hα observations. Results: Following the disappearance of an initial Hα filament aligned along the polarity inversion line (PIL) of the AR, a new Hα filament formed in its place some 20 h later, which remained stable for, at least, another 1.5 days. The creation of the new Hα filament was driven by the ascent of horizontal magnetic fields from the photosphere into the chromosphere at three separate locations along the PIL. The magnetic fields at two of these locations were situated directly underneath the initial Hα filament and formed orphan penumbrae already aligned along the Hα filament channel. The 700 G orphan penumbrae were stable and trapped in the photosphere until the disappearance of the overlying initial Hα filament, after which they started to ascend into the chromosphere at 10 ± 5 m/s. Each ascent was associated with a simultaneous magnetic flux reduction of up to 50% in the photosphere. The ascended orphan penumbrae formed dark seed structures in Hα in parallel with the PIL, which elongated and merged to form an Hα filament. The filament channel featured horizontal magnetic fields of on average 260 G at log (τ) = -2 suspended above the nearly field-free lower photosphere. The fields took on an overall inverse configuration at log (τ) = -2 suggesting a flux rope topology for the new Hα filament. The destruction of the initial Hα filament was likely caused by the flux emergence at the third location along the PIL. Conclusions: We present a new

  20. Orphan drugs for rare diseases: is it time to revisit their special market access status?

    PubMed

    Simoens, Steven; Cassiman, David; Dooms, Marc; Picavet, Eline

    2012-07-30

    Orphan drugs are intended for diseases with a very low prevalence, and many countries have implemented legislation to support market access of orphan drugs. We argue that it is time to revisit the special market access status of orphan drugs. Indeed, evidence suggests that there is no societal preference for treating rare diseases. Although society appears to assign a greater value to severity of disease, this criterion is equally relevant to many common diseases. Furthermore, the criterion of equity in access to treatment, which underpins orphan drug legislation, puts more value on health improvement in rare diseases than in common diseases and implies that population health is not maximized. Finally, incentives for the development, pricing and reimbursement of orphan drugs have created market failures, including monopolistic prices and the artificial creation of rare diseases. We argue that, instead of awarding special market access status to orphan drugs, there is scope to optimize research and development (R&D) of orphan drugs and to control prices of orphan drugs by means of, for example, patent auctions, advance purchase commitments, pay-as-you-go schemes and dose-modification studies. Governments should consider carefully the right incentive strategy for R&D of orphan drugs in rare diseases.

  1. ROR nuclear receptors: structures, related diseases, and drug discovery

    PubMed Central

    Zhang, Yan; Luo, Xiao-yu; Wu, Dong-hai; Xu, Yong

    2015-01-01

    Nuclear receptors (NRs) are ligand-regulated transcription factors that regulate metabolism, development and immunity. The NR superfamily is one of the major classes of drug targets for human diseases. Retinoic acid receptor-related orphan receptor (ROR) α, β and γ belong to the NR superfamily, and these receptors are still considered as 'orphan' receptors because the identification of their endogenous ligands has been controversial. Recent studies have demonstrated that these receptors are regulated by synthetic ligands, thus emerge as important drug targets for the treatment of multiple sclerosis, rheumatoid arthritis, psoriasis, etc. Studying the structural basis and ligand development of RORs will pave the way for a better understanding of the roles of these receptors in human diseases. Here, we review the structural basis, disease relevance, strategies for ligand identification, and current status of development of therapeutic ligands for RORs. PMID:25500868

  2. Conceptions of mental health among Ugandan youth orphaned by AIDS.

    PubMed

    Harms, Sheila; Kizza, Ruth; Sebunnya, Joshua; Jack, Susan

    2009-03-01

    The AIDS epidemic has disproportionately affected developing or low-income sub-Saharan African countries. Within the context of the epidemic, children and youth are at risk of losing their parents at an early age. The experience of orphanhood due to AIDS has the potential to negatively impact on a child's mental health. A qualitative study was conducted to comprehensively describe the experience of orphanhood and its impact on mental health from the culturally specific perspective of Ugandan youths. We conducted interviews with a purposeful sample of 13 youths (ages 12 to 18) who had lost one or both parents to AIDS illness and who were also affiliated with a non-governmental organisation providing support to orphans. The orphaned youths experienced significant ongoing emotional difficulties following the death of their parent(s). The youths in this study were unfamiliar with the term 'mental health,' however they easily identified factors associated with good or poor mental health. In general, good mental health was associated with social conduct that is culturally appropriate. Poor mental health was perceived as a form of madness or insanity and it was associated with a loss of basic life necessities, such as access to food, education or shelter. The youths also identified factors that promote more successful orphans. The findings of this study suggest that Western terminologies and symptom constellations in the Diagnostic and Statistical Manual IV may not be applicable in an African cultural context. There are several clinical implications, including the development of a mental health intervention paradigm that emphasises resilience.

  3. Housing conditions and mental health of orphans in South Africa

    PubMed Central

    Marais, Lochner; Sharp, Carla; Pappin, Michele; Lenka, Molefi; Cloete, Jan; Skinner, Donald; Serekoane, Joe

    2013-01-01

    Literature from the developed world suggests that poor housing conditions and housing environments contribute to poor mental health outcomes, although research results are mixed. This study investigates the relationship between housing conditions and the socio-emotional health of orphans and vulnerable children (OVC) in South Africa. The results of the study are mainly inconclusive, although it is suggested that methodological considerations play a vital role in explaining the mixed results. However, a positive relationship was found between living in informal settlements and better socio-emotional health of the OVC. We speculate that the historical context of informal settlement formation in South Africa helps to explain this unexpected result. PMID:24013088

  4. HIV Orphanhood Research and the Representation of Older Orphans in Sub-Saharan Africa: A Literature Review.

    PubMed

    Popoola, Tosin; Mchunu, Gugu

    2016-01-01

    One impact of incurable HIV infection is the large number of orphans and vulnerable children (OVC) who are affected by HIV. The age-based criteria used to determine support eligibility for HIV orphans, however, exclude older orphans (≥18 years of age) from support. We conducted a literature survey in order to explore possible inclusion of older orphans (ages 18-24 years) in HIV orphanhood research. We found 17 studies conducted in eight countries that met the review inclusion criteria. Findings from the review revealed that older HIV orphans are underrepresented in the OVC literature. The emerging, but limited, evidence suggests that older orphans are at risk for poorer psychosocial and reproductive outcomes. We recommend increasing inclusion of older orphans in HIV orphan research because of their complex physical, reproductive, and psychosocial needs. This inclusion is necessary to allow their experiences and needs to become clearer. PMID:26482073

  5. HIV Orphanhood Research and the Representation of Older Orphans in Sub-Saharan Africa: A Literature Review.

    PubMed

    Popoola, Tosin; Mchunu, Gugu

    2016-01-01

    One impact of incurable HIV infection is the large number of orphans and vulnerable children (OVC) who are affected by HIV. The age-based criteria used to determine support eligibility for HIV orphans, however, exclude older orphans (≥18 years of age) from support. We conducted a literature survey in order to explore possible inclusion of older orphans (ages 18-24 years) in HIV orphanhood research. We found 17 studies conducted in eight countries that met the review inclusion criteria. Findings from the review revealed that older HIV orphans are underrepresented in the OVC literature. The emerging, but limited, evidence suggests that older orphans are at risk for poorer psychosocial and reproductive outcomes. We recommend increasing inclusion of older orphans in HIV orphan research because of their complex physical, reproductive, and psychosocial needs. This inclusion is necessary to allow their experiences and needs to become clearer.

  6. Neglect and perceived stigmatization impact psychological distress of orphans in Tanzania

    PubMed Central

    Hermenau, Katharin; Eggert, Ina; Landolt, Markus A.; Hecker, Tobias

    2015-01-01

    Background Research has shown that orphans in sub-Saharan Africa are at increased risk for mental health problems. Exposure to maltreatment and HIV/AIDS-related stigmatization are related to orphans’ psychological distress. Yet, researchers stress the need for more research in low-income countries to identify which factors of being an orphan may lead to psychological distress. Objectives The present study aims to systematically investigate orphans’ experiences of maltreatment and stigmatization to identify factors that relate to their psychological distress. Methods In total, 89 Tanzanian children who had lost at least one parent were compared to 89 matched non-orphans (mean age: 11 years; 51% boys). We measured exposure to maltreatment and perceived stigmatization as an orphan. Mental health was assessed using the Strengths and Difficulties Questionnaire, the Children's Depression Inventory, the UCLA PTSD Index for Children, and the Reactive–Proactive Questionnaire. Results Orphans reported significantly more experiences of neglect, but not of abuse. A group comparison revealed more depressive symptoms, posttraumatic stress symptoms, and aggressive behavior among orphans. Neglect, abuse, and stigmatization correlated with orphans’ internalizing and externalizing problems, yet only neglect and stigmatization were related to orphans’ depression severity. Perceived stigmatization moderated the relationship between neglect and depression. Conclusions Our findings suggest that orphans in Tanzania are at increased risk of experiencing neglect. Maltreatment and perceived stigmatization may play a role in orphans’ psychological distress. Culturally appropriate and evidence-based interventions may help to prevent maltreatment and stigmatization of orphans. PMID:26589257

  7. Persisting Mental Health Problems among AIDS-Orphaned Children in South Africa

    ERIC Educational Resources Information Center

    Cluver, Lucie D.; Orkin, Mark; Gardner, Frances; Boyes, Mark E.

    2012-01-01

    Background: By 2008, 12 million children in sub-Saharan Africa were orphaned by AIDS. Cross-sectional studies show psychological problems for AIDS-orphaned children, but until now no longitudinal study has explored enduring psychological effects of AIDS-orphanhood in the developing world. Methods: A 4-year longitudinal follow-up of AIDS-orphaned…

  8. 21 CFR 316.28 - Publication of orphan-drug designations.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... the drug and the date of the granting of orphan-drug designation; (c) The rare disease or condition... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Publication of orphan-drug designations. 316.28 Section 316.28 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN...

  9. 21 CFR 316.29 - Revocation of orphan-drug designation.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    .... (c) Where a drug has been designated as an orphan drug because the prevalence of a disease or... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Revocation of orphan-drug designation. 316.29 Section 316.29 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN...

  10. 21 CFR 316.20 - Content and format of a request for orphan-drug designation.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... designation of a drug for a specified rare disease or condition shall submit each request in the form and... and obtain orphan-drug designation for the subsequent drug for the same rare disease or condition if.... More than one sponsor may receive orphan-drug designation of the same drug for the same rare disease...

  11. 77 FR 71452 - Extension of Comment Period: Orphan Works and Mass Digitization

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-11-30

    ... Copyright Office Extension of Comment Period: Orphan Works and Mass Digitization AGENCY: Copyright Office, Library of Congress. ACTION: Extension of comment period. SUMMARY: The Copyright Office is extending the... issues relating to orphan works and mass digitization under U.S. copyright law. DATES: Comments are...

  12. Risk and Resilience in Orphaned Adolescents Living in a Community Affected by AIDS

    ERIC Educational Resources Information Center

    Wild, Lauren G.; Flisher, Alan J.; Robertson, Brian A.

    2013-01-01

    The AIDS pandemic has resulted in a dramatic rise in the number of orphans in South Africa. This study was designed to investigate the associations between family, peer, and community factors and resilience in orphaned adolescents. Self-report questionnaires were administered verbally to 159 parentally bereaved adolescents (aged 10-19) in an…

  13. Providing Psychosocial Support to Special Needs Children: A Case of Orphans and Vulnerable Children in Zimbabwe

    ERIC Educational Resources Information Center

    Chitiyo, Morgan; Changara, Darlington M.; Chitiyo, George

    2008-01-01

    The AIDS pandemic has orphaned hundreds of thousands of children worldwide and most of these are in sub-Saharan Africa. Being orphaned by AIDS creates peculiar circumstances which may affect the children's ability to benefit from regular education. The impact of vulnerability on children's well-being has been documented by UNAIDS, UNICEF and by…

  14. Educational Inequalities and Ukrainian Orphans' Future Pathways: Social Reproduction or Transformation through the Hidden Curriculum?

    ERIC Educational Resources Information Center

    Korzh, Alla

    2013-01-01

    This qualitative multi-site case study, situated in the context of Ukraine's post-Soviet political economy, examined how orphanage educators' expectations and beliefs about orphans' academic abilities and potential, curriculum, peer relationships, and education policy shaped orphans' post-secondary education decisions and trajectories. Examination…

  15. The Care and Education of Orphaned Polish Children: A Success Story

    ERIC Educational Resources Information Center

    Nowak-Fabrykowski, Krystyna

    2004-01-01

    Ongoing changes in the Polish political and economic sectors have led to tremendous changes in its education and health care systems that will likely bring reforms in the care of orphaned children. After the Second World War, many children in Poland were orphaned and an institutional system for their care and education became entrenched. Many…

  16. The Varying Vulnerability of African Orphans: The Case of the Langi, Northern Uganda

    ERIC Educational Resources Information Center

    Oleke, Christopher; Blystad, Astrid; Moland, Karen Marie; Rekdal, Ole Bjorn; Heggenhougen, Kristian

    2006-01-01

    This article is based on a qualitative study carried out in Lira District, northern Uganda, to assess the situation of orphans cared for in extended families. The objective of the article is to bring attention to the varying vulnerability of different categories of orphans. The methods employed in data collection included ethnographic fieldwork,…

  17. Between Charity and Education: Orphans and Orphanages in Early Modern Times

    ERIC Educational Resources Information Center

    Jacobi, Juliane

    2009-01-01

    In early modern times orphans have been children who could not expect sufficient support from their family because of lack of at least one parent, in most cases the father. This article will clarify of whom we are talking if we talk about orphans and what have been the conditions of living in a society which was organised by a high variety of…

  18. Orphan drug incentives in the pharmacogenomic context: policy responses in the US and Canada

    PubMed Central

    Gibson, Shannon; von Tigerstrom, Barbara

    2015-01-01

    Advances in pharmacogenomic research and increasing industry interest in personalized medicine have important implications for the way that orphan drug policies are interpreted and applied. Concerns have been raised about the potential impact of pharmacogenomics and new genomic technologies on our understanding of how disease categories are delineated, and subsequently, how the concept of rare disease should be defined for the purposes of orphan drug policies. This article considers whether orphan drug legislation can be drafted in a way that will maximize benefits and minimize concerns relating to the impact of pharmacogenomics on orphan drug research and development. After reviewing the issues that may arise at the intersection of orphan drug policies and pharmacogenomics, this article will discuss the potential impact of pharmacogenomics at two critical points: orphan designation and approval of the drug product. At each of these points, the relevant aspects of current US orphan drug legislation are examined, focusing on the extent to which recent amendments may address concerns that have been raised previously. This analysis will then provide the foundation for a critical review and recommendations regarding the proposed new Canadian orphan drug framework. PMID:27774196

  19. 78 FR 35277 - Agency Information Collection Activities; Proposed Collection; Comment Request; Orphan Drugs...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-12

    ... highlights the regulatory cooperation between the United States and the European Union mandated by the... Collection; Comment Request; Orphan Drugs; Common European Medicines Agency/Food and Drug Administration... European Medicines Agency (EMA) of the Common EMA/FDA Application Form for Orphan Medicinal...

  20. 76 FR 3910 - Agency Information Collection Activities; Proposed Collection; Comment Request; Orphan Drugs...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-21

    ... highlights the regulatory cooperation between the United States (U.S.) and the European Union (EU) mandated... Collection; Comment Request; Orphan Drugs; Common European Medicines Agency/Food and Drug Administration... European Medicines Agency (EMA) of the Common EMA/FDA Application Form for Orphan Medicinal...

  1. Social Support Disparities for Caregivers of AIDS-Orphaned Children in South Africa

    ERIC Educational Resources Information Center

    Kuo, Caroline; Fitzgerald, Jane; Operario, Don; Casale, Marisa

    2012-01-01

    Drawing upon a sample of 1,599 adults caring for children in HIV-endemic Umlazi Township in South Africa, this cross-sectional survey investigated whether perceived social support varied among caregivers of AIDS-orphaned children (n = 359) as compared with caregivers of children orphaned by other causes (n = 171) and caregivers of nonorphaned…

  2. Maternal versus paternal orphans and HIV/STI risk among adolescent girls in Zimbabwe.

    PubMed

    Kang, M; Dunbar, M; Laver, S; Padian, N

    2008-02-01

    The AIDS epidemic has contributed to a drastic increase in the number of orphans in Zimbabwe. Orphans (whether orphaned by AIDS or other causes) have been shown to have economic and educational disadvantages as well as poor reproductive health outcomes. We recruited a convenience sample of 200 girls in a peri-urban area of Zimbabwe to examine the impact of orphan status (compared to non-orphans) on household composition, education, risk behaviour, pregnancy and prevalent HIV and HSV-2 infection. In our population, maternal orphans were more likely to be in households headed by themselves or a sibling, to be sexually active, to have had an STI, to have been pregnant and to be infected with HIV. Paternal orphans were more likely to have ever been homeless and to be out of school. Our findings suggest that maternal care and support is important for HIV prevention. This finding corroborates previous research in Zimbabwe and has implications for intervention strategies among orphan girls. PMID:18293132

  3. Gender differences in maladaptive cognitive schema in orphans in Dakahlia, Egypt.

    PubMed

    El-Gilany, Abdel-Hady; El-Bilsha, Mona A; Ibrahim, Azza

    2013-01-01

    The objective of this study was to assess the gender differences of maladaptive cognitive schema among orphans in Dakahlia governorate orphanages. A cross-sectional comparative study included 152 orphan boys and 48 orphan girls in all orphanages homes in Dakahlia governorate, Egypt. Data collection tools included a structured interview questionnaire for personal data; early maladaptive schema questionnaire-short form (EMSQ-SF). The mean score of the total YSQ and all the subscales, except self-sacrifice and unrelenting standards, are significantly higher among females than males. Attention should be given to the psychological care of the orphans especially security, trust, confidence, and autonomy with more attention to orphan girls. PMID:24453839

  4. Prioritizing orphan proteins for further study using phylogenomics and gene expression profiles in Streptomyces coelicolor

    PubMed Central

    2011-01-01

    Background Streptomyces coelicolor, a model organism of antibiotic producing bacteria, has one of the largest genomes of the bacterial kingdom, including 7825 predicted protein coding genes. A large number of these genes, nearly 34%, are functionally orphan (hypothetical proteins with unknown function). However, in gene expression time course data, many of these functionally orphan genes show interesting expression patterns. Results In this paper, we analyzed all functionally orphan genes of Streptomyces coelicolor and identified a list of "high priority" orphans by combining gene expression analysis and additional phylogenetic information (i.e. the level of evolutionary conservation of each protein). Conclusions The prioritized orphan genes are promising candidates to be examined experimentally in the lab for further characterization of their function. PMID:21899768

  5. Orphans in Nyanza, Kenya: Coping with the Struggles of Everyday Life in the Context of the HIV/AIDS Pandemic

    ERIC Educational Resources Information Center

    Landry, Tamara; Luginaah, Isaac; Maticka-Tyndale, Eleanor; Elkins, David

    2007-01-01

    This paper examined the everyday challenges, stressors and coping strategies of orphans affected by HIV/AIDS in Nyanza, Kenya. A thematic analysis of six focus group discussions with orphans was guided by Stress and Coping Theoretical Framework. The orphans reported intense stress at the time of their parents' death with their immediate concern…

  6. The Acceptability of Psychosocial Support Interventions for Children Orphaned by HIV/AIDS: An Evaluation of Teacher Ratings

    ERIC Educational Resources Information Center

    Chitiyo, Morgan; Changara, Darlington; Chitiyo, George

    2010-01-01

    The AIDS epidemic has created many orphans around the globe. A majority of these orphans live in sub-Saharan Africa. Children orphaned by HIV/AIDS face many daunting challenges in their struggle to cope with life. The issues they face due to the loss of their parent(s) include poverty, the stigma associated with HIV/AIDS and stress. This study…

  7. Longitudinal evaluation of the psychosocial wellbeing of recent orphans compared with non-orphans in a school-attending cohort in KwaZulu-Natal, South Africa

    PubMed Central

    Bachman DeSilva, Mary; Skalicky, Anne M.; Beard, Jennifer; Cakwe, Mandisa; Zhuwau, Tom; Simon, Jonathon L.

    2013-01-01

    To assess differences in psychosocial wellbeing between recent orphans and non-orphans, we followed a cohort of 157 school-going orphans and 480 non-orphans ages 9-15 in a context of high HIV/AIDS mortality in South Africa from 2004 to 2007. Several findings were contrary to published evidence to date, as we found no difference between orphans and non-orphans in anxiety/depression symptoms, oppositional behavior, self-esteem, or resilience. Female gender, self-reported poor health, and food insecurity were the most important predictors of children’s psychosocial wellbeing. Notably, girls had greater odds of reporting anxiety/depression symptoms than boys, and scored lower on self-esteem and resilience scales. Food insecurity predicted greater anxiety/depression symptoms and lower resilience. Perceived social support was a protective factor, as it was associated with lower odds of anxiety/depression symptoms, lower oppositional scores, and greater self-esteem and resilience. Our findings suggest a need to identify and strengthen psychosocial supports for girls, and for all children in contexts of AIDS-affected and economic adversity. PMID:23457424

  8. Inverse association of natural mentoring relationship with distress mental health in children orphaned by AIDS

    PubMed Central

    2010-01-01

    Background The magnitude of the AIDS-orphaned children crisis in sub-Saharan Africa has so overstretched the resource of most families that the collapse of fostering in the sub-region seems imminent (UNICEF, 2003), fueling the need for a complementary/alternative care. This paper examines the probability of the natural mentoring care to ameliorate distress mental health in children orphaned by AIDS. Methods 952 children, mean age about 14 years, from local community schools and child-care centers in Kampala (Uganda) and Mafikeng/Klerksdorp (South Africa) towns participated in the study. The design has AIDS-orphaned group (n = 373) and two control groups: Other-causes orphaned (n = 287) and non-orphaned (n = 290) children. We use measures of child abuse, depression, social discrimination, anxiety, parental/foster care, self-esteem, and social support to estimate mental health. Natural mentoring care is measured with the Ragins and McFarlin (1990) Mentor Role Instrument as adapted. Results AIDS-orphaned children having a natural mentor showed significant decreased distress mental health factors. Similar evidence was not observed in the control groups. Also being in a natural mentoring relationship inversely related to distress mental health factors in the AIDS-orphaned group, in particular. AIDS-orphaned children who scored high mentoring relationship showed significant lowest distress mental health factors that did those who scored moderate and low mentoring relationship. Conclusions Natural mentoring care seems more beneficial to ameliorate distress mental health in AIDS-orphaned children (many of whom are double-orphans, having no biological parents) than in children in the control groups. PMID:20078888

  9. International Union of Basic and Clinical Pharmacology. LXXXVIII. G Protein-Coupled Receptor List: Recommendations for New Pairings with Cognate Ligands

    PubMed Central

    Alexander, Stephen P. H.; Sharman, Joanna L.; Pawson, Adam J.; Benson, Helen E.; Monaghan, Amy E.; Liew, Wen Chiy; Mpamhanga, Chidochangu P.; Bonner, Tom I.; Neubig, Richard R.; Pin, Jean Philippe; Spedding, Michael; Harmar, Anthony J.

    2013-01-01

    In 2005, the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR) published a catalog of all of the human gene sequences known or predicted to encode G protein-coupled receptors (GPCRs), excluding sensory receptors. This review updates the list of orphan GPCRs and describes the criteria used by NC-IUPHAR to recommend the pairing of an orphan receptor with its cognate ligand(s). The following recommendations are made for new receptor names based on 11 pairings for class A GPCRs: hydroxycarboxylic acid receptors [HCA1 (GPR81) with lactate, HCA2 (GPR109A) with 3-hydroxybutyric acid, HCA3 (GPR109B) with 3-hydroxyoctanoic acid]; lysophosphatidic acid receptors [LPA4 (GPR23), LPA5 (GPR92), LPA6 (P2Y5)]; free fatty acid receptors [FFA4 (GPR120) with omega-3 fatty acids]; chemerin receptor (CMKLR1; ChemR23) with chemerin; CXCR7 (CMKOR1) with chemokines CXCL12 (SDF-1) and CXCL11 (ITAC); succinate receptor (SUCNR1) with succinate; and oxoglutarate receptor [OXGR1 with 2-oxoglutarate]. Pairings are highlighted for an additional 30 receptors in class A where further input is needed from the scientific community to validate these findings. Fifty-seven human class A receptors (excluding pseudogenes) are still considered orphans; information has been provided where there is a significant phenotype in genetically modified animals. In class B, six pairings have been reported by a single publication, with 28 (excluding pseudogenes) still classified as orphans. Seven orphan receptors remain in class C, with one pairing described by a single paper. The objective is to stimulate research into confirming pairings of orphan receptors where there is currently limited information and to identify cognate ligands for the remaining GPCRs. Further information can be found on the IUPHAR Database website (http://www.iuphar-db.org). PMID:23686350

  10. International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list: recommendations for new pairings with cognate ligands.

    PubMed

    Davenport, Anthony P; Alexander, Stephen P H; Sharman, Joanna L; Pawson, Adam J; Benson, Helen E; Monaghan, Amy E; Liew, Wen Chiy; Mpamhanga, Chidochangu P; Bonner, Tom I; Neubig, Richard R; Pin, Jean Philippe; Spedding, Michael; Harmar, Anthony J

    2013-07-01

    In 2005, the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR) published a catalog of all of the human gene sequences known or predicted to encode G protein-coupled receptors (GPCRs), excluding sensory receptors. This review updates the list of orphan GPCRs and describes the criteria used by NC-IUPHAR to recommend the pairing of an orphan receptor with its cognate ligand(s). The following recommendations are made for new receptor names based on 11 pairings for class A GPCRs: hydroxycarboxylic acid receptors [HCA₁ (GPR81) with lactate, HCA₂ (GPR109A) with 3-hydroxybutyric acid, HCA₃ (GPR109B) with 3-hydroxyoctanoic acid]; lysophosphatidic acid receptors [LPA₄ (GPR23), LPA₅ (GPR92), LPA₆ (P2Y5)]; free fatty acid receptors [FFA4 (GPR120) with omega-3 fatty acids]; chemerin receptor (CMKLR1; ChemR23) with chemerin; CXCR7 (CMKOR1) with chemokines CXCL12 (SDF-1) and CXCL11 (ITAC); succinate receptor (SUCNR1) with succinate; and oxoglutarate receptor [OXGR1 with 2-oxoglutarate]. Pairings are highlighted for an additional 30 receptors in class A where further input is needed from the scientific community to validate these findings. Fifty-seven human class A receptors (excluding pseudogenes) are still considered orphans; information has been provided where there is a significant phenotype in genetically modified animals. In class B, six pairings have been reported by a single publication, with 28 (excluding pseudogenes) still classified as orphans. Seven orphan receptors remain in class C, with one pairing described by a single paper. The objective is to stimulate research into confirming pairings of orphan receptors where there is currently limited information and to identify cognate ligands for the remaining GPCRs. Further information can be found on the IUPHAR Database website (http://www.iuphar-db.org).

  11. Steroid Hormone Receptor Signals as Prognosticators for Urothelial Tumor

    PubMed Central

    Ide, Hiroki; Miyamoto, Hiroshi

    2015-01-01

    There is a substantial amount of preclinical or clinical evidence suggesting that steroid hormone receptor-mediated signals play a critical role in urothelial tumorigenesis and tumor progression. These receptors include androgen receptor, estrogen receptors, glucocorticoid receptor, progesterone receptor, vitamin D receptor, retinoid receptors, peroxisome proliferator-activated receptors, and others including orphan receptors. In particular, studies using urothelial cancer tissue specimens have demonstrated that elevated or reduced expression of these receptors as well as alterations of their upstream or downstream pathways correlates with patient outcomes. This review summarizes and discusses available data suggesting that steroid hormone receptors and related signals serve as biomarkers for urothelial carcinoma and are able to predict tumor recurrence or progression. PMID:26770009

  12. Orphanhood and Schooling in South Africa: Trends in the vulnerability of orphans between 1993 and 2005

    PubMed Central

    Ardington, Cally; Leibbrandt, Murray

    2009-01-01

    Using 10 nationally representative surveys conducted between 1993 and 2005 we assess the extent to which the vulnerability of orphans to poorer educational outcomes has changed over time as the AIDS crisis deepens in South Africa. In line with the existing literature we find that at every point in time orphans are at risk of poorer educational outcomes with maternal deaths generally having stronger negative effects than paternal deaths. However, despite a significant increase in the number of orphans over the last decade, we find no evidence of a systematic strengthening of these negative effects. In order to understand this we explore patterns of care giving for orphans. We find that these patterns have shifted over time. While orphans are still absorbed into extended families, single orphans are increasingly less likely to live with the surviving parent and there is an increasing reliance on grandparents as caregivers. Up to this point, these changing patterns of care giving within extended families seem to have avoided further worsening in the educational outcomes for the increasing number of orphans. PMID:20407624

  13. Policy implications of the inadequate support systems for orphans in western Kenya.

    PubMed

    Nyambedha, E O; Wandibba, S; Aagaard-Hansen, J

    2001-10-01

    This paper describes the support systems available for orphans in a rural Luo community in Nyang'oma sub-location in Bondo District of Western Kenya. Qualitative data were collected through in-depth interviews with orphaned children and their caretakers as well as key informants, and through focus group discussions with orphaned children, widows and community elders. Quantitative data were obtained by questionnaires administered to 100 caretakers of orphaned children. The most serious problem was inability of the orphan households to afford school fees, although lack of food, medicare and clothing were also prominent. The traditional, kinship-based support systems made a major contribution to catering for the orphans though the resources were far from enough. Various community-based groups in the area did not contribute significantly. The problem is getting desperate due to a combination of an exponentially increasing prevalence of orphans, poor socio-economic conditions and decline of the traditional support systems. For health planners and policy makers there are two major concerns. In the short term, a big and rapidly growing group of children are without adequate access to health services, while in the long term, the negative consequences for (in particular the girl) orphans' schooling pose a serious threat to the health of their future children. Based on the study findings, two recommendations are made: that the responsible parties address the issue of education for orphans rapidly and sufficiently and with due consideration of their food security and medicare; and that potential community resources such as kinship networks and community groups are mobilised in order to assist in achieving the goal. PMID:11518603

  14. The impact of the declining extended family support system on the education of orphans in Lesotho

    PubMed Central

    Tanga, Pius T

    2013-01-01

    This paper examines the impact of the weakening of the extended family on the education of double orphans in Lesotho through in-depth interviews with participants from 3 of the 10 districts in Lesotho. The findings reveal that in Lesotho the extended family has not yet disintegrated as the literature suggests. However, it shows signs of rupturing, as many orphans reported that they are being taken into extended family households, the incentive for these households being, presumably, the financial and other material assistance that they receive from the government and non-governmental organisations (NGOs) which supplements household income and material wellbeing. The findings show that financial and other assistance given by the government and NGOs have resulted in conflict between the orphans and caregivers. This has also prompted many extended families to shift responsibilities to the government and NGOs. Most of the extended households provided the orphans with poor living conditions, such as unhygienic houses, poor nutrition, and little or no provision of school materials, which has had a negative impact on the education of the orphans. The combined effects of economic crisis and HIV and AIDS have resulted in extended families not being able to care for the needs of the orphans adequately, whilst continuing to accept them into their households. It is recommended that although extended families are still accepting orphans, the government should strengthen and recognise the important role played by families and the communities in caring for these vulnerable children. The government should also introduce social grants for orphans and other vulnerable children and review the current meagre public assistance (R100) it provides for orphans and vulnerable children in Lesotho. Other stakeholders should concentrate on strengthening the capacity of families and communities through programmes and projects which could be more sustainable than the current handouts given by

  15. The New Explorers teacher`s guide: Orphans of Time

    SciTech Connect

    1997-09-01

    The Science Explorers program, sponsored by the Department of Energy, owes its existence to the creativity of Mr. Bill Kurtis (WBBM-TV); the leadership of Dr. Alan Schriesheim, Director of Argonne National Laboratory; and the concern of the US Department of Energy. Mr. Kurtis has created a series of TV programs called The New Explorers which profile individual scientists and their science. He has given use of the tapes of these programs to teachers participating in the Chicago Science Explorers Program and to teachers in several other cities outside the Chicago area who are participating in the National Science Explorers Program. The goal of the program is to introduce students to science as a career possibility for their own lives. To introduce this unit of study students will view the Kurtis Productions science video entitled Orphans of Time. They will be able to note several paths of endangerment and what scientists are doing to try to alleviate the problems.

  16. Estrogen-related receptor β (ERRβ) – renaissance receptor or receptor renaissance?

    PubMed Central

    Divekar, Shailaja D.; Tiek, Deanna M.; Fernandez, Aileen; Riggins, Rebecca B.

    2016-01-01

    Estrogen-related receptors (ERRs) are founding members of the orphan nuclear receptor (ONR) subgroup of the nuclear receptor superfamily. Twenty-seven years of study have yet to identify cognate ligands for the ERRs, though they have firmly placed ERRα and ERRγ at the intersection of cellular metabolism and oncogenesis. The pace of discovery for novel functions of ERRβ, however, has until recently been somewhat slower than that of its family members. ERRβ has also been largely ignored in summaries and perspectives of the ONR literature. Here, we provide an overview of established and emerging knowledge of ERRβ in mouse, man, and other species, highlighting unique aspects of ERRβ biology that set it apart from the other two estrogen-related receptors, with a focus on the impact of alternative splicing on the structure and function of this receptor. PMID:27507929

  17. Estrogen-related receptor β (ERRβ) - renaissance receptor or receptor renaissance?

    PubMed

    Divekar, Shailaja D; Tiek, Deanna M; Fernandez, Aileen; Riggins, Rebecca B

    2016-01-01

    Estrogen-related receptors (ERRs) are founding members of the orphan nuclear receptor (ONR) subgroup of the nuclear receptor superfamily. Twenty-seven years of study have yet to identify cognate ligands for the ERRs, though they have firmly placed ERRα and ERRγ at the intersection of cellular metabolism and oncogenesis. The pace of discovery for novel functions of ERRβ, however, has until recently been somewhat slower than that of its family members. ERRβ has also been largely ignored in summaries and perspectives of the ONR literature. Here, we provide an overview of established and emerging knowledge of ERRβ in mouse, man, and other species, highlighting unique aspects of ERRβ biology that set it apart from the other two estrogen-related receptors, with a focus on the impact of alternative splicing on the structure and function of this receptor.

  18. Estrogen-related receptor β (ERRβ) - renaissance receptor or receptor renaissance?

    PubMed

    Divekar, Shailaja D; Tiek, Deanna M; Fernandez, Aileen; Riggins, Rebecca B

    2016-01-01

    Estrogen-related receptors (ERRs) are founding members of the orphan nuclear receptor (ONR) subgroup of the nuclear receptor superfamily. Twenty-seven years of study have yet to identify cognate ligands for the ERRs, though they have firmly placed ERRα and ERRγ at the intersection of cellular metabolism and oncogenesis. The pace of discovery for novel functions of ERRβ, however, has until recently been somewhat slower than that of its family members. ERRβ has also been largely ignored in summaries and perspectives of the ONR literature. Here, we provide an overview of established and emerging knowledge of ERRβ in mouse, man, and other species, highlighting unique aspects of ERRβ biology that set it apart from the other two estrogen-related receptors, with a focus on the impact of alternative splicing on the structure and function of this receptor. PMID:27507929

  19. Bazedoxifene, a new orphan drug for the treatment of bleeding in hereditary haemorrhagic telangiectasia.

    PubMed

    Zarrabeitia, Roberto; Ojeda-Fernandez, Luisa; Recio, Lucia; Bernabéu, Carmelo; Parra, Jose A; Albiñana, Virginia; Botella, Luisa M

    2016-06-01

    Hereditary haemorrhagic telangiectasia (HHT), or Rendu-Osler-Weber syndrome, is a dominant genetic vascular disorder. In HHT, blood vessels are weak and prone to bleeding, leading to epistaxis and anaemia, severely affecting patients' quality of life. Development of vascular malformations in HHT patients is originated mainly by mutations in ACVRL1/ALK1 (activin receptor-like kinase type I) or Endoglin (ENG) genes. These genes encode proteins of the TGF-β signalling pathway in endothelial cells, controlling angiogenesis. Haploinsufficiency of these proteins is the basis of HHT pathogenicity. It was our objective to study the efficiency of Bazedoxifene, a selective estrogen receptor modulator (SERM) in HHT, looking for a decrease in epistaxis, and understanding the underlying molecular mechanism. Plasma samples of five HHT patients were collected before, and after 1 and 3 months of Bazedoxifene treatment. ENG and ALK1 expression in activated mononuclear cells derived from blood, as well as VEGF plasma levels, were measured. Quantification of Endoglin and ALK1 mRNA was done in endothelial cells derived from HHT and healthy donors, after in vitro treatment with Bazedoxifene. Angiogenesis was also measured by tubulogenesis and wound healing assays. Upon Bazedoxifene treatment, haemoglobin levels of HHT patients increased and the quantity and frequency of epistaxis decreased. Bazedoxifene increased Endoglin and ALK1 mRNA levels, in cells derived from blood samples and in cultured endothelial cells, promoting tube formation. In conclusion, Bazedoxifene seems to decrease bleeding in HHT by partial compensation of haploinsufficiency. The results shown here are the basis of a new orphan drug designation for HHT by the European Medicine Agency (EMA). PMID:26818701

  20. Current progress in the management of rare diseases and orphan drugs in China

    PubMed Central

    Gong, Shiwei; Jin, Si

    2012-01-01

    Summary Currently, the issues of how to treat rare diseases and to improve accessibility to orphan drugs are arousing more and more concerns in China. Here we describe the push and pull incentive policies for rare diseases and orphan drugs and analyze the coverage and reimbursement level of rare diseases in the current Chinese medical insurance system. Three key obstacle factors that hinder Chinese patients' accessibility to timely drug treatment are summarized. Based on a comprehensive analysis, the measures of orphan drugs legislation, incentive mechanism, supply mechanism, and reimbursement mechanism are urgently expected to be established with the purpose of improving healthcare for patients with rare diseases in China. PMID:25343073

  1. Orphan symptoms in advanced cancer patients followed at home.

    PubMed

    Mercadante, Sebastiano; Porzio, Giampiero; Valle, Alessandro; Fusco, Flavio; Aielli, Federica; Adile, Claudio; Casuccio, Alessandra

    2013-12-01

    Orphan symptoms are rarely assessed, particularly at home. The aim of this multicenter prospective study was to assess the prevalence of these symptoms and eventual factors possibly associated in advanced cancer patients at admission of a home care program. A prospective study was performed at three home care programs in Italy. Patients' data were collected, including age, sex, diagnosis, and Karnofsky status. Possible contributing factors were analyzed; preexisting neurological diseases, cerebral metastases, hyperthermia, diabetes, a state of dehydration clinically evident and/or oliguria, possible biochemical parameters when available, data regarding recent chemotherapy, opioids and doses, use of neuroleptics, benzodiazepine or anticonvulsants, corticosteroids, anti-inflammatory, and antibiotics were collected. Myoclonus, hiccup, sweating, pruritus, and tenesmus, either rectal or vesical, were assessed, according to a preliminary definition, at time of home care program admission. Three hundred sixty-two patients were surveyed at the three home care programs. Globally, 48 patients presented one or more orphan symptoms in the period taken into consideration, and 7 patients presented more than 1 symptom. One patient presented occasional and diffuse myoclonus. Nineteen patients presented sweating, 13 patients presented pruritus, and 14 patients presented hiccup. Finally, nine patients presented rectal or vesical tenesmus. There was a significant correlation between sweating and transdermal fentanyl use (P = 0.044), fever (P = 0.001), hiccup (P < 0.0005), and vesical tenesmus (P = 0.028). Pruritus was not associated to any factor. Hiccup was associated with gender (males, P = 0.006) and sweating (P < 0.0005). Vesical tenesmus was associated with fever (P = 0.019) and sweating (P = 0.028). Although the symptoms examined have a low prevalence in advanced cancer patients admitted to home care, the distress for patients may be high and

  2. Unveiling the population of orphan γ-ray bursts

    NASA Astrophysics Data System (ADS)

    Ghirlanda, G.; Salvaterra, R.; Campana, S.; Vergani, S. D.; Japelj, J.; Bernardini, M. G.; Burlon, D.; D'Avanzo, P.; Melandri, A.; Gomboc, A.; Nappo, F.; Paladini, R.; Pescalli, A.; Salafia, O. S.; Tagliaferri, G.

    2015-06-01

    Gamma-ray bursts (GRBs) are detectable in the γ-ray band if their jets are oriented toward the observer. However, for each GRB with a typical θjet, there should be ~2/θ2jet bursts whose emission cone is oriented elsewhere in space. These off-axis bursts can eventually be detected when, due to the deceleration of their relativistic jets, the beaming angle becomes comparable to the viewing angle. Orphan afterglows (OAs) should outnumber the current population of bursts detected in the γ-ray band even if they have not been conclusively observed so far at any frequency. We compute the expected flux of the population of orphan afterglows in the mm, optical, and X-ray bands through a population synthesis code of GRBs and the standard afterglow emission model. We estimate the detection rate of OAs with ongoing and forthcoming surveys. The average duration of OAs as transients above a given limiting flux is derived and described with analytical expressions: in general OAs should appear as daily transients in optical surveys and as monthly/yearly transients in the mm/radio band. We find that ~2 OA yr-1 could already be detected by Gaia and up to 20 OA yr-1 could be observed by the ZTF survey. A larger number of 50 OA yr-1 should be detected by LSST in the optical band. For the X-ray band, ~26 OA yr-1 could be detected by the eROSITA. For the large population of OA detectable by LSST, the X-ray and optical follow up of the light curve (for the brightest cases) and/or the extensive follow up of their emission in the mm and radio band could be the key to disentangling their GRB nature from other extragalactic transients of comparable flux density.

  3. Currents and Hydrographic Variability in Orphan Basin, 2004-2010

    NASA Astrophysics Data System (ADS)

    Loder, J. W.; Geshelin, Y.; Yashayaev, I.

    2010-12-01

    Orphan Basin is a deep (>3000m) and broad (>200km) indentation of the continental margin north of Flemish Cap which partially lies in the exit pathways of the Labrador Current (LC) and Deep Western Boundary Current (DWBC) from the Labrador Sea. Since 2004, the Bedford Institute of Oceanography has been carrying out a moored measurement and annual survey program to describe and understand currents and hydrographic variability in the area, with focus on ocean climate variability and energetic features relevant to oil and gas exploration. The observations have identified seasonal and interannual variability in water mass properties that can be linked to upstream variability on the AR7W line in the Labrador Sea, thereby helping to understand the fate of Labrador Sea Water and other DWBC waters. The moored measurements have confirmed the expectation that low-frequency currents and drift are equatorward and generally weak across the basin, but with some near-bottom intensification of the flow associated with the DWBC and a stronger barotropic intensification associated with the LC over the slope. The measurements have also identified two energetic and unexpected types of current features at higher frequencies - tall and isolated mesoscale eddies, and strong upper-ocean inertial oscillations. The eddies extend over the entire water column and drift with the flow in water depths of 2200-2800m, with radii of order 20 km, peak (cyclonic) currents of about 0.5 m/s at mid depths, and a local occurrence rate of about one eddy every few months. The intermittent inertial oscillations penetrate to 300-m depth, with near-surface speeds up to 1 m/s, persistence over periods up to 10-30 days, and horizontal coherence over distances exceeding 80 km. This presentation will provide an overview of the observed variability in Orphan Basin during 2004-2010 with focus on the features noted above.

  4. Orphan GPR110 (ADGRF1) targeted by N-docosahexaenoylethanolamine in development of neurons and cognitive function

    PubMed Central

    Lee, Ji-Won; Huang, Bill X.; Kwon, HeungSun; Rashid, Md Abdur; Kharebava, Giorgi; Desai, Abhishek; Patnaik, Samarjit; Marugan, Juan; Kim, Hee-Yong

    2016-01-01

    Docosahexaenoic acid (DHA, 22:6n-3) is an omega-3 fatty acid essential for proper brain development. N-docosahexaenoylethanolamine (synaptamide), an endogenous metabolite of DHA, potently promotes neurogenesis, neuritogenesis and synaptogenesis; however, the underlying molecular mechanism is not known. Here, we demonstrate orphan G-protein coupled receptor 110 (GPR110, ADGRF1) as the synaptamide receptor, mediating synaptamide-induced bioactivity in a cAMP-dependent manner. Mass spectrometry-based proteomic characterization and cellular fluorescence tracing with chemical analogues of synaptamide reveal specific binding of GPR110 to synaptamide, which triggers cAMP production with low nM potency. Disruption of this binding or GPR110 gene knockout abolishes while GPR110 overexpression enhances synaptamide-induced bioactivity. GPR110 is highly expressed in fetal brains but rapidly decreases after birth. GPR110 knockout mice show significant deficits in object recognition and spatial memory. GPR110 deorphanized as a functional synaptamide receptor provides a novel target for neurodevelopmental control and new insight into mechanisms by which DHA promotes brain development and function. PMID:27759003

  5. The genomisotopic approach: a systematic method to isolate products of orphan biosynthetic gene clusters.

    PubMed

    Gross, Harald; Stockwell, Virginia O; Henkels, Marcella D; Nowak-Thompson, Brian; Loper, Joyce E; Gerwick, William H

    2007-01-01

    With the increasing number of genomes sequenced and available in the public domain, a large number of orphan gene clusters, for which the encoded natural product is unknown, have been identified. These orphan gene clusters represent a tremendous source of novel and possibly bioactive compounds. Here, we describe a "genomisotopic approach," which employs a combination of genomic sequence analysis and isotope-guided fractionation to identify unknown compounds synthesized from orphan gene clusters containing nonribosomal peptide synthetases. Analysis of the Pseudomonas fluorescens Pf-5 genome led to the identification of an orphan gene cluster predicted to code for the biosynthesis of a lipopeptide natural product. Application of the genomisotopic approach to isolate the product of this gene cluster resulted in the discovery of orfamide A, founder of a group of bioactive cyclic lipopeptides.

  6. 77 FR 65709 - Agency Information Collection Activities: Petition To Classify Orphan as an Immediate Relative...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-10-30

    ... uses Form I-600 to determine whether a child alien is an eligible orphan. Form I-600A is used to... adult member (age 18 and older), who lives in the home of the prospective adoptive parent(s), except...

  7. Nuclear receptors and pathogenesis of pancreatic cancer

    PubMed Central

    Polvani, Simone; Tarocchi, Mirko; Tempesti, Sara; Galli, Andrea

    2014-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a median overall survival time of 5 mo and the five years survival less than 5%, a rate essentially unchanged over the course of the years. A well defined progression model of accumulation of genetic alterations ranging from single point mutations to gross chromosomal abnormalities has been introduced to describe the origin of this disease. However, due to the its subtle nature and concurring events PDAC cure remains elusive. Nuclear receptors (NR) are members of a large superfamily of evolutionarily conserved ligand-regulated DNA-binding transcription factors functionally involved in important cellular functions ranging from regulation of metabolism, to growth and development. Given the nature of their ligands, NR are very tempting drug targets and their pharmacological modulation has been widely exploited for the treatment of metabolic and inflammatory diseases. There are now clear evidences that both classical ligand-activated and orphan NR are involved in the pathogenesis of PDAC from its very early stages; nonetheless many aspects of their role are not fully understood. The purpose of this review is to highlight the striking connections that link peroxisome proliferator activated receptors, retinoic acid receptors, retinoid X receptor, androgen receptor, estrogen receptors and the orphan NR Nur, chicken ovalbumin upstream promoter transcription factor II and the liver receptor homologue-1 receptor to PDAC development, connections that could lead to the identification of novel therapies for this disease. PMID:25232244

  8. The evolving drug development landscape: from blockbusters to niche busters in the orphan drug space.

    PubMed

    Kumar Kakkar, Ashish; Dahiya, Neha

    2014-06-01

    Strategy, Management and Health Policy Large pharmaceutical companies have traditionally focused on the development of blockbuster drugs that target disease states with large patient populations. However, with large-scale patent expirations and competition from generics and biosimilars, anemic pipelines, escalating clinical trial costs, and global health-care reform, the blockbuster model has become less viable. Orphan drug initiatives and the incentives accompanied by these have fostered renewed research efforts in the area of rare diseases and have led to the approval of more than 400 orphan products. Despite targeting much smaller patient populations, the revenue-generating potential of orphan drugs has been shown to be huge, with a greater return on investment than non-orphan drugs. The success of these "niche buster" therapeutics has led to a renewed interest from "Big Pharma" in the rare disease landscape. This article reviews the key drivers for orphan drug research and development, their profitability, and issues surrounding the emergence of large pharmaceutical firms into the orphan drug space.

  9. The Burden of Orphans and Vulnerable Children Due to HIV/AIDS in Cameroon

    PubMed Central

    Nsagha, Dickson S; Bissek, Anne-Cécile ZK; Nsagha, Sarah M; Assob, Jules-Clement N; Kamga, Henri-Lucien F; Njamnshi, Dora M; Njunda, Anna L; Obama, Marie-Thérèse O; Njamnshi, Alfred K

    2012-01-01

    HIV/AIDS is a major public health problem in Cameroon and Africa, and the challenges of orphans and vulnerable children are a threat to child survival, growth and development. The HIV prevalence in Cameroon was estimated at 5.1% in 2010. The objective of this study was to assess the burden of orphans and vulnerable children due to HIV/AIDS in Cameroon. A structured search to identify publications on orphans and other children made vulnerable by AIDS was carried out. A traditional literature search on google, PubMed and Medline using the keywords: orphans, vulnerable children, HIV/AIDS and Cameroon was conducted to identify potential AIDS orphans publications, we included papers on HIV prevalence in Cameroon, institutional versus integrated care of orphans, burden of children orphaned by AIDS and projections, impact of AIDS orphans on Cameroon, AIDS orphans assisted through the integrated care approach, and comparism of the policies of orphans care in the central African sub-region. We also used our participatory approach working experience with traditional rulers, administrative authorities and health stakeholders in Yaounde I and Yaounde VI Councils, Nanga Eboko Health District, Isangelle and Ekondo Titi Health Areas, Bafaka-Balue, PLAN Cameroon, the Pan African Institute for Development-West Africa, Save the orphans Foundation, Ministry of Social Affairs, and the Ministry of Public Health. Results show that only 9% of all OVC in Cameroon are given any form of support. AIDS death continue to rise in Cameroon. In 1995, 7,900 people died from AIDS in the country; and the annual number rose to 25,000 in 2000. Out of 1,200,000 orphans and vulnerable children in Cameroon in 2010, 300,000(25%) were AIDS orphans. Orphans and the number of children orphaned by AIDS has increased dramatically from 13,000 in 1995 to 304,000 in 2010. By 2020, this number is projected to rise to 350,000. These deaths profoundly affect families, which often are split up and left without any

  10. Melatonin Receptor Genes in Vertebrates

    PubMed Central

    Li, Di Yan; Smith, David Glenn; Hardeland, Rüdiger; Yang, Ming Yao; Xu, Huai Liang; Zhang, Long; Yin, Hua Dong; Zhu, Qing

    2013-01-01

    Melatonin receptors are members of the G protein-coupled receptor (GPCR) family. Three genes for melatonin receptors have been cloned. The MT1 (or Mel1a or MTNR1A) and MT2 (or Mel1b or MTNR1B) receptor subtypes are present in humans and other mammals, while an additional melatonin receptor subtype, Mel1c (or MTNR1C), has been identified in fish, amphibians and birds. Another melatonin related orphan receptor, GPR50, which does not bind melatonin, is found exclusively in mammals. The hormone melatonin is secreted primarily by the pineal gland, with highest levels occurring during the dark period of a circadian cycle. This hormone acts systemically in numerous organs. In the brain, it is involved in the regulation of various neural and endocrine processes, and it readjusts the circadian pacemaker, the suprachiasmatic nucleus. This article reviews recent studies of gene organization, expression, evolution and mutations of melatonin receptor genes of vertebrates. Gene polymorphisms reveal that numerous mutations are associated with diseases and disorders. The phylogenetic analysis of receptor genes indicates that GPR50 is an outgroup to all other melatonin receptor sequences. GPR50 may have separated from a melatonin receptor ancestor before the split between MTNR1C and the MTNR1A/B ancestor. PMID:23712359

  11. Preeclampsia – Will Orphan Drug Status Facilitate Innovative Biological Therapies?

    PubMed Central

    Hahn, Sinuhe

    2015-01-01

    It is generally accepted that the development of novel therapies to treat pregnancy-related disorders, such as preeclampsia, is hampered by the paucity of research funding. Hence, it is with great interest to become aware of at least three novel therapeutic approaches for the treatment of this disorder: exploiting either the anticoagulant activity of antithrombin, the free radical scavenging activity of alpha-1-microglobulin, or the regenerative capacity of placenta-derived mesenchymal stem cells. As these projects are being carried out by small biotech enterprises, the question arises of how they are able to fund such undertakings. A novel strategy adopted by two of these companies is that they successfully petitioned US and EU agencies in order that preeclampsia is accepted in the register of rare or orphan diseases. This provides a number of benefits including market exclusivity, assistance with clinical trials, and dedicated funding schemes. Other strategies to supplement meager research funds, especially to test novel approaches, could be crowdfunding, a venture that relies on intimate interaction with advocacy groups. In other words, preeclampsia meets Facebook. Perhaps similar strategies can be adopted to examine novel therapies targeting either the imbalance in pro- or anti-angiogenic growth factors, complement activation, reduced levels of placenta protein 13, or excessive neutrophil activation evident in preeclampsia. PMID:25767802

  12. Preeclampsia - will orphan drug status facilitate innovative biological therapies?

    PubMed

    Hahn, Sinuhe

    2015-01-01

    It is generally accepted that the development of novel therapies to treat pregnancy-related disorders, such as preeclampsia, is hampered by the paucity of research funding. Hence, it is with great interest to become aware of at least three novel therapeutic approaches for the treatment of this disorder: exploiting either the anticoagulant activity of antithrombin, the free radical scavenging activity of alpha-1-microglobulin, or the regenerative capacity of placenta-derived mesenchymal stem cells. As these projects are being carried out by small biotech enterprises, the question arises of how they are able to fund such undertakings. A novel strategy adopted by two of these companies is that they successfully petitioned US and EU agencies in order that preeclampsia is accepted in the register of rare or orphan diseases. This provides a number of benefits including market exclusivity, assistance with clinical trials, and dedicated funding schemes. Other strategies to supplement meager research funds, especially to test novel approaches, could be crowdfunding, a venture that relies on intimate interaction with advocacy groups. In other words, preeclampsia meets Facebook. Perhaps similar strategies can be adopted to examine novel therapies targeting either the imbalance in pro- or anti-angiogenic growth factors, complement activation, reduced levels of placenta protein 13, or excessive neutrophil activation evident in preeclampsia.

  13. Exiling children, creating orphans: when immigration policies hurt citizens.

    PubMed

    Zayas, Luis H; Bradlee, Mollie H

    2014-04-01

    Citizen-children born in the United States to undocumented immigrants have become collateral damage of immigration enforcement. These children suffer the effects of immigration laws designed to deport large numbers of people. In removal proceedings, parents often must decide to either leave their citizen-children behind in the care of others or take them to a country the child may have never known. Accordingly, immigration policy frequently creates two de facto classes of children: exiles and orphans. In discussing these classes, the authors offer a summary of how U.S. citizen-children come into contact with the immigration enforcement system. The article explores the impact of detention and deportation on the health, mental health, and developmental trajectories of citizen-children and argues for reforms in policy and practice that will adhere to the highest standards of child welfare practice. By integrating these children into the immigration discourse, practitioners and policymakers will be better able to understand the effects of immigration enforcement, reduce harm to children, and provide for the protection of their rights.

  14. HIV infection and related risk behaviors: does school support level the playing field between orphans and nonorphans in Zimbabwe?

    PubMed

    Luseno, Winnie; Zhang, Lei; Rusakaniko, Simbarashe; Cho, Hyunsan; Hallfors, Denise

    2015-01-01

    Research is limited on whether providing school support to female adolescent orphans mitigates their HIV risk disadvantage compared to other female adolescents. This paper examines 2011 Zimbabwe Demographic and Health Survey (ZDHS) HIV-related biomarker and behavior data for orphaned and nonorphaned rural adolescent females to compare findings from a similar sample participating in a randomized controlled trial (RCT) testing school support as HIV prevention. HIV status, marriage, pregnancy, sexual debut, school dropout, years of schooling, and socioeconomic status were analyzed with the combined data-sets. Bivariate analyses compared variables between RCT comprehensive intervention and delayed partial intervention conditions, and between ZDHS orphan and nonorphan groups. Multivariable analyses included a series of group comparisons as follows: ZDHS orphans vs. ZDHS nonorphans; RCT orphans in each condition vs. ZDHS nonorphans; RCT orphans in each condition vs. ZDHS orphans. Analyses methods accounted for the complex survey sampling design within each data-set. A total of 751 observations were included. All orphan groups had consistently higher odds of HIV infection than ZDHS nonorphans. ZDHS orphans had higher odds of marriage, pregnancy, and sexual debut than ZDHS nonorphans. Comprehensive intervention participants had lower odds of marriage, sexual debut, and school dropout than ZDHS nonorphans. RCT participants in both conditions had lower odds of marriage, sexual debut, and school dropout than ZDHS orphans. The findings indicate that orphans are at a distinct disadvantage to HIV risk compared to nonorphans, and much of this is likely related to vertical transmission. We found no evidence that provision of school fees to orphans will reduce their risk of HIV infection relative to nonorphans but further evidence that such programs may reduce risk behaviors including early sexual debut, child marriage, and school dropout. Further research is needed to determine

  15. What makes orphans in Kigali, Rwanda, non-adherent to antiretroviral therapy? Perspectives of their caregivers

    PubMed Central

    Kikuchi, Kimiyo; Poudel, Krishna C; Muganda, John; Sato, Tomoko; Mutabazi, Vincent; Muhayimpundu, Ribakare; Majyambere, Adolphe; Nyonsenga, Simon P; Sase, Eriko; Jimba, Masamine

    2014-01-01

    Introduction Every year, approximately 260,000 children are infected with HIV in low- and middle-income countries. The timely initiation and high level of maintenance of antiretroviral therapy (ART) are crucial to reducing the suffering of HIV-positive children. We need to develop a better understanding of the background of children's ART non-adherence because it is not well understood. The purpose of this study is to explore the background related to ART non-adherence, specifically in relation to the orphan status of children in Kigali, Rwanda. Methods We conducted 19 focus group discussions with a total of 121 caregivers of HIV-positive children in Kigali. The primary data for analysis were verbatim transcripts and socio-demographic data. A content analysis was performed for qualitative data analysis and interpretation. Results The study found several contextual factors that influenced non-adherence: among double orphans, there was psychological distance between the caregivers and children, whereas economic burden was the primary issue among paternal orphans. The factors promoting adherence also were unique to each orphan status, such as the positive attitude about disclosing serostatus to the child by double orphans’ caregivers, and feelings of guilt about the child's condition among non-orphaned caregivers. Conclusions Knowledge of orphan status is essential to elucidate the factors influencing ART adherence among HIV-positive children. In this qualitative study, we identified the orphan-related contextual factors that influenced ART adherence. Understanding the social context is important in dealing with the challenges to ART adherence among HIV-positive children. PMID:25477050

  16. TRACING THE ORPHAN STREAM TO 55 kpc WITH RR LYRAE STARS

    SciTech Connect

    Sesar, Branimir; Cohen, Judith G.; Bellm, Eric C.; Levitan, David; Tang, Sumin; Waszczak, Adam; Kulkarni, Shrinivas R.; Prince, Thomas A.; Grillmair, Carl J.; Laher, Russ R.; Surace, Jason A.; Bhalerao, Varun B.; Ofek, Eran O.

    2013-10-10

    We report positions, velocities, and metallicities of 50 ab-type RR Lyrae (RRab) stars observed in the vicinity of the Orphan stellar stream. Using about 30 RRab stars classified as being likely members of the Orphan stream, we study the metallicity and the spatial extent of the stream. We find that RRab stars in the Orphan stream have a wide range of metallicities, from –1.5 dex to –2.7 dex. The average metallicity of the stream is –2.1 dex, identical to the value obtained by Newberg et al. using blue horizontal branch stars. We find that the most distant parts of the stream (40-50 kpc from the Sun) are about 0.3 dex more metal-poor than the closer parts (within ∼30 kpc), suggesting a possible metallicity gradient along the stream's length. We have extended the previous studies and have mapped the stream up to 55 kpc from the Sun. Even after a careful search, we did not identify any more distant RRab stars that could plausibly be members of the Orphan stream. If confirmed with other tracers, this result would indicate a detection of the end of the leading arm of the stream. We have compared the distances of Orphan stream RRab stars with the best-fit orbits obtained by Newberg et al. We find that model 6 of Newberg et al. cannot explain the distances of the most remote Orphan stream RRab stars, and conclude that the best fit to distances of Orphan stream RRab stars and to the local circular velocity is provided by potentials where the total mass of the Galaxy within 60 kpc is M{sub 60} ∼ 2.7 × 10{sup 11} M{sub ☉}, or about 60% of the mass found by previous studies. More extensive modeling that would consider non-spherical potentials and the possibility of misalignment between the stream and the orbit is highly encouraged.

  17. Rapid identification of sequences for orphan enzymes to power accurate protein annotation.

    PubMed

    Ramkissoon, Kevin R; Miller, Jennifer K; Ojha, Sunil; Watson, Douglas S; Bomar, Martha G; Galande, Amit K; Shearer, Alexander G

    2013-01-01

    The power of genome sequencing depends on the ability to understand what those genes and their proteins products actually do. The automated methods used to assign functions to putative proteins in newly sequenced organisms are limited by the size of our library of proteins with both known function and sequence. Unfortunately this library grows slowly, lagging well behind the rapid increase in novel protein sequences produced by modern genome sequencing methods. One potential source for rapidly expanding this functional library is the "back catalog" of enzymology--"orphan enzymes," those enzymes that have been characterized and yet lack any associated sequence. There are hundreds of orphan enzymes in the Enzyme Commission (EC) database alone. In this study, we demonstrate how this orphan enzyme "back catalog" is a fertile source for rapidly advancing the state of protein annotation. Starting from three orphan enzyme samples, we applied mass-spectrometry based analysis and computational methods (including sequence similarity networks, sequence and structural alignments, and operon context analysis) to rapidly identify the specific sequence for each orphan while avoiding the most time- and labor-intensive aspects of typical sequence identifications. We then used these three new sequences to more accurately predict the catalytic function of 385 previously uncharacterized or misannotated proteins. We expect that this kind of rapid sequence identification could be efficiently applied on a larger scale to make enzymology's "back catalog" another powerful tool to drive accurate genome annotation.

  18. Database identifies FDA-approved drugs with potential to be repurposed for treatment of orphan diseases.

    PubMed

    Xu, Kui; Coté, Timothy R

    2011-07-01

    Facing substantial obstacles to developing new therapies for rare diseases, some sponsors are looking to 'repurpose' drugs already approved for other conditions and use those therapies to treat rare diseases. In an effort to facilitate such repurposing and speed the delivery of new therapies to people who need them, we have established a new resource, the Rare Disease Repurposing Database (RDRD). The advantages of repurposed compounds include their demonstrated efficacy (in some clinical contexts), their observed toxicity profiles and their clearly described manufacturing controls. To create the RDRD, we matched the US Food and Drug Administration (FDA) orphan designation database to FDA drug and biological product approval lists. The RDRD lists 236 products that have received orphan status designation--that is, were found to be 'promising' for the treatment of a rare disease--and though not yet approved for marketing for that rare disease, they are already approved for marketing to treat some other disease or condition. The RDRD contains three tables: Orphan-designated products with at least one marketing approval for a common disease indication (N = 109); orphan-designated products with at least one marketing approval for a rare disease indication (N = 76); and orphan-designated products with marketing approvals for both common and rare disease indications (N = 51). While the data included in the database is a re-configuration/cross-indexing of information already released by the FDA, it offers sponsors a new tool for finding special opportunities to develop niche therapies for rare disease patients.

  19. The orphans of Eritrea: a five-year follow-up study.

    PubMed

    Wolff, P H; Fesseha, G

    1999-11-01

    A group of 4-7-year-old war orphans were examined for the first time while living in an institution (the Solomuna Orphanage) during a protracted war between Eritrea and Ethiopia. At that time, they were compared to a group of refugee children living in a nearby camp with one or both parents. The orphans exhibited significantly more behavioral symptoms than the refugee children, but performed the cognitive tests at a more advanced level. Five years later, the orphans were re-examined; and they were compared to unaccompanied 9-12-year-children living in one of two residential settings that differed qualitatively in their social climate, principles of child care, and patterns of staff-child interactions. Although the severity of their behavioral symptoms had diminished, the orphans still exhibited many symptoms of emotional distress. On the other hand, they performed the cognitive measures as well as, or better than, unaccompanied children who had been protected from the terrors of war. The cross-sectional comparisons indicated that a residential setting that respects the individuality of children and promotes their close personal ties with at least one staff member can ameliorate many of the more serious psychological sequelae of having lost both parents and being exposed to the physical dangers of the war. The implications for war orphans in other Third World countries are discussed.

  20. Changing patterns of orphan care due to the HIV epidemic in western Kenya.

    PubMed

    Nyambedha, Erick Otieno; Wandibba, Simiyu; Aagaard-Hansen, Jens

    2003-07-01

    The HIV/AIDS epidemic has given rise to major demographic changes including an alarming number of orphans in sub-Saharan Africa. The study describes a rural community in western Kenya in which one out of three children below 18 years of age had lost at least one biological parent-and one out of nine had lost both. The main problems these children faced were lack of school fees, food and access to medical care. The high number of orphans has overwhelmed the traditional mechanisms for orphan care, which were based on patrilineal kinship ties. Thus, 28% of the orphans were looked after by culturally "inappropriate" categories such as matrilineal kin or strangers. Furthermore, many of the caretakers were themselves not capable due to ill health or old age. Factors such as poverty, negative attitudes, and traditional funeral customs made the orphans' situation even worse. The authors conclude that though community-based interventions are urgently needed as the most appropriate way to address the issue, the complex, local reality in which cultural factors, kinship ties, and poverty are interwoven needs to be taken into consideration if sustainable solutions are to be found. PMID:12765710

  1. Hunting the parent of the Orphan stream. II. The first high-resolution spectroscopic study

    SciTech Connect

    Casey, Andrew R.; Keller, Stefan C.; Da Costa, Gary; Maunder, Elizabeth; Frebel, Anna

    2014-03-20

    We present the first high-resolution spectroscopic study on the Orphan stream for five stream candidates, observed with the Magellan Inamori Kyocera Echelle spectrograph on the Magellan Clay telescope. The targets were selected from the low-resolution catalog of Casey et al.: three high-probability members, one medium, and one low-probability stream candidate were observed. Our analysis indicates that the low- and medium-probability targets are metal-rich field stars. The remaining three high-probability targets range over ∼1 dex in metallicity, and are chemically distinct compared to the other two targets and all standard stars: low [α/Fe] abundance ratios are observed, and lower limits are ascertained for [Ba/Y], which sit well above the Milky Way trend. These chemical signatures demonstrate that the undiscovered parent system is unequivocally a dwarf spheroidal galaxy, consistent with dynamical constraints inferred from the stream width and arc. As such, we firmly exclude the proposed association between NGC 2419 and the Orphan stream. A wide range in metallicities adds to the similarities between the Orphan stream and Segue 1, although the low [α/Fe] abundance ratios in the Orphan stream are in tension with the high [α/Fe] values observed in Segue 1. Open questions remain before Segue 1 could possibly be claimed as the 'parent' of the Orphan stream. The parent system could well remain undiscovered in the southern sky.

  2. Changing patterns of orphan care due to the HIV epidemic in western Kenya.

    PubMed

    Nyambedha, Erick Otieno; Wandibba, Simiyu; Aagaard-Hansen, Jens

    2003-07-01

    The HIV/AIDS epidemic has given rise to major demographic changes including an alarming number of orphans in sub-Saharan Africa. The study describes a rural community in western Kenya in which one out of three children below 18 years of age had lost at least one biological parent-and one out of nine had lost both. The main problems these children faced were lack of school fees, food and access to medical care. The high number of orphans has overwhelmed the traditional mechanisms for orphan care, which were based on patrilineal kinship ties. Thus, 28% of the orphans were looked after by culturally "inappropriate" categories such as matrilineal kin or strangers. Furthermore, many of the caretakers were themselves not capable due to ill health or old age. Factors such as poverty, negative attitudes, and traditional funeral customs made the orphans' situation even worse. The authors conclude that though community-based interventions are urgently needed as the most appropriate way to address the issue, the complex, local reality in which cultural factors, kinship ties, and poverty are interwoven needs to be taken into consideration if sustainable solutions are to be found.

  3. Orphan Gamma-Ray Burst Radio Afterglows: Candidates and Constraints on Beaming

    NASA Astrophysics Data System (ADS)

    Levinson, Amir; Ofek, Eran O.; Waxman, Eli; Gal-Yam, Avishay

    2002-09-01

    The number of orphan radio afterglows associated with gamma-ray bursts (GRBs) that should be detected by a flux-limited radio survey is calculated. It is shown that for jetted GRBs, this number is smaller for a smaller jet opening angle θ, contrary to naive expectation. For a beaming factor f-1b≡(θ2/2)- 1~=500, roughly the value inferred by Frail et al. from analysis of afterglow light curves, we predict that between several hundred to several thousand orphan radio afterglows should be detectable (over all sky) above 1 mJy at GHz frequencies at any given time. This orphan population is dominated by sources lying at distances of a few hundred Mpc and having an age of ~1 yr. A search for pointlike radio transients with flux densities greater than 6 mJy was conducted using the FIRST and NVSS surveys, yielding a list of nine orphan candidates. We argue that most of the candidates are unlikely to be radio supernovae. However, the possibility that they are radio-loud active galactic nuclei cannot be ruled out without further observation. Our analysis sets a conservative 95% CL upper limit for the all-sky number of radio orphans, which corresponds to a lower limit f-1b>13 on the beaming factor. Rejection of all candidates found in our search would imply f-1b>80. This, and the possibility that some candidates may indeed be radio afterglows, strongly motivate further observations of these transients.

  4. GRB Orphan Afterglows in Present and Future Radio Transient Surveys

    NASA Astrophysics Data System (ADS)

    Ghirlanda, G.; Burlon, D.; Ghisellini, G.; Salvaterra, R.; Bernardini, M. G.; Campana, S.; Covino, S.; D'Avanzo, P.; D'Elia, V.; Melandri, A.; Murphy, T.; Nava, L.; Vergani, S. D.; Tagliaferri, G.

    2014-05-01

    Orphan Afterglows (OA) are slow transients produced by Gamma Ray Bursts seen off-axis that become visible on timescales of days/years at optical/NIR and radio frequencies, when the prompt emission at high energies (X and γ rays) has already ceased. Given the typically estimated jet opening angle of GRBs θjet ~ 3°, for each burst pointing to the Earth there should be a factor ~ 700 more GRBs pointing in other directions. Despite this, no secure OAs have been detected so far. Through a population synthesis code we study the emission properties of the population of OA at radio frequencies. OAs reach their emission peak on year-timescales and they last for a comparable amount of time. The typical peak fluxes (which depend on the observing frequency) are of few μJy in the radio band with only a few OA reaching the mJy level. These values are consistent with the upper limits on the radio flux of SN Ib/c observed at late times. We find that the OA radio number count distribution has a typical slope - 1.7 at high fluxes and a flatter ( - 0.4) slope at low fluxes with a break at a frequency-dependent flux. Our predictions of the OA rates are consistent with the (upper) limits of recent radio surveys and archive searches for radio transients. Future radio surveys like VAST/ASKAP at 1.4 GHz should detect ~ 3 × 10- 3 OA deg- 2 yr- 1, MeerKAT and EVLA at 8.4 GHz should see ~ 3 × 10- 1 OA deg- 2 yr- 1. The SKA, reaching the μJy flux limit, could see up to ~ 0.2 - 1.5 OA deg- 2 yr- 1. These rates also depend on the duration of the OA above a certain flux limit and we discuss this effect with respect to the survey cadence.

  5. Profitability and Market Value of Orphan Drug Companies: A Retrospective, Propensity-Matched Case-Control Study

    PubMed Central

    Hughes, Dyfrig A.; Poletti-Hughes, Jannine

    2016-01-01

    Background Concerns about the high cost of orphan drugs has led to questions being asked about the generosity of the incentives for development, and associated company profits. Methods We conducted a retrospective, propensity score matched study of publicly-listed orphan companies. Cases were defined as holders of orphan drug market authorisation in Europe or the USA between 2000–12. Control companies were selected based on their propensity for being orphan drug market authorisation holders. We applied system General Method of Moments to test whether companies with orphan drug market authorization are valued higher, as measured by the Tobin’s Q and market to book value ratios, and are more profitable based on return on assets, than non-orphan drug companies. Results 86 companies with orphan drug approvals in European (4), USA (61) or both (21) markets were matched with 258 controls. Following adjustment, orphan drug market authorization holders have a 9.6% (95% confidence interval, 0.6% to 18.7%) higher return on assets than non-orphan drug companies; Tobin’s Q was higher by 9.9% (1.0% to 19.7%); market to book value by 15.7% (3.1% to 30.0%) and operating profit by 516% (CI 19.8% to 1011%). For each additional orphan drug sold, return on assets increased by 11.1% (0.6% to 21.3%), Tobin’s Q by 2.7% (0.2% to 5.2%), and market to book value ratio by 5.8% (0.7% to 10.9%). Conclusions Publicly listed pharmaceutical companies that are orphan drug market authorization holders are associated with higher market value and greater profits than companies not producing treatments for rare diseases. PMID:27768685

  6. A Review of Melatonin, Its Receptors and Drugs

    PubMed Central

    Emet, Mucahit; Ozcan, Halil; Ozel, Lutfu; Yayla, Muhammed; Halici, Zekai; Hacimuftuoglu, Ahmet

    2016-01-01

    After a Turkish scientist took Nobel Prize due to his contributions to understand clock genes, melatonin, closely related to these genes, may begin to shine. Melatonin, a hormone secreted from the pineal gland at night, plays roles in regulating sleep-wake cycle, pubertal development and seasonal adaptation. Melatonin has antinociceptive, antidepressant, anxiolytic, antineophobic, locomotor activity-regulating, neuroprotective, anti-inflammatory, pain-modulating, blood pressure-reducing, retinal, vascular, anti-tumor and antioxidant effects. It is related with memory, ovarian physiology, and osteoblast differentiation. Pathologies associated with an increase or decrease in melatonin levels are summarized in the review. Melatonin affects by four mechanisms: 1) Binding to melatonin receptors in plasma membrane, 2) Binding to intracellular proteins such as calmoduline, 3) Binding to Orphan nuclear receptors, and 4) Antioxidant effect. Receptors associated with melatonin are as follows: 1) Melatonin receptor type 1a: MT1 (on cell membrane), 2) Melatonin receptor type 1b: MT2 (on cell membrane), 3) Melatonin receptor type 1c (found in fish, amphibians and birds), 4) Quinone reductase 2 enzyme (MT3 receptor, a detoxification enzyme), 5) RZR/RORα: Retinoid-related Orphan nuclear hormone receptor (with this receptor, melatonin binds to the transcription factors in nucleus), and 6) GPR50: X-linked Melatonin-related Orphan receptor (it is effective in binding of melatonin to MT1). Melatonin agonists such as ramelteon, agomelatine, circadin, TIK-301 and tasimelteon are introduced and side effects will be discussed. In conclusion, melatonin and related drugs is a new and promising era for medicine. Melatonin receptors and melatonin drugs will take attention with greater interest day by day in the future. PMID:27551178

  7. A Review of Melatonin, Its Receptors and Drugs.

    PubMed

    Emet, Mucahit; Ozcan, Halil; Ozel, Lutfu; Yayla, Muhammed; Halici, Zekai; Hacimuftuoglu, Ahmet

    2016-06-01

    After a Turkish scientist took Nobel Prize due to his contributions to understand clock genes, melatonin, closely related to these genes, may begin to shine. Melatonin, a hormone secreted from the pineal gland at night, plays roles in regulating sleep-wake cycle, pubertal development and seasonal adaptation. Melatonin has antinociceptive, antidepressant, anxiolytic, antineophobic, locomotor activity-regulating, neuroprotective, anti-inflammatory, pain-modulating, blood pressure-reducing, retinal, vascular, anti-tumor and antioxidant effects. It is related with memory, ovarian physiology, and osteoblast differentiation. Pathologies associated with an increase or decrease in melatonin levels are summarized in the review. Melatonin affects by four mechanisms: 1) Binding to melatonin receptors in plasma membrane, 2) Binding to intracellular proteins such as calmoduline, 3) Binding to Orphan nuclear receptors, and 4) Antioxidant effect. Receptors associated with melatonin are as follows: 1) Melatonin receptor type 1a: MT1 (on cell membrane), 2) Melatonin receptor type 1b: MT2 (on cell membrane), 3) Melatonin receptor type 1c (found in fish, amphibians and birds), 4) Quinone reductase 2 enzyme (MT3 receptor, a detoxification enzyme), 5) RZR/RORα: Retinoid-related Orphan nuclear hormone receptor (with this receptor, melatonin binds to the transcription factors in nucleus), and 6) GPR50: X-linked Melatonin-related Orphan receptor (it is effective in binding of melatonin to MT1). Melatonin agonists such as ramelteon, agomelatine, circadin, TIK-301 and tasimelteon are introduced and side effects will be discussed. In conclusion, melatonin and related drugs is a new and promising era for medicine. Melatonin receptors and melatonin drugs will take attention with greater interest day by day in the future. PMID:27551178

  8. Orphans and at-risk children in Haiti: vulnerabilities and human rights issues postearthquake.

    PubMed

    Nicholas, Patrice K; George, Erin K; Raymond, Nadia; Lewis-OʼConnor, Annie; Victoria, Stephanie; Lucien, Sergeline; Peters-Lewis, Angelleen; Hickey, Nancy; Corless, Inge B; Tyer-Viola, Lynda; Davis, Sheila M; Barry, Donna; Marcelin, Naomie; Valcourt, Roodeline

    2012-01-01

    The vulnerability of children in Haiti has increased dramatically since the earthquake in January 2010. Prior to the earthquake, the prevalence of orphans and at-risk children was high but since the earthquake, more than 1 million people-with more than 380,000 children remaining displaced and living in over 1200 displacement sites. These existing conditions leave orphans and at-risk children vulnerable to exploitation, abuse, and increased risk of HIV/AIDS. This article will focus on the complex issues affecting orphans and at-risk children and the intersection with HIV/AIDS and human rights. Specific recommendations by United Nations Children's Fund are discussed. Nursing in Haiti must address the policy-related and population-specific approaches for the care of children living with or affected by HIV/AIDS.

  9. Inclusiveness: a mental health strategy for preventing future mental health problems among adolescents orphaned by AIDS.

    PubMed

    Thupayagale-Tshweneagae, G; Mokomane, Z

    2012-10-01

    The purpose of this paper is to raise an argument that inclusiveness will lessen the pain of losing a parent among adolescents orphaned by AIDS and as a result, prevent future mental health problems that may occur because of inappropriate grieving and maladaptive coping strategies. Participation of adolescents orphaned by AIDS in decisions pertaining to their parents' illnesses and funeral arrangements, for example, may shorten the grieving process and allow for closure. The paper draws data from focus group discussions that were held with 15 adolescents orphaned by AIDS in urban South Africa. The focus group discussions that were structured around four themes: grieving patterns; coping strategies; experience with loss; and expectations. The results of the study demonstrate inclusiveness as an overarching factor in the healing process. The concept is thus a strong recommendation for mental health practice and further study. PMID:22192336

  10. Development of an orphan drug by a start-up company. MetroGel for rosacea.

    PubMed

    Borgman, R J

    1992-01-01

    The Orphan Drug Act of 1983, along with the discovery of a new use for a known drug and an investor willing to assume the necessary risk, brought about the formation of a start-up pharmaceutical company. The primary incentive of the Orphan Drug Act of seven years of marketing exclusivity provided the protection from competition necessary for recovery of the significant research and development and marketing costs. The orphan product, MetroGel, for the treatment of rosacea, required approximately five years of development before it was approved for marketing by the Food and Drug Administration. MetroGel has become the number one drug in the United States for the treatment of rosacea. It currently is marketed in other countries through a licensing agreement with a major pharmaceutical company.

  11. Recent progress on nuclear receptor RORγ modulators.

    PubMed

    Cyr, Patrick; Bronner, Sarah M; Crawford, James J

    2016-09-15

    The retinoic acid receptor-related orphan receptor RORγ plays key roles in the development and differentiation of TH17 cells, and thus in IL-17 expression, thymocyte development and regulation of metabolism. With the recent progression into phase 2 clinical trials of both oral and topically administered inverse agonists, and with others close behind, there is significant interest in the discovery of RORγ modulators. This digest covers key developments around RORγ agonists, antagonists and inverse agonists; orthosteric and allosteric binders; and aims to summarize the available information concerning the potential utility of RORγ modulators. PMID:27542308

  12. Provision of Vocational Skills Education to Orphans: Lessons from Orphanage Centres in Dar es Salaam City, Tanzania

    ERIC Educational Resources Information Center

    Meli, Benjamin Mbeba

    2015-01-01

    This paper utilises data from a study that investigated the efficacy of vocational skills training provided to orphans from three orphanages in Temeke District, Dar es Salaam. The three orphanage centres that were studied are Kurasini National Children Home, Saudia and Don Bosco Vocational Centre. The sample comprised of 45 orphans, an official…

  13. Tectono-stratigraphic evolution and crustal architecture of the Orphan Basin during North Atlantic rifting

    NASA Astrophysics Data System (ADS)

    Gouiza, Mohamed; Hall, Jeremy; Welford, J. Kim

    2016-06-01

    The Orphan Basin is located in the deep offshore of the Newfoundland margin, and it is bounded by the continental shelf to the west, the Grand Banks to the south, and the continental blocks of Orphan Knoll and Flemish Cap to the east. The Orphan Basin formed in Mesozoic time during the opening of the North Atlantic Ocean between eastern Canada and western Iberia-Europe. This work, based on well data and regional seismic reflection profiles across the basin, indicates that the continental crust was affected by several extensional episodes between the Jurassic and the Early Cretaceous, separated by events of uplift and erosion. The preserved tectono-stratigraphic sequences in the basin reveal that deformation initiated in the eastern part of the Orphan Basin in the Jurassic and spread towards the west in the Early Cretaceous, resulting in numerous rift structures filled with a Jurassic-Lower Cretaceous syn-rift succession and overlain by thick Upper Cretaceous to Cenozoic post-rift sediments. The seismic data show an extremely thinned crust (4-16 km thick) underneath the eastern and western parts of the Orphan Basin, forming two sub-basins separated by a wide structural high with a relatively thick crust (17 km thick). Quantifying the crustal architecture in the basin highlights the large discrepancy between brittle extension localized in the upper crust and the overall crustal thinning. This suggests that continental deformation in the Orphan Basin involved, in addition to the documented Jurassic and Early Cretaceous rifting, an earlier brittle rift phase which is unidentifiable in seismic data and a depth-dependent thinning of the crust driven by localized lower crust ductile flow.

  14. Evolution and dynamics of orphan penumbrae in the solar photosphere: Analysis from multi-instrument observations

    SciTech Connect

    Zuccarello, Francesca; Guglielmino, Salvo L.; Romano, Paolo

    2014-05-20

    We investigate the dynamics and magnetic properties of orphan penumbrae observed in the solar photosphere to understand the formation process of such structures. We observed two orphan penumbrae in active region NOAA 11089 during a coordinated observing campaign carried out in 2010 July, involving the Hinode/Solar Optical Telescope (SOT) and Dutch Open Telescope (DOT), benefiting also from continuous observations acquired by the SDO satellite. We follow their evolution during about three days. The two structures form in different ways: one seems to break off the penumbra of a nearby sunspot, the other is formed through the emergence of new flux. Then they fragment while evolving. The SDO Helioseismic and Magnetic Imager measurements indicate the presence of strong line-of-sight motions in the regions occupied by these orphan penumbrae, lasting for several hours and decreasing with time. This is confirmed by SOT spectro-polarimetric measurements of the Fe I 630.2 nm pair. The latter also show that Stokes parameters exhibit significant asymmetries in the orphan penumbral regions, typical of an uncombed filamentary structure. The orphan penumbrae lie above polarity inversion lines, where peculiar plasma motions take place with velocities larger than ±3 km s{sup –1}. The vector magnetic field in these regions is highly inclined, with the average magnetic field strength decreasing with time. The DOT observations in the Hα line and SDO Atmospheric Imaging Assembly measurements in the He II 30.4 nm line indicate that there is no counterpart for the orphan penumbrae at midchromospheric heights or above. Our findings suggest that in at least one of the features investigated the emerging flux may be trapped in the low atmospheric layers by the overlying pre-existing fields, forming these filamentary structures.

  15. Psychosocial support and parents’ social life determine the self-esteem of orphan children

    PubMed Central

    Erango, Markos Abiso; Ayka, Zikie Ataro

    2015-01-01

    Parental death affects the life of children in many ways, one of which is self-esteem problems. Providing psychosocial support and equipping orphans play a vital role in their lifes. A cross-sectional study was conducted on 7–18-year-old orphans at 17 local districts of Gamo Gofa Zone, Southern Regional State of Ethiopia. From a total of 48,270 orphans in these areas, 4,368 were selected using stratified simple random sampling technique. Data were collected with a designed questionnaire based on the Rosenberg’s rating scale to measure their self-esteem levels. Self-esteem with a score less than or equal to an average score was considered to be low self-esteem in the analysis. Binary logistic regression model was used to analyze the data using the SPSS software. The results of the study revealed that the probability of orphans suffering from low self-esteem was 0.59. Several risk factors were found to be significant at the level of 5%. Psychosocial support (good guidance, counseling and treatment, physical protection and amount of love shared, financial and material support, and fellowship with other children), parents living together before death, strong relationship between parents before death, high average monthly income, voluntary support, and consideration from the society are some of the factors that decrease the risk of being low in self-esteem. There are many orphans with low self-esteem in the study areas. The factors negatively affecting the self-esteem of orphans include the lack of psychosocial support, poor social life of parents, and death of parents due to AIDS. Society and parents should be aware of the consequences of these factors which can influence their children’s future self-esteem. PMID:26508894

  16. Psychosocial support and parents' social life determine the self-esteem of orphan children.

    PubMed

    Erango, Markos Abiso; Ayka, Zikie Ataro

    2015-01-01

    Parental death affects the life of children in many ways, one of which is self-esteem problems. Providing psychosocial support and equipping orphans play a vital role in their lifes. A cross-sectional study was conducted on 7-18-year-old orphans at 17 local districts of Gamo Gofa Zone, Southern Regional State of Ethiopia. From a total of 48,270 orphans in these areas, 4,368 were selected using stratified simple random sampling technique. Data were collected with a designed questionnaire based on the Rosenberg's rating scale to measure their self-esteem levels. Self-esteem with a score less than or equal to an average score was considered to be low self-esteem in the analysis. Binary logistic regression model was used to analyze the data using the SPSS software. The results of the study revealed that the probability of orphans suffering from low self-esteem was 0.59. Several risk factors were found to be significant at the level of 5%. Psychosocial support (good guidance, counseling and treatment, physical protection and amount of love shared, financial and material support, and fellowship with other children), parents living together before death, strong relationship between parents before death, high average monthly income, voluntary support, and consideration from the society are some of the factors that decrease the risk of being low in self-esteem. There are many orphans with low self-esteem in the study areas. The factors negatively affecting the self-esteem of orphans include the lack of psychosocial support, poor social life of parents, and death of parents due to AIDS. Society and parents should be aware of the consequences of these factors which can influence their children's future self-esteem.

  17. Evolution and Dynamics of Orphan Penumbrae in the Solar Photosphere: Analysis from Multi-instrument Observations

    NASA Astrophysics Data System (ADS)

    Zuccarello, Francesca; Guglielmino, Salvo L.; Romano, Paolo

    2014-05-01

    We investigate the dynamics and magnetic properties of orphan penumbrae observed in the solar photosphere to understand the formation process of such structures. We observed two orphan penumbrae in active region NOAA 11089 during a coordinated observing campaign carried out in 2010 July, involving the Hinode/Solar Optical Telescope (SOT) and Dutch Open Telescope (DOT), benefiting also from continuous observations acquired by the SDO satellite. We follow their evolution during about three days. The two structures form in different ways: one seems to break off the penumbra of a nearby sunspot, the other is formed through the emergence of new flux. Then they fragment while evolving. The SDO Helioseismic and Magnetic Imager measurements indicate the presence of strong line-of-sight motions in the regions occupied by these orphan penumbrae, lasting for several hours and decreasing with time. This is confirmed by SOT spectro-polarimetric measurements of the Fe I 630.2 nm pair. The latter also show that Stokes parameters exhibit significant asymmetries in the orphan penumbral regions, typical of an uncombed filamentary structure. The orphan penumbrae lie above polarity inversion lines, where peculiar plasma motions take place with velocities larger than ±3 km s-1. The vector magnetic field in these regions is highly inclined, with the average magnetic field strength decreasing with time. The DOT observations in the Hα line and SDO Atmospheric Imaging Assembly measurements in the He II 30.4 nm line indicate that there is no counterpart for the orphan penumbrae at midchromospheric heights or above. Our findings suggest that in at least one of the features investigated the emerging flux may be trapped in the low atmospheric layers by the overlying pre-existing fields, forming these filamentary structures.

  18. Petrology and tectonic significance of seamounts within transitional crust east of Orphan Knoll, offshore eastern Canada

    NASA Astrophysics Data System (ADS)

    Pe-Piper, Georgia; Meredyk, Shawn; Zhang, Yuanyuan; Piper, David J. W.; Edinger, Evan

    2013-12-01

    The Early Cretaceous separation of Newfoundland from Iberia-Ireland is a classic example of a magma-poor continental margin with hyperextension and with widespread minor magmatism resulting in seamounts. This study defines the distribution of seamounts east of Orphan Knoll, and documents and interprets the geochemical character of the one recovered lava sample. Video imagery of lava outcrops, and the sample, were obtained by ROV from Orphan seamount, one of a linear series of small seamounts overlying transitional thinned continental crust on the seaward side of Orphan Knoll. New multibeam bathymetry and legacy seismic data show several seamounts that extend irregularly along the fault-bound NE margin of Orphan Knoll. Whole rock geochemistry shows the sample to be highly alkaline basanite or possibly tephrite. Diopside-hedenbergite, kaersutite and K-feldspar phenocrysts were analyzed by electron microprobe and scanning electron microscope, and alteration minerals including kaolinite were identified by X-ray diffraction. The highly alkaline character of the basanite is similar only to Early Cretaceous volcanic and sub-volcanic rocks erupted through thick continental crust of the Mesoproterozoic Grenville Orogeny. The location of the linear set of seamounts is related to margin-parallel faults on the seaward side of Orphan Knoll that provided a pathway for magma, although ENE-trending lineaments in individual seamounts or seamount groups suggest the influence of oceanic fracture zones. A lower gradient crest to Orphan seamount above 2,200 m suggests subaerial erosion, consistent with the presence of kaolinite as an alteration product and the absence of lava pillows at and above this depth.

  19. Psychosocial support and parents' social life determine the self-esteem of orphan children.

    PubMed

    Erango, Markos Abiso; Ayka, Zikie Ataro

    2015-01-01

    Parental death affects the life of children in many ways, one of which is self-esteem problems. Providing psychosocial support and equipping orphans play a vital role in their lifes. A cross-sectional study was conducted on 7-18-year-old orphans at 17 local districts of Gamo Gofa Zone, Southern Regional State of Ethiopia. From a total of 48,270 orphans in these areas, 4,368 were selected using stratified simple random sampling technique. Data were collected with a designed questionnaire based on the Rosenberg's rating scale to measure their self-esteem levels. Self-esteem with a score less than or equal to an average score was considered to be low self-esteem in the analysis. Binary logistic regression model was used to analyze the data using the SPSS software. The results of the study revealed that the probability of orphans suffering from low self-esteem was 0.59. Several risk factors were found to be significant at the level of 5%. Psychosocial support (good guidance, counseling and treatment, physical protection and amount of love shared, financial and material support, and fellowship with other children), parents living together before death, strong relationship between parents before death, high average monthly income, voluntary support, and consideration from the society are some of the factors that decrease the risk of being low in self-esteem. There are many orphans with low self-esteem in the study areas. The factors negatively affecting the self-esteem of orphans include the lack of psychosocial support, poor social life of parents, and death of parents due to AIDS. Society and parents should be aware of the consequences of these factors which can influence their children's future self-esteem. PMID:26508894

  20. Orphans and Vulnerable Children Affected by Human Immunodeficiency Virus in Sub-Saharan Africa.

    PubMed

    Bryant, Malcolm; Beard, Jennifer

    2016-02-01

    In Sub-Saharan Africa, 15.1 million children have been orphaned because of human immunodeficiency virus (HIV). They face significant vulnerabilities, including stigma and discrimination, trauma and stress, illness, food insecurity, poverty, and difficulty accessing education. Millions of additional children who have living parents are vulnerable because their parents or other relatives are infected. This article reviews the current situation of orphans and vulnerable children, explores the underlying determinants of vulnerability and resilience, describes the response by the global community, and highlights the challenges as the HIV pandemic progresses through its fourth decade.

  1. Evaluation of a Memory Book intervention with orphaned children in South Africa.

    PubMed

    Braband, Barbara J; Faris, Tamara; Wilson-Anderson, Kaye

    2014-01-01

    The purpose of this collaborative research study was to evaluate the use of the Memory Book intervention for orphaned children's grief and loss recovery. A qualitative phenomenological approach was implemented to evaluate the Memory Book intervention with orphaned children at two children's homes in South Africa. Study findings support the ability of children to work through loss and grief when they are assisted in preserving and telling their story. The Memory Book intervention assists children to chronicle their lives and demonstrates the potential to guide future interventions by care providers and nurses in this context.

  2. Evaluation of a Memory Book intervention with orphaned children in South Africa.

    PubMed

    Braband, Barbara J; Faris, Tamara; Wilson-Anderson, Kaye

    2014-01-01

    The purpose of this collaborative research study was to evaluate the use of the Memory Book intervention for orphaned children's grief and loss recovery. A qualitative phenomenological approach was implemented to evaluate the Memory Book intervention with orphaned children at two children's homes in South Africa. Study findings support the ability of children to work through loss and grief when they are assisted in preserving and telling their story. The Memory Book intervention assists children to chronicle their lives and demonstrates the potential to guide future interventions by care providers and nurses in this context. PMID:24582647

  3. Drug discovery and development for Huntington's disease - an orphan indication with high medical need.

    PubMed

    Heitz, Freddy; La Rosa, Salvatore; Gonzalez-Couto, Eduardo; Gaviraghi, Giovanni; Terstappen, Georg C

    2008-09-01

    Huntington's disease (HD) is a rare neurodegenerative disorder that progressively destroys the mental capacity and motor control of patients. This loss of motor control results in abnormal body movements (chorea) - the hallmark of HD. Given that no disease-modifying therapy for HD exists and that available symptomatic treatments are not highly efficacious, the medical need for this 'orphan' disease remains high. The number of compounds that are undergoing discovery and development for the treatment of HD has increased significantly in recent years, spurred by legislative incentives for orphan drug development and by support from non-profit foundations. Thus, hope exists for patients with HD that efficacious medicines will become available.

  4. Orphans and Vulnerable Children Affected by Human Immunodeficiency Virus in Sub-Saharan Africa.

    PubMed

    Bryant, Malcolm; Beard, Jennifer

    2016-02-01

    In Sub-Saharan Africa, 15.1 million children have been orphaned because of human immunodeficiency virus (HIV). They face significant vulnerabilities, including stigma and discrimination, trauma and stress, illness, food insecurity, poverty, and difficulty accessing education. Millions of additional children who have living parents are vulnerable because their parents or other relatives are infected. This article reviews the current situation of orphans and vulnerable children, explores the underlying determinants of vulnerability and resilience, describes the response by the global community, and highlights the challenges as the HIV pandemic progresses through its fourth decade. PMID:26613693

  5. Ghrelin Receptor Mutations and Human Obesity.

    PubMed

    Wang, W; Tao, Y-X

    2016-01-01

    Growth hormone secretagogue receptor (GHSR) was originally identified as an orphan receptor in porcine and rat anterior pituitary membranes. In 1999, GHSR was deorphanized and shown to be a receptor for ghrelin, a peptide hormone secreted from the stomach. Therefore, GHSR is also called ghrelin receptor. In addition to regulating growth hormone secretion, ghrelin receptor regulates various physiological processes, including food intake and energy expenditure, glucose metabolism, cardiovascular functions, gastric acid secretion and motility, and immune function. Several human genetic studies conducted in populations originated from Europe, Africa, South America, and East Asia identified rare mutations and single nucleotide polymorphisms that might be associated with human obesity and short stature. Functional analyses of mutant GHSRs reveal multiple defects, including cell surface expression, ligand binding, and basal and stimulated signaling. With growing understanding in the functionality of naturally occurring GHSR mutations, potential therapeutic strategies including pharmacological chaperones and novel ligands could be used to correct the GHSR mutants. PMID:27288828

  6. Barriers and Incentives to Orphan Care in a Time of AIDS and Economic Crisis: A Cross-Sectional Survey of Caregivers in Rural Zimbabwe

    ERIC Educational Resources Information Center

    Howard, Brian H.; Phillips, Carl V.; Matinhure, Nelia; Goodman, Karen J.; McCurdy, Sheryl A; Johnson, Cary A.

    2007-01-01

    Background: Africa is in an orphan-care crisis. In Zimbabwe, where one-fourth of adults are HIV-positive and one-fifth of children are orphans, AIDS and economic decline are straining society's ability to care for orphans within their extended families. Lack of stable care is putting thousands of children at heightened risk of malnourishment,…

  7. The Self-Concept and Academic Performance of Institutionalized and Non-Institutionalized HIV/AIDS Orphaned Children in Kisumu Municipality

    ERIC Educational Resources Information Center

    Kimani, Chege Gabriel; Cheboswony, M.; Kodero, H. M.; Misigo, Benard L.

    2009-01-01

    The HIV/AIDS pandemic has increasingly become a major factor in the emergence of orphans in the developing countries. These orphans are usually traumatized due to the multiple losses, isolation, stigma and grief. The study sought to investigate the effect of institutionalization of children on the self-concept of the AIDS-orphaned children and to…

  8. A fair share for the orphans: ethical guidelines for a fair distribution of resources within the bounds of the 10-year-old European Orphan Drug Regulation.

    PubMed

    Pinxten, Wim; Denier, Yvonne; Dooms, Marc; Cassiman, Jean-Jacques; Dierickx, Kris

    2012-03-01

    For a significant number of patients, there exists no, or only little, interest in developing a treatment for their disease or condition. Especially with regard to rare diseases, the lack of commercial interest in drug development is a burning issue. Several interventions have been made in the regulatory field in order to address the commercial disinterest in these conditions. However, existing regulations mainly focus on the provision of incentives to the sponsors of clinical trials of orphan drugs, and leave unanswered the overarching question about the rightful place of orphan drugs in resource allocation systems. In this article, we analyse the ethical aspects of funding research and development in the field of rare diseases. We then propose an ethical framework that can help health policy makers move forward in the difficult matter of fairly allocating resources for the prevention, diagnosis and treatment of rare diseases.

  9. A cross-national comparative study of orphan drug policies in the United States, the European Union, and Japan: towards a made-in-China orphan drug policy.

    PubMed

    Liu, Bao-cheng; He, Lin; He, Guang; He, Yun

    2010-12-01

    Rare diseases can severely impact patient life quality as well as impose a serious burden on society. But research and development for drugs to treat these disorders has stagnated because of lack of demand, insufficient knowledge of pathophysiological mechanisms, and too few patients for clinical trials. In several countries--the United States, the EU, and Japan--specific legislation has been enacted to encourage pharmaceutical companies to expedite the development of drugs for rare diseases, orphan drugs, and to assure access to them. We analyze the strengths and weaknesses of the incentives in these laws and describe the status of rare diseases in China. We offer some recommendations for orphan drug legislation in China, based on local research on rare diseases.

  10. The role of globalization in drug development and access to orphan drugs: orphan drug legislation in the US/EU and in Latin America

    PubMed Central

    Arnold, Renée J.G.; Bighash, Lida; Bryón Nieto, Alejandro; Tannus Branco de Araújo, Gabriela; Gay-Molina, Juan Gabriel; Augustovski, Federico

    2015-01-01

    Compared to a decade ago, nearly three times as many drugs for rare diseases are slated for development. This article addresses the market access issues associated with orphan drug status in Europe and the United States in contrast to the legislation in five Latin American (LA) countries that have made strides in this regard--Mexico, Brazil, Colombia, Chile and Argentina. Based on the success of orphan drug legislation in the EU and US, LA countries should strive to adopt similar strategies with regard to rare diseases and drug development. With the implementation of new targeted regulations, reimbursement strategies, and drug approvals, accessibility to treatment will be improved for people afflicted with rare diseases in these developing countries. PMID:25844162

  11. A cross-national comparative study of orphan drug policies in the United States, the European Union, and Japan: towards a made-in-China orphan drug policy.

    PubMed

    Liu, Bao-cheng; He, Lin; He, Guang; He, Yun

    2010-12-01

    Rare diseases can severely impact patient life quality as well as impose a serious burden on society. But research and development for drugs to treat these disorders has stagnated because of lack of demand, insufficient knowledge of pathophysiological mechanisms, and too few patients for clinical trials. In several countries--the United States, the EU, and Japan--specific legislation has been enacted to encourage pharmaceutical companies to expedite the development of drugs for rare diseases, orphan drugs, and to assure access to them. We analyze the strengths and weaknesses of the incentives in these laws and describe the status of rare diseases in China. We offer some recommendations for orphan drug legislation in China, based on local research on rare diseases. PMID:21119648

  12. The orphan nuclear receptor Nur77 regulates decidual prolactin expression in human endometrial stromal cells

    SciTech Connect

    Jiang, Yue; Hu, Yali; Zhao, Jing; Zhen, Xin; Yan, Guijun; Sun, Haixiang

    2011-01-14

    Research highlights: {yields} Decidually produced PRL plays a key role during pregnancy. {yields} Overexpression of Nur77 increased PRL mRNA expression and enhanced decidual PRL promoter activity. {yields} Knockdown of Nur77 decreased decidual PRL secretion induced by 8-Br-cAMP and MPA. {yields} Nur77 is a novel transcription factor that plays an active role in decidual prolactin expression. -- Abstract: Prolactin (PRL) is synthesized and released by several extrapituitary tissues, including decidualized stromal cells. Despite the important role of decidual PRL during pregnancy, little is understood about the factors involved in the proper regulation of decidual PRL expression. Here we present evidence that the transcription factor Nur77 plays an active role in decidual prolactin expression in human endometrial stromal cells (hESCs). Nur77 mRNA expression in hESCs was significantly increased after decidualization stimulated by 8-Br-cAMP and medroxyprogesterone acetate (MPA). Adenovirus-mediated overexpression of Nur77 in hESCs markedly increased PRL mRNA expression and enhanced decidual PRL promoter (dPRL/-332Luc) activity in a concentration-dependent manner. Furthermore, knockdown of Nur77 in hESCs significantly decreased decidual PRL promoter activation and substantially attenuated PRL mRNA expression and PRL secretion (P < 0.01) induced by 8-Br-cAMP and MPA. These results demonstrate that Nur77 is a novel transcription factor that contributes significantly to the regulation of prolactin gene expression in human endometrial stromal cells.

  13. Orphan nuclear receptor SHP regulates iron metabolism through inhibition of BMP6-mediated hepcidin expression

    PubMed Central

    Kim, Don-Kyu; Kim, Yong-Hoon; Jung, Yoon Seok; Kim, Ki-Sun; Jeong, Jae-Ho; Lee, Yong-Soo; Yuk, Jae-Min; Oh, Byung-Chul; Choy, Hyon E.; Dooley, Steven; Muckenthaler, Martina U.; Lee, Chul-Ho; Choi, Hueng-Sik

    2016-01-01

    Small heterodimer partner (SHP) is a transcriptional corepressor regulating diverse metabolic processes. Here, we show that SHP acts as an intrinsic negative regulator of iron homeostasis. SHP-deficient mice maintained on a high-iron diet showed increased serum hepcidin levels, decreased expression of the iron exporter ferroportin as well as iron accumulation compared to WT mice. Conversely, overexpression of either SHP or AMP-activated protein kinase (AMPK), a metabolic sensor inducing SHP expression, suppressed BMP6-induced hepcidin expression. In addition, an inhibitory effect of AMPK activators metformin and AICAR on BMP6-mediated hepcidin gene expression was significantly attenuated by ablation of SHP expression. Interestingly, SHP physically interacted with SMAD1 and suppressed BMP6-mediated recruitment of the SMAD complex to the hepcidin gene promoter by inhibiting the formation of SMAD1 and SMAD4 complex. Finally, overexpression of SHP and metformin treatment of BMP6 stimulated mice substantially restored hepcidin expression and serum iron to baseline levels. These results reveal a previously unrecognized role for SHP in the transcriptional control of iron homeostasis. PMID:27688041

  14. Molecular basis for amino acid sensing by family C G-protein-coupled receptors

    PubMed Central

    Wellendorph, P; Bräuner-Osborne, H

    2009-01-01

    Family C of human G-protein-coupled receptors (GPCRs) is constituted by eight metabotropic glutamate receptors, two γ-aminobutyric acid type B (GABAB1–2) subunits forming the heterodimeric GABAB receptor, the calcium-sensing receptor, three taste1 receptors (T1R1–3), a promiscuous L-α-amino acid receptor G-protein-coupled receptor family C, group 6, subtype A (GPRC6A) and seven orphan receptors. Aside from the orphan receptors, the family C GPCRs are dimeric receptors characterized by a large extracellular Venus flytrap domain which bind the endogenous agonists. Except from the GABAB1–2 and T1R2–3 receptor, all receptors are either activated or positively modulated by amino acids. In this review, we outline mutational, biophysical and structural studies which have elucidated the interaction of the amino acids with the Venus flytrap domains, molecular mechanisms of receptor selectivity and the initial steps in receptor activation. PMID:19298394

  15. Educating Orphaned and Vulnerable Children in Elgeyo-Marakwet County, Kenya

    ERIC Educational Resources Information Center

    Jepkemboi, Grace; Jolly, Pauline; Gillyard, KaNesha; Lissanu, Lydia

    2016-01-01

    According to UNICEF, 13.3 million children (0-17 years) worldwide have lost one or both parents to AIDS. Nearly 12 million of these children live in sub-Saharan Africa. Together, with other children who have been severely impacted by the AIDS pandemic, these orphaned and vulnerable children (OVC) are at higher risk of missing out on schooling,…

  16. Psychological Distress amongst AIDS-Orphaned Children in Urban South Africa

    ERIC Educational Resources Information Center

    Cluver, Lucie; Gardner, Frances; Operario, Don

    2007-01-01

    Background: South Africa is predicted to have 2.3 million children orphaned by Acquired Immune Deficiency Syndrome (AIDS) by 2020 (Actuarial Society of South Africa, 2005). There is little knowledge about impacts of AIDS-related bereavement on children, to aid planning of services. This study aimed to investigate psychological consequences of AIDS…

  17. Exploring emerging technologies using metaphors--a study of orphan drugs and pharmacogenomics.

    PubMed

    Boon, Wouter; Moors, Ellen

    2008-05-01

    Due to uncertainties of several aspects of emerging health technologies, there is a need to anticipate these developments early. A first step would be to gather information and develop future visions about the technology. This paper introduces metaphor analysis as a novel way to do this. Specifically, we study the future of pharmacogenomics by comparing this technology with orphan drugs, which are more established and often act as a model with comparable (economic, research organisation, etc.) characteristics. The analysis consists of describing the dominant metaphors used and structurally exploring (dis)similarities between pharmacogenomics and orphan drugs developments. This comparison leads to lessons that can be learnt for the emerging pharmacogenomics future. We carried out a comprehensive literature review, extracting metaphors in a structured way from different areas of the drug research and development pipeline. The paper argues that (1) there are many similarities between orphan drugs and pharmacogenomics, especially in terms of registration, and social and economic impacts; (2) pharmacogenomics developments are regarded both as a future 'poison' and a 'chance', whereas orphan drugs are seen as a 'gift', and at the same time as a large 'problem'; and (3) metaphor analysis proves to be a tool for creating prospective images of pharmacogenomics and other emerging technologies.

  18. Instruments of Science and Citizenship: Science Education for Dutch Orphans during the Late Eighteenth Century

    ERIC Educational Resources Information Center

    Roberts, Lissa L.

    2012-01-01

    One of the two most extensive instrument collections in the Netherlands during the second half of the eighteenth century--rivaling the much better known collection at the University of Leiden--belonged to an orphanage in The Hague that was specially established to mold hand-picked orphans into productive citizens. (The other was housed at the…

  19. Orphan Trains: Teaching about an Early Twentieth-Century Social Experiment

    ERIC Educational Resources Information Center

    Chiodo, John J.; Meliza, Evette

    2014-01-01

    Between 1854 and 1930, over 200,000 children left New York City, as well as other major east coast cities, bound for families in rural areas. They traveled to towns in New England, the Midwest, the South, and even as far west as Texas, California, Oregon, and Washington. These orphans were the children of immigrant families who were pouring into…

  20. I Am All about the Future World: Cambodian Children's Views on Their Status as Orphans

    ERIC Educational Resources Information Center

    Emond, Ruth

    2009-01-01

    The dominant representation of children living in majority world orphanages highlights their vulnerability and fragility. However, little is known about their lived experiences of orphanage care and their perspectives on being regarded as "orphans". This article draws on data from a pilot project undertaken in one orphanage in Cambodia to…

  1. South African AIDS Orphans: Examining Assumptions around Vulnerability from the Perspective of Rural Children and Youth

    ERIC Educational Resources Information Center

    Henderson, Patricia C.

    2006-01-01

    The article examines assumptions circulating in development or interventionist discourse concerning the vulnerabilities of AIDS orphans in South Africa. Ongoing ethnographic research, begun in March 2003, with 31 rural children and youth between the ages of 14 and 22, in Magangangozi, KwaZulu-Natal, points to the ways in which global terms may…

  2. Doctoral "Orphans": Nurturing and Supporting the Success of Postgraduates Who Have Lost Their Supervisors

    ERIC Educational Resources Information Center

    Wisker, Gina; Robinson, Gillian

    2013-01-01

    Much research into doctoral student-supervisor relations focuses on developing positive interactions. For many students, however, the research experience can be troubled by breakdowns in communication and even the loss of the supervisor(s), turning the student into a doctoral "orphan" and impacting on their academic identity and ability and…

  3. The psychological well-being of children orphaned by AIDS in Cape Town, South Africa

    PubMed Central

    Cluver, Lucie; Gardner, Frances

    2006-01-01

    Background An estimated 2 million children are parentally bereaved by AIDS in South Africa. Little is known about mental health outcomes for this group. Methods This study aimed to investigate mental health outcomes for urban children living in deprived settlements in Cape Town. 30 orphaned children and 30 matched controls were compared using standardised questionnaires (SDQ) on emotional and behavioural problems, peer and attention difficulties, and prosocial behaviour. The orphan group completed a modified version of a standardised questionnaire (IES-8), measuring Post-Traumatic Stress symptoms. Group differences were tested using t-tests and Pearson's chi-square. Results Both groups scored highly for peer problems, emotional problems and total scores. However, orphans were more likely to view themselves as having no good friends (p = .002), to have marked concentration difficulties (p = .03), and to report frequent somatic symptoms (p = .05), but were less likely to display anger through loss of temper (p = .03). Orphans were more likely to have constant nightmares (p = .01), and 73% scored above the cut-off for Post-Traumatic Stress Disorder. Conclusion Findings suggest important areas for larger-scale research for parentally-bereaved children. PMID:16848910

  4. Making Good on a Promise: The Education of Civil War Orphans in Pennsylvania, 1863-1893

    ERIC Educational Resources Information Center

    Bair, Sarah D.

    2011-01-01

    During and after the American Civil War, individual state governments, faced with numerous economic demands, struggled to meet the needs of soldiers and their families. Among other pressing questions, they had to decide what to do with the massive number of dependent children orphaned by the war. In order to protect children, it became more…

  5. 78 FR 44016 - Exclusion of Orphan Drugs for Certain Covered Entities Under 340B Program

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-23

    ... outpatient early intervention services for HIV disease); (5) A state- operated AIDS drug purchasing... condition or disease for which the orphan drug was designated under section 526 of the Federal Food, Drug... designated for a rare disease or condition as indicated in the Affordable Care Act and intended by...

  6. Art Therapy with Orphaned Children: Dynamics of Early Relational Trauma and Repetition Compulsion

    ERIC Educational Resources Information Center

    Meshcheryakova, Ksenia

    2012-01-01

    This article explores the dynamics of orphaned children's engagement with art therapy in a group of preadolescent children living in a Russian orphanage. The phenomenon of repetition compulsion (i.e., origins in past traumatic experiences, destructive consequences, and protective psychic function) is discussed with respect to the children's…

  7. 78 FR 5828 - Agency Information Collection Activities: Petition To Classify Orphan as an Immediate Relative...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-01-28

    ..., at 77 FR 65709, allowing for a 60-day public comment period. USCIS did receive two comments in... uses Form I-600 to determine whether a child alien is an eligible orphan. Form I-600A is used to... adult member (age 18 and older), who lives in the home of the prospective adoptive parent(s), except...

  8. Teaching Medication Compliance to Psychiatric Residents: Placing an Orphan Topic into a Training Curriculum

    ERIC Educational Resources Information Center

    Weiden, Peter J.; Rao, Nyapati

    2005-01-01

    OBJECTIVE: Medication compliance is an orphan topic. Training in the understanding and management of noncompliance does not neatly fall within the domain of psychopharmacology, nor does it clearly fit into other core curricula areas, such as clinical interviewing or psychotherapy training. The objective of this article is to increase awareness…

  9. Orphaned Children: An Analysis of Life and Practices in a Residential Institution

    ERIC Educational Resources Information Center

    Astoiants, M. S.

    2007-01-01

    This article attempts to enter the world of orphaned children by describing how their daily activities are organized in a social rehabilitation center for minor children, called Center N in this article. The article was based on materials of a study that resulted from participant observation between 1995 and 2002, reflecting a few aspects of the…

  10. A generalizable pre-clinical research approach for orphan disease therapy

    PubMed Central

    2012-01-01

    With the advent of next-generation DNA sequencing, the pace of inherited orphan disease gene identification has increased dramatically, a situation that will continue for at least the next several years. At present, the numbers of such identified disease genes significantly outstrips the number of laboratories available to investigate a given disorder, an asymmetry that will only increase over time. The hope for any genetic disorder is, where possible and in addition to accurate diagnostic test formulation, the development of therapeutic approaches. To this end, we propose here the development of a strategic toolbox and preclinical research pathway for inherited orphan disease. Taking much of what has been learned from rare genetic disease research over the past two decades, we propose generalizable methods utilizing transcriptomic, system-wide chemical biology datasets combined with chemical informatics and, where possible, repurposing of FDA approved drugs for pre-clinical orphan disease therapies. It is hoped that this approach may be of utility for the broader orphan disease research community and provide funding organizations and patient advocacy groups with suggestions for the optimal path forward. In addition to enabling academic pre-clinical research, strategies such as this may also aid in seeding startup companies, as well as further engaging the pharmaceutical industry in the treatment of rare genetic disease. PMID:22704758

  11. Educational Support for Orphans and Vulnerable Children in Primary Schools: Challenges and Interventions

    ERIC Educational Resources Information Center

    Mwoma, Teresa; Pillay, Jace

    2016-01-01

    Educational status is an important indicator of children's wellbeing and future life opportunities. It can predict growth potential and economic viability of a state. While this is an ideal situation for all children, the case may be different for orphans and vulnerable children (OVC) due to the challenges they go through on a daily basis. This…

  12. Computational identification and analysis of orphan assembly-line polyketide synthases

    PubMed Central

    O’Brien, Robert V; Davis, Ronald W; Khosla, Chaitan; Hillenmeyer, Maureen E

    2014-01-01

    The increasing availability of DNA sequence data offers an opportunity for identifying new assembly-line polyketide synthases (PKSs) that produce biologically active natural products. We developed an automated method to extract and consolidate all multimodular PKS sequences (including hybrid PKS/non-ribosomal peptide synthetases) in the National Center for Biotechnology Information (NCBI) database, generating a non-redundant catalog of 885 distinct assembly-line PKSs, the majority of which were orphans associated with no known polyketide product. Two in silico experiments highlight the value of this search method and resulting catalog. First, we identified an orphan that could be engineered to produce an analog of albocycline, an interesting antibiotic whose gene cluster has not yet been sequenced. Second, we identified and analyzed a hitherto overlooked family of metazoan multimodular PKSs, including one from Caenorhabditis elegans. We also developed a comparative analysis method that identified sequence relationships among known and orphan PKSs. As expected, PKS sequences clustered according to structural similarities between their polyketide products. The utility of this method was illustrated by highlighting an interesting orphan from the genus Burkholderia that has no close relatives. Our search method and catalog provide a community resource for the discovery of new families of assembly-line PKSs and their antibiotic products. PMID:24301183

  13. Education and Nutritional Status of Orphans and Children of HIV-Infected Parents in Kenya

    ERIC Educational Resources Information Center

    Mishra, Vinod; Arnold, Fred; Otieno, Fredrick; Cross, Anne; Hong, Rathavuth

    2007-01-01

    We examined whether orphaned and fostered children and children of HIV-infected parents are disadvantaged in schooling, nutrition, and health care. We analyzed data on 2,756 children aged 0-4 years and 4,172 children aged 6-14 years included in the 2003 Kenya Demographic and Health Survey, with linked anonymous HIV testing, using multivariate…

  14. The QQS orphan gene regulates carbon and nitrogen partitioning across species via NF-YC interactions

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The allocation of carbon and nitrogen resources to the synthesis of plant proteins, carbohydrates, and lipids is complex and under the control of many genes; much remains to be understood about this process. QQS (Qua Quine Starch, At3g30720), an orphan gene unique to Arabidopsis thaliana, regulates...

  15. Orphaned and Abused Youth Are Vulnerable to Pregnancy and Suicide Risk

    ERIC Educational Resources Information Center

    Zapata, Lauren B.; Kissin, Dmitry M.; Bogoliubova, Olga; Yorick, Roman V.; Kraft, Joan Marie; Jamieson, Denise J.; Marchbanks, Polly A.; Hillis, Susan D.

    2013-01-01

    Objective: Little is known about the magnitude and consequences of violence against children for those living outside family care. We sought to estimate the frequency of childhood abuse and examine its association with lifetime pregnancy involvement (LPI) and past year suicide ideation among orphaned youth. Methods: We analyzed data collected via…

  16. The Lived Experiences of Orphaned Learners in South Africa: Implications for the Provision of Quality Education

    ERIC Educational Resources Information Center

    Motha, Kholofelo Charlotte; Frempong, George

    2014-01-01

    Learners living in impoverished communities and subjected to the kind of disadvantage in operation in their home environment are at risk of receiving education of an inferior quality. The situation is worse for orphans, especially those residing in poor communities in that they bring to school peculiar attributes which poses challenges for the…

  17. Reconsidering the orphan problem: the emergence of male caregivers in Lesotho.

    PubMed

    Block, Ellen

    2016-01-01

    Care for AIDS orphans in southern Africa is frequently characterized as a "crisis", where kin-based networks of care are thought to be on the edge of collapse. Yet these care networks, though strained by AIDS, are still the primary mechanisms for orphan care, in large part because of the essential role grandmothers play in responding to the needs of orphans. Ongoing demographic shifts as a result of HIV/AIDS and an increasingly feminized labor market continue to disrupt and alter networks of care for orphans and vulnerable children. This paper examines the emergence of a small but growing number of male caregivers who are responding to the needs of the extended family. While these men are still few in number, the strength of gendered ideologies of female care means that this group of men is socially, if not statistically significant. Men continue to be considered caregivers of last resort, but their care will close a small but growing gap that threatens to undermine kin-based networks of care in Lesotho and across the region. The adaptation of gender roles reinforces the strength and resilience of kinship networks even when working against deeply entrenched ideas about gendered division of domestic labor. PMID:27297796

  18. 21 CFR 316.26 - Amendment to orphan-drug designation.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... designation. (a) At any time prior to approval of a marketing application for a designated orphan drug, the... condition. (b) FDA will grant the amendment if it finds that the initial designation request was made in... submission of the amendment request, the amendment would not result in exceeding the prevalence or...

  19. Children as Ethnographers: Reflections on the Importance of Participatory Research in Assessing Orphans' Needs

    ERIC Educational Resources Information Center

    Cheney, Kristen E.

    2011-01-01

    Critiques of child participation within aid programming suggest that it is superficial and insubstantive for the fulfilment of children's rights. By employing former child research participants as youth research assistants, the collaborative research design developed for my research project on the survival strategies of African orphans and…

  20. 21 CFR 316.30 - Annual reports of holder of orphan-drug designation.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 5 2014-04-01 2014-04-01 false Annual reports of holder of orphan-drug designation. 316.30 Section 316.30 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... process, sponsors should discuss any disparity between the probable marketing indication and...

  1. 21 CFR 316.30 - Annual reports of holder of orphan-drug designation.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 5 2011-04-01 2011-04-01 false Annual reports of holder of orphan-drug designation. 316.30 Section 316.30 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... process, sponsors should discuss any disparity between the probable marketing indication and...

  2. 21 CFR 316.30 - Annual reports of holder of orphan-drug designation.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 5 2013-04-01 2013-04-01 false Annual reports of holder of orphan-drug designation. 316.30 Section 316.30 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... process, sponsors should discuss any disparity between the probable marketing indication and...

  3. 21 CFR 316.30 - Annual reports of holder of orphan-drug designation.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 5 2012-04-01 2012-04-01 false Annual reports of holder of orphan-drug designation. 316.30 Section 316.30 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... process, sponsors should discuss any disparity between the probable marketing indication and...

  4. 21 CFR 316.30 - Annual reports of holder of orphan-drug designation.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Annual reports of holder of orphan-drug designation. 316.30 Section 316.30 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... process, sponsors should discuss any disparity between the probable marketing indication and...

  5. An Initial Exploration of the Therapeutic Impact of Music on Genocide Orphans in Rwanda

    ERIC Educational Resources Information Center

    d'Ardenne, Patricia; Kiyendeye, Moses

    2015-01-01

    The 1994 Rwandan Genocide murdered over a million and brought on incalculable distress to survivors. An non-governmental organisation, "Network for Africa," has a music programme to rehabilitate orphans in Kigali, now entering adulthood. This naturalistic study investigated whether music had transformational meaning for participants.…

  6. Stigma, marginalization and psychosocial well-being of orphans in Rwanda: exploring the mediation role of social support.

    PubMed

    Caserta, Tehetna Alemu; Pirttilä-Backman, Anna-Maija; Punamäki, Raija-Leena

    2016-01-01

    Stigma and marginalization are one of the major challenges orphans face in their daily lives, particularly in developing countries, but little is known about their impacts on mental health. This study examines how orphan-related characteristics, stigma and marginalization are associated with psychosocial well-being. It further analyses the role of social support in mediating between stigma and marginalization and mental health, indicated by emotional well-being and mental distress. The participants in this study were 430 Rwandan orphans who were 10-25 years of age, and of whom 179 were females and 251 were males. Results showed that high levels of stigma and marginalization were associated with a lower level of emotional well-being and higher levels of mental distress. A mediation analysis indicated that low level of social support due to stigma and marginalization contributed significantly to low level of emotional well-being. Once stigma, marginalization and social support were fully accounted for, AIDS orphans exhibited higher levels of mental distress than those who were orphaned by genocide or other causes. Future interventions designed to reduce stigma and marginalization for orphans and actions that facilitate social support can significantly improve emotional well-being and reduce mental distress among orphans.

  7. Stigma, marginalization and psychosocial well-being of orphans in Rwanda: exploring the mediation role of social support.

    PubMed

    Caserta, Tehetna Alemu; Pirttilä-Backman, Anna-Maija; Punamäki, Raija-Leena

    2016-01-01

    Stigma and marginalization are one of the major challenges orphans face in their daily lives, particularly in developing countries, but little is known about their impacts on mental health. This study examines how orphan-related characteristics, stigma and marginalization are associated with psychosocial well-being. It further analyses the role of social support in mediating between stigma and marginalization and mental health, indicated by emotional well-being and mental distress. The participants in this study were 430 Rwandan orphans who were 10-25 years of age, and of whom 179 were females and 251 were males. Results showed that high levels of stigma and marginalization were associated with a lower level of emotional well-being and higher levels of mental distress. A mediation analysis indicated that low level of social support due to stigma and marginalization contributed significantly to low level of emotional well-being. Once stigma, marginalization and social support were fully accounted for, AIDS orphans exhibited higher levels of mental distress than those who were orphaned by genocide or other causes. Future interventions designed to reduce stigma and marginalization for orphans and actions that facilitate social support can significantly improve emotional well-being and reduce mental distress among orphans. PMID:26883484

  8. Drinking correlates of DSM-IV alcohol use disorder diagnostic orphans in college students.

    PubMed

    Hagman, Brett T; Cohn, Amy M

    2012-01-01

    One major limitation of the DSM-IV criteria for alcohol abuse and dependence is that a cluster of individuals who endorse a subthreshold number of dependence criteria and no abuse criteria do not receive a formal diagnosis; despite elevated risk for alcohol-related problems relative to those with an abuse diagnosis. These individuals have been referred to as diagnostic orphans. The primary aim of this study was to examine alcohol use correlates of a group of diagnostic orphans in a sample of 396 nontreatment seeking college students who reported drinking on at least one occasion in the last 90 days. DSM-IV criteria were assessed using a modified version of the Composite International Diagnostic Interview-Substance Abuse Module (CIDI-SAM). Diagnostic orphans represented 34.1% (n = 135) of the original sample who did not receive a formal diagnosis; with the most frequently endorsed dependence criteria being tolerance and drinking larger/longer amounts than intended. Diagnostic orphans reported a range of alcohol-related negative consequences and reported greater frequencies of social and enhancement drinking motives in comparison to coping motives. They were similar to alcohol abusers and dissimilar to those with dependence or those without a diagnosis on alcohol consumption, alcohol problem severity, drinking motives and restraint variables. The present findings indicate that diagnostic orphans in college students represent a distinct group of drinkers who may be at risk for the development of alcohol use disorders and may be in need of intervention, given their similarity to those with an abuse diagnosis. Prevention and intervention efforts across college campuses should target this group to prevent escalation of alcohol problem severity.

  9. Hunting the Parent of the Orphan Stream. II. The First High-resolution Spectroscopic Study

    NASA Astrophysics Data System (ADS)

    Casey, Andrew R.; Keller, Stefan C.; Da Costa, Gary; Frebel, Anna; Maunder, Elizabeth

    2014-03-01

    We present the first high-resolution spectroscopic study on the Orphan stream for five stream candidates, observed with the Magellan Inamori Kyocera Echelle spectrograph on the Magellan Clay telescope. The targets were selected from the low-resolution catalog of Casey et al.: three high-probability members, one medium, and one low-probability stream candidate were observed. Our analysis indicates that the low- and medium-probability targets are metal-rich field stars. The remaining three high-probability targets range over ~1 dex in metallicity, and are chemically distinct compared to the other two targets and all standard stars: low [α/Fe] abundance ratios are observed, and lower limits are ascertained for [Ba/Y], which sit well above the Milky Way trend. These chemical signatures demonstrate that the undiscovered parent system is unequivocally a dwarf spheroidal galaxy, consistent with dynamical constraints inferred from the stream width and arc. As such, we firmly exclude the proposed association between NGC 2419 and the Orphan stream. A wide range in metallicities adds to the similarities between the Orphan stream and Segue 1, although the low [α/Fe] abundance ratios in the Orphan stream are in tension with the high [α/Fe] values observed in Segue 1. Open questions remain before Segue 1 could possibly be claimed as the "parent" of the Orphan stream. The parent system could well remain undiscovered in the southern sky. This paper includes data gathered with the 6.5 m Magellan Telescopes located at Las Campanas Observatory, Chile.

  10. GPR55 and the vascular receptors for cannabinoids.

    PubMed

    Hiley, C R; Kaup, S S

    2007-11-01

    CB1 and CB2 receptors mediate most responses to cannabinoids but not some of the cardiovascular actions of endocannabinoids such as anandamide and virodhamine, or those of some synthetic agents, like abnormal cannabidiol (abn-cbd). These agents induce vasorelaxation which is antagonised by rimonabant but only at high concentrations relative to those required to block CB1 receptors. Vasorelaxation to anandamide is sensitive to Pertussis toxin (though that to abn-cbd is not), and so is thought to be mediated by a G protein-coupled receptor through Gi/o. An orphan receptor, GPR55, apparently a cannabinoid receptor, is activated by abn-cbd, but is not the receptor mediating vasorelaxation to this agent, as the response persists in vessels from GPR55 knockout mice. However, the activity of anandamide in GPR55 knockout mice is not yet reported and so the role of GPR55 as a cannabinoid receptor mediating vascular responses has yet to be finalised.

  11. Thirty Years of Orphan Drug Legislation and the Development of Drugs to Treat Rare Seizure Conditions: A Cross Sectional Analysis

    PubMed Central

    Hoffmann, Georg F.

    2016-01-01

    Background Epilepsy is a serious chronic health condition with a high morbidity impairing the life of patients and afflicted families. Many epileptic conditions, especially those affecting children, are rare disorders generating an urgent medical need for more efficacious therapy options. Therefore, we assessed the output of the US and European orphan drug legislations. Methods Quantitative analysis of the FDA and EMA databases for orphan drug designations according to STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) criteria. Results Within the US Orphan Drug Act 40 designations were granted delivering nine approvals, i.e. clobazam, diazepam viscous solution for rectal administration, felbamate, fosphenytoin, lamotrigine, repository corticotropin, rufinamide, topiramate, and vigabatrin. Since 2000 the EMA granted six orphan drug designations whereof two compounds were approved, i.e. rufinamide and stiripentol. In the US, two orphan drug designations were withdrawn. Orphan drugs were approved for conditions including Lennox-Gastaut syndrome, infantile spasms, Dravet syndrome, and status epilepticus. Comparing time to approval for rufinamide, which was approved in the US and the EU to treat rare seizure conditions, the process seems faster in the EU (2.2 years) than in the US (4.3 years). Conclusion Orphan drug development in the US and in the EU delivered only few molecular entities to treat rare seizure disorders. The development programs focused on already approved antiepileptic drugs or alternative pharmaceutical formulations. Most orphan drugs approved in the US are not approved in the EU to treat rare seizures although some were introduced after 2000 when the EU adopted the Orphan Drug Regulation. PMID:27557111

  12. Rabeprazole: a second-generation proton pump inhibitor in the treatment of acid-related disease.

    PubMed

    Pallotta, Stefano; Pace, Fabio; Marelli, Silvia

    2008-08-01

    Rabeprazole is a proton pump inhibitor (PPI) presenting a very advantageous pharmacodynamic and pharmacokinetic profile over older PPIs. In particular, this drug has a very fast onset of action, due to a short activation time and a very high pKa, and may therefore be defined as a 'second generation' PPI. The aim of this article is to provide an update on the pharmacology and clinical profile of rabeprazole and its use in acid-related disorders, with a particular focus on its role in gastroesophageal reflux disease; in the treatment and prevention of duodenal and gastric ulcers and Zollinger-Ellison syndrome; in the therapy of the extraesophageal manifestations of gastroesophageal reflux disease (in particular the respiratory and ear, nose and throat ones); and in the eradication of Helicobacter pylori.

  13. The hallucinogen N,N-dimethyltryptamine (DMT) is an endogenous sigma-1 receptor regulator.

    PubMed

    Fontanilla, Dominique; Johannessen, Molly; Hajipour, Abdol R; Cozzi, Nicholas V; Jackson, Meyer B; Ruoho, Arnold E

    2009-02-13

    The sigma-1 receptor is widely distributed in the central nervous system and periphery. Originally mischaracterized as an opioid receptor, the sigma-1 receptor binds a vast number of synthetic compounds but does not bind opioid peptides; it is currently considered an orphan receptor. The sigma-1 receptor pharmacophore includes an alkylamine core, also found in the endogenous compound N,N-dimethyltryptamine (DMT). DMT acts as a hallucinogen, but its receptor target has been unclear. DMT bound to sigma-1 receptors and inhibited voltage-gated sodium ion (Na+) channels in both native cardiac myocytes and heterologous cells that express sigma-1 receptors. DMT induced hypermobility in wild-type mice but not in sigma-1 receptor knockout mice. These biochemical, physiological, and behavioral experiments indicate that DMT is an endogenous agonist for the sigma-1 receptor.

  14. Melatonin membrane receptors in peripheral tissues: Distribution and functions

    PubMed Central

    Slominski, Radomir M.; Reiter, Russel J.; Schlabritz-Loutsevitch, Natalia; Ostrom, Rennolds S.; Slominski, Andrzej T.

    2012-01-01

    Many of melatonin’s actions are mediated through interaction with the G-protein coupled membrane bound melatonin receptors type 1 and type 2 (MT1 and MT2, respectively) or, indirectly with nuclear orphan receptors from the RORα/RZR family. Melatonin also binds to the quinone reductase II enzyme, previously defined the MT3 receptor. Melatonin receptors are widely distributed in the body; herein we summarize their expression and actions in non-neural tissues. Several controversies still exist regarding, for example, whether melatonin binds the RORα/RZR family. Studies of the peripheral distribution of melatonin receptors are important since they are attractive targets for immunomodulation, regulation of endocrine, reproductive and cardiovascular functions, modulation of skin pigmentation, hair growth, cancerogenesis, and aging. Melatonin receptor agonists and antagonists have an exciting future since they could define multiple mechanisms by which melatonin modulates the complexity of such a wide variety of physiological and pathological processes. PMID:22245784

  15. An experimental validation of orphan genes of Buchnera, a symbiont of aphids.

    PubMed

    Shimomura, Sayaka; Shigenobu, Shuji; Morioka, Mizue; Ishikawa, Hajime

    2002-03-22

    Although Buchnera sp. APS, an intracellular symbiont of pea aphids, is a close relative of Escherichia coli, its genome has been extensively modified because of its prolonged intracellular life. In our previous studies on the Buchnera genome, computer analysis predicted three "orphan" genes, yba2, yba3, and yba4, which are open reading frames (ORFs) with no homologs in the database. In this paper, we successfully validated all these orphan genes by RT-PCR and Northern hybridization. The present study also revealed that yba3 and yba4 formed an operon, suggesting that they function in concert. Sequences around transcriptional start sites suggests that these genes are under the control of sigma 70. In view of codon usage and AT bias observed in these genes, it is likely that Buchnera have maintained them for an evolutionarily long time. PMID:11890702

  16. More than the loss of a parent: potentially traumatic events among orphaned and abandoned children.

    PubMed

    Whetten, Kathryn; Ostermann, Jan; Whetten, Rachel; O'Donnell, Karen; Thielman, Nathan

    2011-04-01

    This study examines rates of potentially traumatic events and associated anxiety and emotional/behavioral difficulties among 1,258 orphaned and abandoned children in 5 low- and middle-income countries. The study quantifies the types of events the children experienced and demonstrates that anxiety and emotional/behavioral difficulties increase with additional exposure. As policies for orphaned and abandoned children are being implemented, this study helps policy makers and care providers recognize that (a) children and caregivers are willing to report experiences of potentially traumatic events, (b) those who report such events are at higher risk for experiencing additional events, (c) resulting symptomatology indicates a need for appropriate mental health services, and (d) boys are as vulnerable as girls, indicating an equal need for protection.

  17. Orphan γ-ray flares from relativistic blobs encountering luminous stars

    NASA Astrophysics Data System (ADS)

    Banasiński, P.; Bednarek, W.; Sitarek, J.

    2016-11-01

    We propose that {\\gamma} -rays in blazars can be produced during encounters of relativistic blobs of plasma with radiation field produced by luminous stars within (or close to) the jet. The blob is expected to contain relativistic electrons which comptonize stellar radiation to the GeV-TeV energies. Produced {\\gamma} -rays can initiate the Inverse Compton e+/- pair cascade in the stellar radiation. We propose that such a scenario can be responsible for the appearance of the so-called orphan {\\gamma} -ray flares. We show that the relativistic blob/luminous star collision model can explain the appearance of the extreme orphan {\\gamma} -ray flare observed in the GeV and sub-TeV energy range from the flat spectrum radio quasar PKS 1222+21.

  18. Orphan drug development and the impact on non-medical support groups.

    PubMed

    Manuel, Jeremy; Collin-Histed, Tanya

    2013-11-01

    The Orphan Drug legislation in the United States and later in the EU has had a significant impact on patients worldwide who suffer from an orphan condition. Apart from providing statutory encouragement and incentives to pharmaceutical companies to develop therapeutic products it has resulted in the encouragement of patients to come together to form patient bodies to advocate on behalf of patients. Starting in a modest way patient groups have gained experience in working with clinicians and scientists and representing their members to companies and to healthcare providers in national European and global environments. This article describes the history and evolution of the patient body and the coming together of national patient groups through umbrella organisations which have proven to be a powerful advocate for pan European and global collaboration and humanitarian aid. It also will review of some unintended consequences of the legislation.

  19. Access to orphan drugs in the Middle East: Challenge and perspective

    PubMed Central

    Almalki, Ziyad S.; Alahmari, Abdullah K.; Guo, Jeff J.; Kelton, Christina M.L.

    2012-01-01

    Summary An orphan drug is a drug developed specifically to treat a rare medical condition. With a combined population of less than 400 million, about 2.8 million patients are estimated to be suffering from a rare disease in the Middle East. Some disorders such as hemoglobinopathy, glucose-6-phosphate dehydrogenase deficiency, autosomal recessive syndromes, and several metabolic disorders have a presence throughout the Middle East. In order to promote the treatment of these diseases, Middle Eastern governments need to facilitate education and training of healthcare personnel; develop and execute a method for obtaining and paying for orphan drugs; and, finally, provide tax, marketing, and other incentives to domestic and international firms to develop drugs specifically for the diseases of most importance to Middle Eastern patients. PMID:25343087

  20. Access to orphan drugs in the Middle East: Challenge and perspective.

    PubMed

    Almalki, Ziyad S; Alahmari, Abdullah K; Guo, Jeff J; Kelton, Christina M L

    2012-11-01

    An orphan drug is a drug developed specifically to treat a rare medical condition. With a combined population of less than 400 million, about 2.8 million patients are estimated to be suffering from a rare disease in the Middle East. Some disorders such as hemoglobinopathy, glucose-6-phosphate dehydrogenase deficiency, autosomal recessive syndromes, and several metabolic disorders have a presence throughout the Middle East. In order to promote the treatment of these diseases, Middle Eastern governments need to facilitate education and training of healthcare personnel; develop and execute a method for obtaining and paying for orphan drugs; and, finally, provide tax, marketing, and other incentives to domestic and international firms to develop drugs specifically for the diseases of most importance to Middle Eastern patients. PMID:25343087

  1. Functional profiles of orphan membrane transporters in the life cycle of the malaria parasite.

    PubMed

    Kenthirapalan, Sanketha; Waters, Andrew P; Matuschewski, Kai; Kooij, Taco W A

    2016-01-01

    Assigning function to orphan membrane transport proteins and prioritizing candidates for detailed biochemical characterization remain fundamental challenges and are particularly important for medically relevant pathogens, such as malaria parasites. Here we present a comprehensive genetic analysis of 35 orphan transport proteins of Plasmodium berghei during its life cycle in mice and Anopheles mosquitoes. Six genes, including four candidate aminophospholipid transporters, are refractory to gene deletion, indicative of essential functions. We generate and phenotypically characterize 29 mutant strains with deletions of individual transporter genes. Whereas seven genes appear to be dispensable under the experimental conditions tested, deletion of any of the 22 other genes leads to specific defects in life cycle progression in vivo and/or host transition. Our study provides growing support for a potential link between heavy metal homeostasis and host switching and reveals potential targets for rational design of new intervention strategies against malaria. PMID:26796412

  2. Functional profiles of orphan membrane transporters in the life cycle of the malaria parasite

    PubMed Central

    Kenthirapalan, Sanketha; Waters, Andrew P.; Matuschewski, Kai; Kooij, Taco W. A.

    2016-01-01

    Assigning function to orphan membrane transport proteins and prioritizing candidates for detailed biochemical characterization remain fundamental challenges and are particularly important for medically relevant pathogens, such as malaria parasites. Here we present a comprehensive genetic analysis of 35 orphan transport proteins of Plasmodium berghei during its life cycle in mice and Anopheles mosquitoes. Six genes, including four candidate aminophospholipid transporters, are refractory to gene deletion, indicative of essential functions. We generate and phenotypically characterize 29 mutant strains with deletions of individual transporter genes. Whereas seven genes appear to be dispensable under the experimental conditions tested, deletion of any of the 22 other genes leads to specific defects in life cycle progression in vivo and/or host transition. Our study provides growing support for a potential link between heavy metal homeostasis and host switching and reveals potential targets for rational design of new intervention strategies against malaria. PMID:26796412

  3. Social Capital, Savings, and Educational Performance of Orphaned Adolescents in Sub-Saharan Africa

    PubMed Central

    Ssewamala, Fred M.; Karimli, Leyla; Chang-Keun, Han; Ismayilova, Leyla

    2010-01-01

    We examine the impact of social capital on savings and educational performance of orphaned adolescents participating in a family-level economic strengthening program in Uganda. Findings indicate that if given the opportunity, poor families in Uganda will use financial institutions to save for the education of their adolescent youth. Moreover, although the results are mixed, overall, adolescents with higher levels of social capital and social support, including participation in youth groups, are likely to report better saving performance compared to their counterparts with lower levels of social capital and social support. The results point to: (1) the role for family-economic strengthening programs specifically focused on improving the educational outcomes of orphaned adolescents in sub-Saharan Africa, and (2) the need for adolescents to be encouraged to participate in youth groups since these groups seem to offer the much needed supportive informal institutional structure for positive adolescent outcomes. PMID:20948971

  4. Drug discovery and development for Huntington's disease - an orphan indication with high medical need.

    PubMed

    Heitz, Freddy; La Rosa, Salvatore; Gonzalez-Couto, Eduardo; Gaviraghi, Giovanni; Terstappen, Georg C

    2008-09-01

    Huntington's disease (HD) is a rare neurodegenerative disorder that progressively destroys the mental capacity and motor control of patients. This loss of motor control results in abnormal body movements (chorea) - the hallmark of HD. Given that no disease-modifying therapy for HD exists and that available symptomatic treatments are not highly efficacious, the medical need for this 'orphan' disease remains high. The number of compounds that are undergoing discovery and development for the treatment of HD has increased significantly in recent years, spurred by legislative incentives for orphan drug development and by support from non-profit foundations. Thus, hope exists for patients with HD that efficacious medicines will become available. PMID:18763216

  5. A Burkholderia thailandensis Acyl-Homoserine Lactone-Independent Orphan LuxR Homolog That Activates Production of the Cytotoxin Malleilactone

    PubMed Central

    Truong, Thao T.; Seyedsayamdost, Mohammad; Greenberg, E. Peter

    2015-01-01

    ABSTRACT Burkholderia thailandensis has three acyl-homoserine lactone (AHL) LuxR-LuxI quorum-sensing circuits and two orphan LuxR homologs. Orphans are LuxR-type transcription factors that do not have cognate LuxI-type AHL synthases. One of the orphans, MalR, is genetically linked to the mal gene cluster, which encodes enzymes required for production of the cytotoxic polyketide malleilactone. Under normal laboratory conditions the mal gene cluster is silent; however, antibiotics like trimethoprim induce mal transcription. We show that trimethoprim-dependent induction of the mal genes requires MalR. MalR has all of the conserved amino acid residues characteristic of AHL-responsive LuxR homologs, but in B. thailandensis, MalR activation of malleilactone synthesis genes is not responsive to AHLs. MalR can activate transcription from the mal promoter in E. coli without addition of AHLs or trimethoprim. Expression of malR in B. thailandensis is induced by trimethoprim. Our data indicate that MalR binds to a lux box-like element in the mal promoter and activates transcription of the mal genes in an AHL-independent manner. Antibiotics like trimethoprim appear to activate mal gene expression indirectly by somehow activating malR expression. MalR activation of the mal genes represents an example of a LuxR homolog that is not a receptor for an AHL quorum-sensing signal. Our evidence is consistent with the idea that mal gene activation depends solely on sufficient transcription of the malR gene. IMPORTANCE LuxR proteins are transcription factors that are typically activated by acyl-homoserine lactone (AHL) signals. We demonstrate that a conserved LuxR family protein, MalR, activates genes independently of AHLs. MalR is required for transcription of genes coding for synthesis of the cytotoxic polyketide malleilactone. These genes are not expressed when cells are grown under normal laboratory conditions. In laboratory culture, MalR induction of malleilactone requires certain

  6. The orphan tsunami of 1700—Japanese clues to a parent earthquake in North America

    USGS Publications Warehouse

    Atwater, Brian F.; Musumi-Rokkaku, Satoko; Satake, Kenji; Tsuji, Yoshinobu; Ueda, Kazue; Yamaguchi, David K.

    2005-09-15

    The Orphan Tsunami of 1700, now in its second edition, tells this scientific detective story through its North American and Japanese clues. The discoveries underpin many of today’s precautions against earthquakes and tsunamis in the Cascadia region of northwestern North America. The Japanese tsunami of March 2011 called attention to those hazards as a mirror image of the transpacific waves of January 1700.

  7. The orphan tsunami of 1700—Japanese clues to a parent earthquake in North America

    USGS Publications Warehouse

    Atwater, Brian F.; Musumi-Rokkaku, Satoko; Satake, Kenji; Tsuji, Yoshinobu; Ueda, Kazue; Yamaguchi, David K.

    2005-01-01

    The Orphan Tsunami of 1700, now in its second edition, tells this scientific detective story through its North American and Japanese clues. The discoveries underpin many of today’s precautions against earthquakes and tsunamis in the Cascadia region of northwestern North America. The Japanese tsunami of March 2011 called attention to those hazards as a mirror image of the transpacific waves of January 1700.

  8. The Drosophila IR20a clade of Ionotropic Receptors are candidate taste and pheromone receptors

    PubMed Central

    Koh, Tong-Wey; He, Zhe; Gorur-Shandilya, Srinivas; Menuz, Karen; Larter, Nikki K.; Stewart, Shannon; Carlson, John R.

    2014-01-01

    Insects use taste to evaluate food, hosts, and mates. Drosophila has many “orphan” taste neurons that express no known taste receptors. The Ionotropic Receptor (IR) superfamily is best known for its role in olfaction, but virtually nothing is known about a clade of ~35 members, the IR20a clade. Here, a comprehensive analysis of this clade reveals expression in all taste organs of the fly. Some members are expressed in orphan taste neurons, whereas others are coexpressed with bitter- or sugar-sensing Gustatory receptor (Gr) genes. Analysis of the closely related IR52c and IR52d genes reveals signatures of adaptive evolution, roles in male mating behavior, and sexually dimorphic expression in neurons of the male foreleg, which contacts females during courtship. These neurons are activated by conspecific females and contact a neural circuit for sexual behavior. Together, these results greatly expand the repertoire of candidate taste and pheromone receptors in the fly. PMID:25123314

  9. The evolutionary analysis of "orphans" from the Drosophila genome identifies rapidly diverging and incorrectly annotated genes.

    PubMed

    Schmid, K J; Aquadro, C F

    2001-10-01

    In genome projects of eukaryotic model organisms, a large number of novel genes of unknown function and evolutionary history ("orphans") are being identified. Since many orphans have no known homologs in distant species, it is unclear whether they are restricted to certain taxa or evolve rapidly, either because of a lack of constraints or positive Darwinian selection. Here we use three criteria for the selection of putatively rapidly evolving genes from a single sequence of Drosophila melanogaster. Thirteen candidate genes were chosen from the Adh region on the second chromosome and 1 from the tip of the X chromosome. We succeeded in obtaining sequence from 6 of these in the closely related species D. simulans and D. yakuba. Only 1 of the 6 genes showed a large number of amino acid replacements and in-frame insertions/deletions. A population survey of this gene suggests that its rapid evolution is due to the fixation of many neutral or nearly neutral mutations. Two other genes showed "normal" levels of divergence between species. Four genes had insertions/deletions that destroy the putative reading frame within exons, suggesting that these exons have been incorrectly annotated. The evolutionary analysis of orphan genes in closely related species is useful for the identification of both rapidly evolving and incorrectly annotated genes.

  10. Widows' and orphans' property disputes: the impact of AIDS in Rakai District, Uganda.

    PubMed

    Roys, C

    1995-11-01

    The 1991 census identified 44,000 orphans in the Rakai District of Uganda. The Child Social Care Project (CSCP) in the district helps ensure that orphaned children under 18 years who have lost one or both parents to AIDS receive the property rights to which they are entitled. The property rights of widows are also championed by the CSCP. The project has enjoyed considerable success in settling individual disputes. The CSCP has also had some success in enabling communities to deal appropriately with the conflicts without recourse to experts. The author notes that while it is important to promote the empowerment of women, the phrase is so overused that it is in danger of becoming meaningless. That said, a vital aspect of empowerment is economic independence. The CSCP helps women claim the right to own property, land, and housing, as well as to care for their children in the attempt to give them some degree of economic control over their destiny and that of their children. The paper discusses widows' and orphans' property disputes in sections on wills, customary law, and statutory law. The CSCP is described followed by a case study and consideration of gender and legal reform.

  11. Process and outcome evaluation of a community intervention for orphan adolescents in western Kenya.

    PubMed

    Hallfors, Denise D; Cho, Hyunsan; Mbai, Isabella; Milimo, Benson; Itindi, Janet

    2012-10-01

    We conducted a 2-year pilot randomized controlled trial (N = 105) in a high HIV-prevalence area in rural western Kenya to test whether providing young orphan adolescents with uniforms, school fees, and community visitors improves school retention and reduces HIV risk factors. The trial was a community intervention, limited to one community. In this paper, we examined intervention implementation and its association with outcomes using longitudinal data. We used both quantitative and qualitative methods to evaluate the community-based model for orphan HIV prevention, with recommendations for future studies. Despite promising effects after 1 year, GEE analyses showed null effects after 2 years. Volunteer community visitors, a key element of the intervention, showed little of the expected effect although qualitative reports documented active assistance to prevent orphans' school absence. For future research, we recommend capturing the transition to high school, a larger sample size, and biomarker data to add strength to the research design. We also recommend a school-based intervention approach to improve implementation and reduce infrastructure costs. Finally, we recommend evaluating nurses as agents for improving school attendance and preventing dropout because of their unique ability to address critical biopsychosocial problems. PMID:22350730

  12. HUNTING THE PARENT OF THE ORPHAN STREAM: IDENTIFYING STREAM MEMBERS FROM LOW-RESOLUTION SPECTROSCOPY

    SciTech Connect

    Casey, Andrew R.; Da Costa, Gary; Keller, Stefan C.; Maunder, Elizabeth

    2013-02-10

    We present candidate K-giant members in the Orphan Stream that have been identified from low-resolution data taken with the AAOmega spectrograph on the Anglo-Australian Telescope. From modest signal-to-noise spectra and independent cuts in photometry, kinematics, gravity, and metallicity we yield self-consistent, highly probable stream members. We find a revised stream distance of 22.5 {+-} 2.0 kpc near the celestial equator and our kinematic signature peaks at V {sub GSR} = 82.1 {+-} 1.4 km s{sup -1}. The observed velocity dispersion of our most probable members is consistent with arising from the velocity uncertainties alone. This indicates that at least along this line of sight, the Orphan Stream is kinematically cold. Our data indicate an overall stream metallicity of [Fe/H] = -1.63 {+-} 0.19 dex which is more metal-rich than previously found and unbiased by spectral type. Furthermore, the significant metallicity dispersion displayed by our most probable members, {sigma}([Fe/H]) = 0.56 dex, suggests that the unidentified Orphan Stream parent is a dSph satellite. We highlight likely members for high-resolution spectroscopic follow-up.

  13. Proton pump inhibitors--their pharmacological impact on the clinical management of acid-related disorders.

    PubMed

    Klotz, Ulrich

    2009-01-01

    Acid secretion or intragastric pH play a very important role in the pathophysiology of acid-related disorders such as peptic ulcer (PU), gastrooesophageal reflux disease (GERD) or nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal lesions. Proton pump inhibitors (PPIs) represent the most potent/effective antisecretory drugs for these indications. For the selection among the various agents (omeprazole/esomeprazole (CAS 73590-58-6/119141-88-7), pantoprazole (CAS 102625-70-7), lansoprazole (CAS103577-45-3), rabeprazole (CAS 117976-83-3)) some features of their pharmacokinetic (PK) and pharmacodynamic (PD) properties should be considered as the clinical outcome depends on systemic drug exposure (PK) and elevation of intragastric pH about certain threshold levels (PD). The present review updates PK, PD and clinical data to provide some guidance between the PPIs which differ somewhat in their metabolic pattern and drug interaction potential. Based on 24-h intragastric pH assessments the relative potencies of the PPIs compared to omeprazole were in healthy volunteers (in GERD patients): 0.42 (0.59), 1.0 (0.8), 1.0 (1.0), 1.25 (1.25) and 2.0 (1.4) for pantoprazole, lansoprazole, omeprazole, esomeprazole and rabeprazole, respectively. In general, the clinical benefits of PPI are well documented but some patients can be regarded as non-responders and thus represent a challenge for future clinical research. PMID:19634508

  14. Nuclear hormone receptors put immunity on sterols

    PubMed Central

    Santori, Fabio R.

    2015-01-01

    Nuclear hormone receptors (NHRs) are transcription factors regulated by small molecules. The functions of NHRs range from development of primary and secondary lymphoid organs, to regulation of differentiation and function of DCs, macrophages and T cells. The human genome has 48 classic (hormone and vitamin receptors) and non-classic (all others) NHRs; 17 non-classic receptors are orphans, meaning that the endogenous ligand is unknown. Understanding the function of orphan NHRs requires the identification of their natural ligands. The mevalonate pathway, including its sterol and non-sterol intermediates and derivatives, is a source of ligands for many classic and non-classic NHRs. For example, cholesterol biosynthetic intermediates (CBIs) are natural ligands for RORγ/γt. CBIs are universal endogenous metabolites in mammalian cells, and to study NHRs that bind CBIs requires ligand-free reporters system in sterol auxotroph cells. Furthermore, RORγ/γt shows broad specificity to sterol lipids, suggesting that RORγ/γt is either a general sterol sensor or specificity is defined by an abundant endogenous ligand. Unlike other NHRs, which regulate specific metabolic pathways, there is no connection between the genetic programs induced by RORγ/γt and ligand biosynthesis. In this review we summarize the roles of non-classic NHRs and their potential ligands in the immune system. PMID:26222181

  15. Nuclear hormone receptors put immunity on sterols.

    PubMed

    Santori, Fabio R

    2015-10-01

    Nuclear hormone receptors (NHRs) are transcription factors regulated by small molecules. The functions of NHRs range from development of primary and secondary lymphoid organs, to regulation of differentiation and function of DCs, macrophages and T cells. The human genome has 48 classic (hormone and vitamin receptors) and nonclassic (all others) NHRs; 17 nonclassic receptors are orphans, meaning that the endogenous ligand is unknown. Understanding the function of orphan NHRs requires the identification of their natural ligands. The mevalonate pathway, including its sterol and nonsterol intermediates and derivatives, is a source of ligands for many classic and nonclassic NHRs. For example, cholesterol biosynthetic intermediates (CBIs) are natural ligands for RORγ/γt. CBIs are universal endogenous metabolites in mammalian cells, and to study NHRs that bind CBIs requires ligand-free reporters system in sterol auxotroph cells. Furthermore, RORγ/γt shows broad specificity to sterol lipids, suggesting that RORγ/γt is either a general sterol sensor or specificity is defined by an abundant endogenous ligand. Unlike other NHRs, which regulate specific metabolic pathways, there is no connection between the genetic programs induced by RORγ/γt and ligand biosynthesis. In this review, we summarize the roles of nonclassic NHRs and their potential ligands in the immune system.

  16. Reconsidering GHB: orphan drug or new model antidepressant?

    PubMed

    Bosch, Oliver G; Quednow, Boris B; Seifritz, Erich; Wetter, Thomas C

    2012-05-01

    For six decades, the principal mode of action of antidepressant drugs is the inhibition of monoamine re-uptake from the synaptic cleft. Tricyclic antidepressants, selective serotonin re-uptake inhibitors (SSRIs) and the new generation of dual antidepressants all exert their antidepressant effects by this mechanism. In the early days of the monoaminergic era, other efforts have been made to ameliorate the symptoms of depression by pharmacological means. The gamma-aminobutyric acid (GABA) system was and possibly still is one of the main alternative drug targets. Gammahydroxybutyrate (GHB) was developed as an orally active GABA analogue. It was tested in animal models of depression and human studies. The effects on sleep, agitation, anhedonia and depression were promising. However, the rise of benzodiazepines and tricyclic antidepressants brought GHB out of the scope of possible treatment alternatives. GHB is a GABA(B) and GHB receptor agonist with a unique spectrum of behavioural, neuroendocrine and sleep effects, and improves daytime sleepiness in various disorders such as narcolepsy, Parkinson's disease and fibromyalgia. Although it was banned from the US market at the end of the 1990s because of its abuse and overdose potential, it later was approved for the treatment of narcolepsy. New research methods and an extended view on other neurotransmitter systems as possible treatment targets of antidepressant treatment brought GHB back to the scene. This article discusses the unique neurobiological effects of GHB, its misuse potential and possible role as a model substance for the development of novel pharmacological treatment strategies in depressive disorders.

  17. ERK/MAPK regulates ERRγ expression, transcriptional activity and receptor-mediated tamoxifen resistance in ER+ breast cancer.

    PubMed

    Heckler, Mary M; Thakor, Hemang; Schafer, Cara C; Riggins, Rebecca B

    2014-05-01

    Selective estrogen receptor modulators such as tamoxifen (TAM) significantly improve breast cancer-specific survival for women with estrogen receptor-positive (ER+) disease. However, resistance to TAM remains a major clinical problem. The resistant phenotype is usually not driven by loss or mutation of the estrogen receptor; instead, changes in multiple proliferative and/or survival pathways over-ride the inhibitory effects of TAM. Estrogen-related receptor γ (ERRγ) is an orphan member of the nuclear receptor superfamily that promotes TAM resistance in ER+ breast cancer cells. This study sought to clarify the mechanism(s) by which this orphan nuclear receptor is regulated, and hence affects TAM resistance. mRNA and protein expression/phosphorylation were monitored by RT-PCR and western blotting, respectively. Site-directed mutagenesis was used to disrupt consensus extracellular signal-regulated kinase (ERK) target sites. Cell proliferation and cell-cycle progression were measured by flow cytometric methods. ERRγ transcriptional activity was assessed by dual-luciferase promoter-reporter assays. We show that ERRγ protein levels are affected by the activation state of ERK/mitogen-activated protein kinase, and mutation of consensus ERK target sites impairs ERRγ-driven transcriptional activity and TAM resistance. These findings shed new light on the functional significance of ERRγ in ER+ breast cancer, and are the first to demonstrate a role for kinase regulation of this orphan nuclear receptor.

  18. Orphans of the HIV epidemic: the challenges from toddlerhood to adolescence and beyond.

    PubMed

    Lala, Mamatha M

    2014-01-01

    This presentation focuses on the challenges and practical issues faced each day by orphans of the HIV epidemic and the holistic care that can be provided, as they continue to grow from toddlerhood to adolescence and beyond. An HIV Research Trust Scholarship enabled me to spend quality time in a sub-Saharan African province worst hit by the HIV epidemic and to interact with local experts and learn from mutual clinical experience. It was an immensely useful exercise as the clinical spectra of the diseases are very similar to ours and they have ongoing active research programs very relevant to our setting. India is arguably home to the largest number of orphans of the HIV epidemic. The responsibility of caring for orphaned children overwhelms and pushes many extended families beyond their ability to cope. Many countries are experiencing large increases in the number of families headed by women and grandparents, or even young children. These households are often unable to meet basic needs, and so the number of children living on the streets is rising. Orphaned children are disadvantaged in many devastating ways. In addition to the trauma of witnessing the sickness and death of one or both parents and perhaps siblings, they lack the necessary parental guidance through crucial life-stages of identity formation and transition into adulthood. They are more likely to suffer damage to their cognitive and emotional development and be subjected to; exploitation in terms of labour, social exclusion, extreme economic uncertainty, physical and sexual abuse, illiteracy, malnutrition and illness. Education remains a distant dream. With stigma and discrimination, they lack legal protection, lose inheritance rights, access to essential services available to other community members and professional help from doctors, teachers and lawyers. The implications for these unfortunate children are extraordinarily grave but governments, international agencies, non-governmental organizations

  19. National Plans of Action for Orphans and Vulnerable Children in Sub-Saharan Africa. Where Are the Youngest Children? Working Papers in Early Childhood Development, No. 50

    ERIC Educational Resources Information Center

    Engle, Patrice

    2008-01-01

    In 2005, an estimated 48 million children aged 0-18 years--12 percent of all children in sub-Saharan Africa--were orphans, and that number is expected to rise to 53 million by 2010. One quarter of all orphans are orphaned because of AIDS, and about 2.6 million children are currently infected with HIV. Untreated, most children born with HIV will…

  20. Orphan Basin crustal structure from a dense wide-angle seismic profile - layered modeling

    NASA Astrophysics Data System (ADS)

    Lau, K. W. Helen; Watremez, Louise; Louden, Keith E.; Nedimović, Mladen R.; Karner, Garry D.

    2014-05-01

    The Orphan Basin is a large, deep water basin to the east of Newfoundland and northwest of Flemish Cap, Canada. It contains a considerably wide series of rift basins that provides an excellent opportunity to study continental crustal deformations under varying degrees of extension. We present a 500-km-long P-wave velocity model across the complete rift system of the Orphan Basin, from Flemish Cap to the Bonavista Platform, using high-resolution refraction and wide-angle reflection data from 89 ocean-bottom seismometers (OBS). This layered model builds on a first-arrival traveltime tomography model (Watremez et al., this session) and is formed using additional constraints from a coincident multichannel seismic reflection profile, gravity data and borehole data from three wells. The layered model helps detail deep sediment and crustal variations across this wide region of extended continental crust. The sedimentary section contains post-rift Tertiary (vp~1.7-3.5 km/s) and syn-rift Cretaceous and Jurassic (vp~4-5.4 km/s) layers within both the eastern and the western sub-basins, separated by three basement highs, suggesting that the two sub-basins may have opened during a single, extended rifting event. The crust is composed of three layers with vp of 5.4-6.1, 6.1-6.5 and 6.3-7.1 km/s of highly variable combined thicknesses, from 32 km beneath Flemish Cap and the Bonavista Platform to <10 km beneath both western and eastern sub-basins. The shape of the crustal thinning appears highly asymmetrical across the two sub-basins. Flemish Cap crust thins westward within the eastern sub-basin into a narrow zone (35 km) of hyperextended crust (<10 km thick) beneath an 8-km-deep sedimentary basin. In contrast, the Bonavista Platform crust thins eastward within the western sub-basin into a wider zone (116 km) of hyperextended crust. Separating the two rift basins is a central section with two distinctive zones of thicker (10-16 km) crust, where muted topography characterizes the

  1. Discovery of Tertiary Sulfonamides as Potent Liver X Receptor Antagonists

    SciTech Connect

    Zuercher, William J.; Buckholz†, Richard G.; Campobasso, Nino; Collins, Jon L.; Galardi, Cristin M.; Gampe, Robert T.; Hyatt, Stephen M.; Merrihew, Susan L.; Moore, John T.; Oplinger, Jeffrey A.; Reid, Paul R.; Spearing, Paul K.; Stanley, Thomas B.; Stewart, Eugene L.; Willson, Timothy M.

    2010-08-12

    Tertiary sulfonamides were identified in a HTS as dual liver X receptor (LXR, NR1H2, and NR1H3) ligands, and the binding affinity of the series was increased through iterative analogue synthesis. A ligand-bound cocrystal structure was determined which elucidated key interactions for high binding affinity. Further characterization of the tertiary sulfonamide series led to the identification of high affinity LXR antagonists. GSK2033 (17) is the first potent cell-active LXR antagonist described to date. 17 may be a useful chemical probe to explore the cell biology of this orphan nuclear receptor.

  2. The orphan pentameric ligand-gated ion channel pHCl-2 is gated by pH and regulates fluid secretion in Drosophila Malpighian tubules.

    PubMed

    Feingold, Daniel; Starc, Tanja; O'Donnell, Michael J; Nilson, Laura; Dent, Joseph A

    2016-09-01

    Pentameric ligand-gated ion channels (pLGICs) constitute a large protein superfamily in metazoa whose role as neurotransmitter receptors mediating rapid, ionotropic synaptic transmission has been extensively studied. Although the vast majority of pLGICs appear to be neurotransmitter receptors, the identification of pLGICs in non-neuronal tissues and homologous pLGIC-like proteins in prokaryotes points to biological functions, possibly ancestral, that are independent of neuronal signalling. Here, we report the molecular and physiological characterization of a highly divergent, orphan pLGIC subunit encoded by the pHCl-2 (CG11340) gene, in Drosophila melanogaster We show that pHCl-2 forms a channel that is insensitive to a wide array of neurotransmitters, but is instead gated by changes in extracellular pH. pHCl-2 is expressed in the Malpighian tubules, which are non-innervated renal-type secretory tissues. We demonstrate that pHCl-2 is localized to the apical membrane of the epithelial principal cells of the tubules and that loss of pHCl-2 reduces urine production during diuresis. Our data implicate pHCl-2 as an important source of chloride conductance required for proper urine production, highlighting a novel role for pLGICs in epithelial tissues regulating fluid secretion and osmotic homeostasis. PMID:27358471

  3. Role of post-translational modifications on structure, function and pharmacology of class C G protein-coupled receptors.

    PubMed

    Nørskov-Lauritsen, Lenea; Bräuner-Osborne, Hans

    2015-09-15

    G protein-coupled receptors are divided into three classes (A, B and C) based on homology of their seven transmembrane domains. Class C is the smallest class with 22 human receptor subtypes including eight metabotropic glutamate (mGlu1-8) receptors, two GABAB receptors (GABAB1 and GABAB2), three taste receptors (T1R1-3), one calcium-sensing (CaS) receptor, one GPCR, class C, group 6, subtype A (GPRC6) receptor, and seven orphan receptors. G protein-coupled receptors undergo a number of post-translational modifications, which regulate their structure, function and/or pharmacology. Here, we review the existence of post-translational modifications in class C G protein-coupled receptors and their regulatory roles, with particular focus on glycosylation, phosphorylation, ubiquitination, SUMOylation, disulphide bonding and lipidation.

  4. A novel human gene encoding a G-protein-coupled receptor (GPR15) is located on chromosome 3

    SciTech Connect

    Heiber, M.; Marchese, A.; O`Dowd, B.F.

    1996-03-05

    We used sequence similarities among G-protein-coupled receptor genes to discover a novel receptor gene. Using primers based on conserved regions of the opioid-related receptors, we isolated a PCR product that was used to locate the full-length coding region of a novel human receptor gene, which we have named GPR15. A comparison of the amino acid sequence of the receptor gene, which we have named GPR15. A comparison of the amino acid sequence of the receptor encoded by GPR15 with other receptors revealed that it shared sequence identity with the angiotensin II AT1 and AT2 receptors, the interleukin 8b receptor, and the orphan receptors GPR1 and AGTL1. GPR15 was mapped to human chromosome 3q11.2-q13.1. 12 refs., 2 figs.

  5. Perilipin, a critical regulator of fat storage and breakdown, is a target gene of estrogen receptor-related receptor {alpha}

    SciTech Connect

    Akter, Mst. Hasina; Yamaguchi, Tomohiro; Hirose, Fumiko; Osumi, Takashi

    2008-04-11

    Perilipin is a protein localized on lipid droplet surfaces in adipocytes and steroidogenic cells, playing a central role in regulated lipolysis. Expression of the perilipin gene is markedly induced during adipogenesis. We found that transcription from the perilipin gene promoter is activated by an orphan nuclear receptor, estrogen receptor-related receptor (ERR){alpha}. A response element to this receptor was identified in the promoter region by a gene reporter assay, the electrophoretic-gel mobility-shift assay and the chromatin immunoprecipitation assay. Peroxisome proliferator-activated receptor {gamma} coactivator (PGC)-1{alpha} enhanced, whereas small heterodimer partner (SHP) repressed, the transactivating function of ERR{alpha} on the promoter. Thus, the perilipin gene expression is regulated by a transcriptional network controlling energy metabolism, substantiating the functional importance of perilipin in the maintenance of body energy balance.

  6. Evolution of the nuclear receptor gene superfamily.

    PubMed Central

    Laudet, V; Hänni, C; Coll, J; Catzeflis, F; Stéhelin, D

    1992-01-01

    Nuclear receptor genes represent a large family of genes encoding receptors for various hydrophobic ligands such as steroids, vitamin D, retinoic acid and thyroid hormones. This family also contains genes encoding putative receptors for unknown ligands. Nuclear receptor gene products are composed of several domains important for transcriptional activation, DNA binding (C domain), hormone binding and dimerization (E domain). It is not known whether these genes have evolved through gene duplication from a common ancestor or if their different domains came from different independent sources. To test these possibilities we have constructed and compared the phylogenetic trees derived from two different domains of 30 nuclear receptor genes. The tree built from the DNA binding C domain clearly shows a common progeny of all nuclear receptors, which can be grouped into three subfamilies: (i) thyroid hormone and retinoic acid receptors, (ii) orphan receptors and (iii) steroid hormone receptors. The tree constructed from the central part of the E domain which is implicated in transcriptional regulation and dimerization shows the same distribution in three subfamilies but two groups of receptors are in a different position from that in the C domain tree: (i) the Drosophila knirps family genes have acquired very different E domains during evolution, and (ii) the vitamin D and ecdysone receptors, as well as the FTZ-F1 and the NGF1B genes, seem to have DNA binding and hormone binding domains belonging to different classes. These data suggest a complex evolutionary history for nuclear receptor genes in which gene duplication events and swapping between domains of different origins took place. PMID:1312460

  7. The Global Threat Reduction Initiative's Orphan Source Recovery Project in the Russian Federation

    SciTech Connect

    Russell, J. W.; Ahumada, A. D.; Blanchard, T. A.

    2012-06-04

    After 9/11, officials at the United States Department of Energy (DOE), National Nuclear Security Administration (NNSA) grew more concerned about radiological materials that were vulnerable to theft and illicit use around the world. The concern was that terrorists could combine stolen radiological materials with explosives to build and detonate a radiological dispersal device (RDD), more commonly known as a “dirty bomb.” In response to this and other terrorist threats, the DOE/NNSA formed what is now known as the Global Threat Reduction Initiative (GTRI) to consolidate and accelerate efforts to reduce and protect vulnerable nuclear and radiological materials located at civilian sites worldwide. Although a cooperative program was already underway in the Russian Federation to secure nuclear materials at a range of different facilities, thousands of sealed radioactive sources remained vulnerable at medical, research, and industrial sites. In response, GTRI began to focus efforts on addressing these materials. GTRI’s Russia Orphan Source Recovery Project, managed at the Nevada National Security Site’s North Las Vegas facility, was initiated in 2002. Throughout the life of the project, Joint Stock Company “Isotope” has served as the primary Russian subcontractor, and the organization has proven to be a successful partner. Since the first orphan source recovery of an industrial cobalt-60 irradiator with 647 curies (Ci) at an abandoned facility in Moscow in 2003, the GTRI Orphan Source Recovery Project in the Russian Federation has accomplished substantial levels of threat reduction. To date, GTRI has recovered and securely disposed of more than 5,100 sources totaling more that 628,000 Ci. This project serves as an extraordinary example of how international cooperation can be implemented by partners with mutual interests to achieve significant goals.

  8. Child and Caregiver Concordance of Potentially Traumatic Events Experienced by Orphaned and Abandoned Children

    PubMed Central

    Guru Rajan, Divya; Shirey, Kristen; Ostermann, Jan; Whetten, Rachel; O’Donnell, Karen; Whetten, Kathryn

    2013-01-01

    Exposure to trauma is associated with significant emotional and behavioral difficulties among children (Perepletchikova & Kaufman, 2010). Overall, reports of trauma and violence experienced by children are discrepant from those of their caregivers (Lewis et al., 2012). Even less is known about the extent of concordance between orphans and their caregivers. This study examines the correlates of concordance in reported traumatic experiences between 1,269 orphaned and abandoned children (OAC) and their caregivers. The OAC lived in family-settings in 5 low and middle income countries and were part of a longitudinal study, “Positive Outcomes for Orphans” (POFO) that enrolled children aged 6 to 12 at baseline. By examining concordance with respect to specific types of trauma reported, this study expands the understanding of who reports which types of traumas experienced by orphaned and abandoned children, thereby improving the potential to provide targeted interventions for children who have experienced such events. In this study, children and caregivers were asked separately if the child had experienced different types of potentially traumatic events. Children were significantly more likely to report physical abuse, sexual abuse and family violence than were caregivers. Caregivers were significantly more likely than children to report natural disasters and accidents. High levels of concordance were found in the reporting of wars, riots, killings, and deaths in the family. The impacts of trauma on behavior and mental health are profound, and highly effective interventions targeting sequelae of childhood trauma are currently being developed for use in low resource areas. Findings from this study demonstrate that it is feasible to conduct screening for potentially traumatic events utilizing child self-report in resource limited settings and that child self-report is crucial in evaluating trauma, particularly family violence and physical or sexual assault. PMID:25379051

  9. The influence of the European paediatric regulation on marketing authorisation of orphan drugs for children

    PubMed Central

    2014-01-01

    Background Drug development for rare diseases is challenging, especially when these orphan drugs (OD) are intended for children. In 2007 the EU Paediatric Drug Regulation was enacted to improve the development of high quality and ethically researched medicines for children through the establishment of Paediatric Investigation Plans (PIPs). The effect of the EU Paediatric Drug Regulation on the marketing authorisation (MA) of drugs for children with rare diseases was studied. Methods Data on all designated orphan drugs, their indication, MA, PIPs and indication group (adult or child) were obtained from the European Medicines Agency (EMA). The outcome and duration of the process from orphan drug designation (ODD) to MA, was compared, per indication, by age group. The effect of the Paediatric Drug Regulation, implemented in 2007, on the application process was assessed with survival analysis. Results Eighty-one orphan drugs obtained MA since 2000 and half are authorised for (a subgroup of) children; another 34 are currently undergoing further investigations in children through agreed PIPs. The Paediatric Drug Regulation did not significantly increase the number of ODDs with potential paediatric indications (58% before vs 64% after 2007 of ODDs, p = 0.1) and did not lead to more MAs for ODs with paediatric indications (60% vs 43%, p = 0.22). ODs authorised after 2007 had a longer time to MA than those authorised before 2007 (Hazard ratio (95% CI) 2.80 (1.84-4.28), p < 0.001); potential paediatric use did not influence the time to MA (Hazard ratio (95% CI) 1.14 (0.77-1.70), p = 0.52). Conclusions The EU Paediatric Drug Regulation had a minor impact on development and availability of ODs for children, was associated with a longer time to MA, but ensured the further paediatric development of drugs still off-label to children. The impact of the Paediatric Drug Regulation on research quantity and quality in children through PIPs is not yet clear. PMID

  10. Are female orphans at risk for early marriage, early sexual debut, and teen pregnancy? Evidence from sub-Saharan Africa.

    PubMed

    Palermo, Tia; Peterman, Amber

    2009-06-01

    Female orphans are widely cited as being at risk for early marriage, early childbearing, and risky sexual behavior; however, to date no studies have examined these linkages using population-level data across multiple countries. This study draws from recent Demographic and Health Surveys from ten sub-Saharan African countries to examine the relationship between orphanhood status and measures of early marriage, early sexual debut, and teen pregnancy among adolescent girls aged 15 to 17. Results indicate that, overall, little association is found between orphanhood and early marriage or teen pregnancy, whereas evidence from seven countries supports associations between orphanhood and early sexual debut. Findings are sensitive to the use of multivariate models, type of orphan, and country setting. Orphanhood status alone may not be a sufficient targeting mechanism for addressing these outcomes in many countries; a broader, multidimensional targeting scheme including orphan type, schooling, and poverty measures would be more robust in identifying and aiding young women at risk.

  11. Neutrino Emission in the Hadronic Synchrotron Mirror Model: The "Orphan" Flare from 1ES 1959+650

    NASA Technical Reports Server (NTRS)

    Reimer, A.; Boettcher, M.; Postnikov, S.

    2005-01-01

    A challenge to standard leptonic synchrotron self-Compton (SSC) models is the so-called orphan TeV flares, i.e., enhanced very high energy (VHE) gamma-ray emission without any contemporaneous X-ray flaring activity, that have recently been observed in TeV blazars (e.g., 1ES 1959+650). In order to explain the orphan TeV flare of 1 ES 1959+650 observed in 2002 June, the so-called hadronic synchrotron mirror model has been developed. Here relativistic protons are proposed to exist in the jet and interact with reflected electron synchrotron radiation of the precursor SSC flare. If the reflector is located in the cloud region, time shifts of several days are possible between the precursor and the orphan flare. The external photons, blue-shifted in the comoving jet frame, are able to excite the Delta(1232) resonance when interacting with protons of Lorentz factors gamma(sub p) approx. 10(exp 3)-10(exp 4). The decay products of this resonance include charged pions, which, on decay, give rise to neutrino production during the orphan flare. In this paper we calculate the expected neutrino emission for the 2002 June 4 orphan TeV flare of 1ES 1959+650. We compare our results with the recent observations of AMANDA-II of a neutrino event in spatial and temporal coincidence with the orphan flare of this blazar. We find that the expected neutrino signal from the hadronic synchrotron mirror model is insufficient to explain the claimed neutrino signal from the direction of 1ES 1959+650.

  12. Lipid Homeostasis and Ligands for Liver X Receptors: Identification and Characterization.

    PubMed

    Lobaccaro, Jean-Marc A; Beaudoin, Claude; Bayala, Bagora; Baron, Silvère; Trousson, Amalia

    2016-01-01

    Screening of bona fide ligands for nuclear receptors is a real tour de force as the identified molecules are supposed to be able to activate the targeted proteins in cell culture as well as in vivo. Indeed orphan nuclear receptors are putative pharmacologically targets for various diseases. It is thus necessary to have quick and reproductive systems that help in identifying new ligands, agonist or antagonist, before using them in vivo in animal models to check for secondary effects. Here, we describe the transient transfections (homologous and heterologous) used for the screening of ligands for liver X receptor α (LXRα, NR1H3) in HeLa cells. PMID:27246331

  13. The Vulnerabilities of Orphaned Children Participating in Research: A Critical Review and Factors for Consideration for Participation in Biomedical and Behavioral Research

    PubMed Central

    Thompson, Rachel T.; Meslin, Eric M.; Braitstein, Paula K. A.; Nyandiko, Winstone M.; Ayaya, Samuel O.; Vreeman, Rachel C.

    2013-01-01

    Orphans are a subpopulation with a unique set of additional vulnerabilities. Increasing focus on children’s rights, pediatric global health, and pediatric research makes it imperative to recognize and address unique vulnerabilities of orphaned children. This paper describes the unique vulnerabilities of the orphaned pediatric population and offers a structured set of factors that require consideration when including orphans in biomedical research. Pediatric orphans are particularly vulnerable due to decreased economic resources, psychosocial instability, increased risk of abuse, and delayed/decreased access to healthcare. These vulnerabilities are significant. By carefully considering each issue in a population in a culturally specific and study-specific manner, researchers can make valuable contributions to the overall health and well-being of this uniquely vulnerable population. PMID:23086048

  14. The multiple universes of estrogen-related receptor α and γ in metabolic control and related diseases

    PubMed Central

    Audet-walsh, Étienne; Giguére, Vincent

    2015-01-01

    The identification of the estrogen-related receptors (ERRs) as the first orphan nuclear receptors ignited a new era in molecular endocrinology, which led to the discovery of new ligand-dependent response systems. Although ERR subfamily members have yet to be associated with a natural ligand, the characterization of these orphan receptors has demonstrated that they occupy a strategic node in the transcriptional control of cellular energy metabolism. In particular, ERRs are required for the response to various environmental challenges that require high energy levels by the organism. As central regulators of energy homeostasis, ERRs may also be implicated in the etiology of metabolic disorders, such as type 2 diabetes and metabolic syndrome. Here, we review the recent evidence that further highlights the role of ERRs in metabolic control, particularly in liver and skeletal muscle, and their likely involvement in metabolic diseases. Consequently, we also explore the promises and pitfalls of ERRs as potential therapeutic targets. PMID:25500872

  15. Fatal herpesvirus hemorrhagic disease in wild and orphan asian elephants in southern India.

    PubMed

    Zachariah, Arun; Zong, Jian-Chao; Long, Simon Y; Latimer, Erin M; Heaggans, Sarah Y; Richman, Laura K; Hayward, Gary S

    2013-04-01

    Up to 65% of deaths of young Asian elephants (Elephas maximus) between 3 mo and 15 yr of age in Europe and North America over the past 20 yr have been attributed to hemorrhagic disease associated with a novel DNA virus called elephant endotheliotropic herpesvirus (EEHV). To evaluate the potential role of EEHV in suspected cases of a similar lethal acute hemorrhagic disease occurring in southern India, we studied pathologic tissue samples collected from field necropsies. Nine cases among both orphaned camp and wild Asian elephants were identified by diagnostic PCR. These were subjected to detailed gene subtype DNA sequencing at multiple PCR loci, which revealed seven distinct strains of EEHV1A and one of EEHV1B. Two orphan calves that died within 3 days of one another at the same training camp had identical EEHV1A DNA sequences, indicating a common epidemiologic source. However, the high level of EEHV1 subtype genetic diversity found among the other Indian strains matches that among over 30 EEHV1 strains that have been evaluated from Europe and North America. These results argue against the previous suggestions that this is just a disease of captive elephants and that the EEHV1 virus has crossed recently from African elephant (Loxodonta africana) hosts to Asian elephants. Instead, both the virus and the disease are evidently widespread in Asia and, despite the disease severity, Asian elephants appear to be the ancient endogenous hosts of both EEHV1A and EEHV1B.

  16. Analysis of in planta Expressed Orphan Genes in the Rice Blast Fungus Magnaporthe oryzae

    PubMed Central

    Sadat, Abu; Jeon, Junhyun; Mir, Albely Afifa; Kim, Seongbeom; Choi, Jaeyoung; Lee, Yong-Hwan

    2014-01-01

    Genomes contain a large number of unique genes which have not been found in other species. Although the origin of such “orphan” genes remains unclear, they are thought to be involved in species-specific adaptive processes. Here, we analyzed seven orphan genes (MoSPC1 to MoSPC7) prioritized based on in planta expressed sequence tag data in the rice blast fungus, Magnaporthe oryzae. Expression analysis using qRT-PCR confirmed the expression of four genes (MoSPC1, MoSPC2, MoSPC3 and MoSPC7) during plant infection. However, individual deletion mutants of these four genes did not differ from the wild-type strain for all phenotypes examined, including pathogenicity. The length, GC contents, codon adaptation index and expression during mycelial growth of the four genes suggest that these genes formed during the evolutionary history of M. oryzae. Synteny analyses using closely related fungal species corroborated the notion that these genes evolved de novo in the M. oryzae genome. In this report, we discuss our inability to detect phenotypic changes in the four deletion mutants. Based on these results, the four orphan genes may be products of de novo gene birth processes, and their adaptive potential is in the course of being tested for retention or extinction through natural selection. PMID:25506301

  17. Development of chidamide for peripheral T-cell lymphoma, the first orphan drug approved in China.

    PubMed

    Lu, Xianping; Ning, Zhiqiang; Li, Zhibin; Cao, Haixiang; Wang, Xinhao

    2016-08-01

    Peripheral T-cell lymphoma (PTCL) is a set of rare and highly heterogeneous group of mature T- and NK-cell neoplasms associated with poor outcomes and lack of standard and effective therapies. The total number of newly diagnosed cases of PTCL yearly in China is estimated about 50,000. Chidamide (CS055) is a novel and orally active benzamide class of histone deacetylase (HDAC) inhibitor that selectively inhibits activity of HDAC1, 2, 3 and 10, the enzymes that are involved and play an important role in tumor initiation and development in both tumor cells and their surrounding micro-environment. Functioning as a genuine epigenetic modulator, chidamide induces growth arrest and apoptosis in tumor cells and enhances cellular antitumor immunity. Based on the overall results from preclinical and phase I clinical studies, exploratory and pivotal phase II trials of chidamide for relapsed or refractory PTCL were conducted from March 2009 to May 2012, and the results led to CFDA approval of chidamide for the indication in December 2014, being the first approved orphan drug according to the research & development approach of orphan drugs in China, as well as the first orally active drug for PTCL in China and worldwide. PMID:27672541

  18. FATAL HERPESVIRUS HEMORRHAGIC DISEASE IN WILD AND ORPHAN ASIAN ELEPHANTS IN SOUTHERN INDIA

    PubMed Central

    Zachariah, Arun; Zong, Jian-Chao; Long, Simon Y.; Latimer, Erin M.; Heaggans, Sarah Y.; Richman, Laura K.; Hayward, Gary S.

    2013-01-01

    Up to 65% of deaths of young Asian elephants (Elephas maximus) between 3 mo and 15 yr of age in Europe and North America over the past 20 yr have been attributed to hemorrhagic disease associated with a novel DNA virus called elephant endotheliotropic herpesvirus (EEHV). To evaluate the potential role of EEHV in suspected cases of a similar lethal acute hemorrhagic disease occurring in southern India, we studied pathologic tissue samples collected from field necropsies. Nine cases among both orphaned camp and wild Asian elephants were identified by diagnostic PCR. These were subjected to detailed gene subtype DNA sequencing at multiple PCR loci, which revealed seven distinct strains of EEHV1A and one of EEHV1B. Two orphan calves that died within 3 days of one another at the same training camp had identical EEHV1A DNA sequences, indicating a common epidemiologic source. However, the high level of EEHV1 subtype genetic diversity found among the other Indian strains matches that among over 30 EEHV1 strains that have been evaluated from Europe and North America. These results argue against the previous suggestions that this is just a disease of captive elephants and that the EEHV1 virus has crossed recently from African elephant (Loxodonta africana) hosts to Asian elephants. Instead, both the virus and the disease are evidently widespread in Asia and, despite the disease severity, Asian elephants appear to be the ancient endogenous hosts of both EEHV1A and EEHV1B. PMID:23568914

  19. Bacteriophage orphan DNA methyltransferases: insights from their bacterial origin, function, and occurrence.

    PubMed

    Murphy, James; Mahony, Jennifer; Ainsworth, Stuart; Nauta, Arjen; van Sinderen, Douwe

    2013-12-01

    Type II DNA methyltransferases (MTases) are enzymes found ubiquitously in the prokaryotic world, where they play important roles in several cellular processes, such as host protection and epigenetic regulation. Three classes of type II MTases have been identified thus far in bacteria which function in transferring a methyl group from S-adenosyl-l-methionine (SAM) to a target nucleotide base, forming N-6-methyladenine (class I), N-4-methylcytosine (class II), or C-5-methylcytosine (class III). Often, these MTases are associated with a cognate restriction endonuclease (REase) to form a restriction-modification (R-M) system protecting bacterial cells from invasion by foreign DNA. When MTases exist alone, which are then termed orphan MTases, they are believed to be mainly involved in regulatory activities in the bacterial cell. Genomes of various lytic and lysogenic phages have been shown to encode multi- and mono-specific orphan MTases that have the ability to confer protection from restriction endonucleases of their bacterial host(s). The ability of a phage to overcome R-M and other phage-targeting resistance systems can be detrimental to particular biotechnological processes such as dairy fermentations. Conversely, as phages may also be beneficial in certain areas such as phage therapy, phages with additional resistance to host defenses may prolong the effectiveness of the therapy. This minireview will focus on bacteriophage-encoded MTases, their prevalence and diversity, as well as their potential origin and function. PMID:24123737

  20. Life after Genocide: Mental Health, Education, and Social Support of Orphaned Survivors

    PubMed Central

    Ng, Lauren C.; Ahishakiye, Naphtal; Miller, Donald E.; Meyerowitz, Beth E.

    2015-01-01

    Thousands of orphaned survivors of the 1994 Rwandan Genocide against the Tutsi were not only exposed to extraordinarily severe forms of violence, but also many of these children took on the responsibility of caring and providing for other child survivors. This study describes the poverty, educational attainment, social support and mental health of orphaned heads of household (OHH) fourteen years after the genocide, and analyzes how violence exposure during the genocide and post-genocide stressors contributed to symptoms of posttraumatic stress disorder (PTSD) and distress. Participants were 61 members of an OHH community organization who were interviewed in 2002 about their genocide experiences and who provided a follow-up assessment of post-genocide risk factors and PTSD and distress symptoms in 2008. Almost all of the OHH in this study reported low social support, high levels of poverty, and high rates of PTSD and distress symptoms. Lower educational attainment predicted PTSD symptoms and partially mediated the association between exposure to genocide violence and PTSD. Distress was predicted by lack of social support and witnessing family members harmed during the genocide. Results suggest that public health and community efforts to improve educational outcomes and to strengthen and expand social support networks may improve mental health outcomes of OHH. PMID:26236560

  1. A Qualitative Study of Mental Health Problems Among Orphaned Children and Adolescents in Tanzania.

    PubMed

    Dorsey, Shannon; Lucid, Leah; Murray, Laura; Bolton, Paul; Itemba, Dafrosa; Manongi, Rachel; Whetten, Kathryn

    2015-11-01

    Low- and middle-income countries have a high number of orphans, many of whom have unmet mental health needs. Effective mental health interventions are needed; however, it is necessary to understand how mental health symptoms and needs are perceived locally to tailor interventions and refine measurement of intervention effects. We used an existing rapid ethnographic assessment approach to identify mental health problems from the perspective of orphans and guardians to inform a subsequent randomized controlled trial of a Western-developed, evidence-based psychosocial intervention, Trauma-focused Cognitive Behavioral Therapy. Local Kiswahili-speaking interviewers conducted 73 free list interviews and 34 key informant interviews. Results identified both common cross-cultural experiences and symptoms as well as uniquely described symptoms (e.g., lacking peace, being discriminated against) not typically targeted by the intervention or included on standardized measures of intervention effects. We discuss implications for adapting mental health interventions in low- and middle-income countries and assessing effectiveness. PMID:26488916

  2. Developing and paying for medicines for orphan indications in oncology: utilitarian regulation vs equitable care?

    PubMed

    Davies, J E; Neidle, S; Taylor, D G

    2012-01-01

    Despite 'orphan drug' legislation, bringing new medicines for rare diseases to market and securing funding for their provision is sometimes both costly and problematic, even in the case of medicines for very rare 'ultra orphan' oncological indications. In this paper difficulties surrounding the introduction of a new treatment for osteosarcoma exemplify the challenges that innovators can face. The implications of current policy debate on 'value-based' medicines pricing in Europe, North America and elsewhere are also explored in the context of sustaining research into and facilitating cancer patient access to medicines for low-prevalence indications. Tensions exist between utilitarian strategies aimed at optimising the welfare of the majority in the society and minority-interest-focused approaches to equitable care provision. Current regulatory and pricing strategies should be revisited with the objective of facilitating fair and timely drug supply to patients without sacrificing safety or overall affordability. Failures effectively to tackle the problems considered here could undermine public interests in developing better therapies for cancer patients.

  3. Development of chidamide for peripheral T-cell lymphoma, the first orphan drug approved in China

    PubMed Central

    Lu, Xianping; Ning, Zhiqiang; Li, Zhibin; Cao, Haixiang; Wang, Xinhao

    2016-01-01

    Summary Peripheral T-cell lymphoma (PTCL) is a set of rare and highly heterogeneous group of mature T- and NK-cell neoplasms associated with poor outcomes and lack of standard and effective therapies. The total number of newly diagnosed cases of PTCL yearly in China is estimated about 50,000. Chidamide (CS055) is a novel and orally active benzamide class of histone deacetylase (HDAC) inhibitor that selectively inhibits activity of HDAC1, 2, 3 and 10, the enzymes that are involved and play an important role in tumor initiation and development in both tumor cells and their surrounding micro-environment. Functioning as a genuine epigenetic modulator, chidamide induces growth arrest and apoptosis in tumor cells and enhances cellular antitumor immunity. Based on the overall results from preclinical and phase I clinical studies, exploratory and pivotal phase II trials of chidamide for relapsed or refractory PTCL were conducted from March 2009 to May 2012, and the results led to CFDA approval of chidamide for the indication in December 2014, being the first approved orphan drug according to the research & development approach of orphan drugs in China, as well as the first orally active drug for PTCL in China and worldwide. PMID:27672541

  4. Francisella novicida forms in vitro biofilms mediated by an orphan response regulator.

    PubMed

    Durham-Colleran, Meghan W; Verhoeven, Anne Brooks; van Hoek, Monique L

    2010-04-01

    Francisella tularensis is associated with water and waterways and infects many species of animals, insects, and protists. The mechanism Francisella utilizes to persist in the environment and in tick vectors is currently unknown. We have demonstrated for the first time that Francisella novicida, a model organism of F. tularensis, forms a biofilm in vitro. Selected F. novicida transposon mutants were tested for their ability to form biofilm compared to the wildtype F. novicida strain. Mutation of the putative qseB gene led to an impairment in the ability to form biofilm with no impairment in bacterial growth. A qseC mutant had impaired growth but demonstrated a marked impairment in biofilm production. Mutation in capC affected both bacterial growth and biofilm formation, but no biofilm production impairment was seen with capB or pilE mutants. A deletion mutant in the orphan response regulator FTN_1465, which we propose is the putative QseB, formed significantly less biofilm than the wildtype. When FTN_1465 was complemented back into the deletion mutant, biofilm formation was restored. Thus, the orphan response regulator FTN_1465 is an important factor in biofilm production in vitro in F. novicida. These results demonstrate that Francisella species are able to form biofilms in vitro, suggesting that biofilm formation may be important for the lifecycle of this organism.

  5. Development of chidamide for peripheral T-cell lymphoma, the first orphan drug approved in China

    PubMed Central

    Lu, Xianping; Ning, Zhiqiang; Li, Zhibin; Cao, Haixiang; Wang, Xinhao

    2016-01-01

    Summary Peripheral T-cell lymphoma (PTCL) is a set of rare and highly heterogeneous group of mature T- and NK-cell neoplasms associated with poor outcomes and lack of standard and effective therapies. The total number of newly diagnosed cases of PTCL yearly in China is estimated about 50,000. Chidamide (CS055) is a novel and orally active benzamide class of histone deacetylase (HDAC) inhibitor that selectively inhibits activity of HDAC1, 2, 3 and 10, the enzymes that are involved and play an important role in tumor initiation and development in both tumor cells and their surrounding micro-environment. Functioning as a genuine epigenetic modulator, chidamide induces growth arrest and apoptosis in tumor cells and enhances cellular antitumor immunity. Based on the overall results from preclinical and phase I clinical studies, exploratory and pivotal phase II trials of chidamide for relapsed or refractory PTCL were conducted from March 2009 to May 2012, and the results led to CFDA approval of chidamide for the indication in December 2014, being the first approved orphan drug according to the research & development approach of orphan drugs in China, as well as the first orally active drug for PTCL in China and worldwide.

  6. Extremely Soft X-Ray Flash as the Indicator of Off-axis Orphan GRB Afterglow

    NASA Astrophysics Data System (ADS)

    Urata, Yuji; Huang, Kuiyun; Yamazaki, Ryo; Sakamoto, Takanori

    2015-06-01

    We verified the off-axis jet model of X-ray flashes (XRFs) and examined a discovery of off-axis orphan gamma-ray burst (GRB) afterglows. The XRF sample was selected on the basis of the following three factors: (1) a constraint on the lower peak energy of the prompt spectrum {E}{obs}{src}, (2) redshift measurements, and (3) multicolor observations of an earlier (or brightening) phase. XRF 020903 was the only sample selected on the basis of these criteria. A complete optical multicolor afterglow light curve of XRF 020903 obtained from archived data and photometric results in the literature showed an achromatic brightening around 0.7 days. An off-axis jet model with a large observing angle (0.21 rad, which is twice the jet opening half-angle, {θ }{jet}) can naturally describe the achromatic brightening and the prompt X-ray spectral properties. This result indicates the existence of off-axis orphan GRB afterglow light curves. Events with a larger viewing angle (\\gt ∼ 2{θ }{jet}) could be discovered using an 8 m class telescope with wide-field imagers such as the Subaru Hyper-Suprime-Cam and the Large Synoptic Survey Telescope.

  7. [Orphans, AIDS, and the Millennium Development Goals: models and capacity to act].

    PubMed

    Kojoué Kamga, Larissa

    2009-01-01

    The impact of HIV/AIDS on children is considerable. Parental illness and loss affect their children's psychosocial, economic and family well-being, limit the children's access to basic social services and undermining their chances of survival and their future. Although these children, orphaned and vulnerable because of HIV/AIDS, present a true social crisis, they have, since the beginning of the epidemic, been largely left out of the global and national fight against AIDS. The aim of this study is to analyse the achievement of Millennium Development Goal (MDG) 6 through the support for these children in Africa. Using an inductive comprehensive approach based on the history of the fight against AIDS in three countries Cameroon, Uganda and South Africa, we seek to show that achievement of the MDGs is largely contextual. The weaknesses, deficiencies and policy failures of MDGs should not be treated as mere technical or local issues. They involve political and social questions that are not new. The second approach, from a top-down perspective, helped us to study the State in action. What can we learn about the State's capacity to reach the MDGs by 2015 from the care they currently provide to orphaned and vulnerable children? PMID:20185389

  8. Bacteriophage Orphan DNA Methyltransferases: Insights from Their Bacterial Origin, Function, and Occurrence

    PubMed Central

    Murphy, James; Mahony, Jennifer; Ainsworth, Stuart; Nauta, Arjen

    2013-01-01

    Type II DNA methyltransferases (MTases) are enzymes found ubiquitously in the prokaryotic world, where they play important roles in several cellular processes, such as host protection and epigenetic regulation. Three classes of type II MTases have been identified thus far in bacteria which function in transferring a methyl group from S-adenosyl-l-methionine (SAM) to a target nucleotide base, forming N-6-methyladenine (class I), N-4-methylcytosine (class II), or C-5-methylcytosine (class III). Often, these MTases are associated with a cognate restriction endonuclease (REase) to form a restriction-modification (R-M) system protecting bacterial cells from invasion by foreign DNA. When MTases exist alone, which are then termed orphan MTases, they are believed to be mainly involved in regulatory activities in the bacterial cell. Genomes of various lytic and lysogenic phages have been shown to encode multi- and mono-specific orphan MTases that have the ability to confer protection from restriction endonucleases of their bacterial host(s). The ability of a phage to overcome R-M and other phage-targeting resistance systems can be detrimental to particular biotechnological processes such as dairy fermentations. Conversely, as phages may also be beneficial in certain areas such as phage therapy, phages with additional resistance to host defenses may prolong the effectiveness of the therapy. This minireview will focus on bacteriophage-encoded MTases, their prevalence and diversity, as well as their potential origin and function. PMID:24123737

  9. Type 1 metabotropic glutamate receptors (mGlu1) trigger the gating of GluD2 delta glutamate receptors

    PubMed Central

    Ady, Visou; Perroy, Julie; Tricoire, Ludovic; Piochon, Claire; Dadak, Selma; Chen, Xiaoru; Dusart, Isabelle; Fagni, Laurent; Lambolez, Bertrand; Levenes, Carole

    2014-01-01

    The orphan GluD2 receptor belongs to the ionotropic glutamate receptor family but does not bind glutamate. Ligand-gated GluD2 currents have never been evidenced, and whether GluD2 operates as an ion channel has been a long-standing question. Here, we show that GluD2 gating is triggered by type 1 metabotropic glutamate receptors, both in a heterologous expression system and in Purkinje cells. Thus, GluD2 is not only an adhesion molecule at synapses but also works as a channel. This gating mechanism reveals new properties of glutamate receptors that emerge from their interaction and opens unexpected perspectives regarding synaptic transmission and plasticity. PMID:24357660

  10. Molecular evolution of GPCRs: Ghrelin/ghrelin receptors.

    PubMed

    Kaiya, Hiroyuki; Kangawa, Kenji; Miyazato, Mikiya

    2014-06-01

    After the discovery in 1996 of the GH secretagogue-receptor type-1a (GHS-R1a) as an orphan G-protein coupled receptor, many research groups attempted to identify the endogenous ligand. Finally, Kojima and colleagues successfully isolated the peptide ligand from rat stomach extracts, determined its structure, and named it ghrelin. The GHS-R1a is now accepted to be the ghrelin receptor. The existence of the ghrelin system has been demonstrated in many animal classes through biochemical and molecular biological strategies as well as through genome projects. Our work, focused on identifying the ghrelin receptor and its ligand ghrelin in laboratory animals, particularly nonmammalian vertebrates, has provided new insights into the molecular evolution of the ghrelin receptor. In mammals, it is assumed that the ghrelin receptor evolution is in line with the plate tectonics theory. In contrast, the evolution of the ghrelin receptor in nonmammalian vertebrates differs from that of mammals: multiplicity of the ghrelin receptor isoforms is observed in nonmammalian vertebrates only. This multiplicity is due to genome duplication and polyploidization events that particularly occurred in Teleostei. Furthermore, it is likely that the evolution of the ghrelin receptor is distinct from that of its ligand, ghrelin, because only one ghrelin isoform has been detected in all species examined so far. In this review, we summarize current knowledge related to the molecular evolution of the ghrelin receptor in mammalian and nonmammalian vertebrates. PMID:24353285

  11. Effectiveness of Group Activity Play Therapy on Internalizing and Externalizing Behavior Problems of Preadolescent Orphans in Uganda

    ERIC Educational Resources Information Center

    Ojiambo, Deborah

    2011-01-01

    This pilot study investigated the impact of group activity play therapy (GAPT) on displaced orphans aged 10 to 12 years living in a large children's village in Uganda. Teachers and housemothers identified 60 preadolescents exhibiting clinical levels of internalizing and externalizing behavior problems. The participants' ethnicity was…

  12. 8 CFR 204.3 - Orphan cases under section 101(b)(1)(F) of the Act (non-Convention cases).

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... effective date, as defined in 8 CFR 204.301, on behalf of a child who is habitually resident in a Convention... paragraph (a)(2) of this section, a child who meets the definition of orphan contained in section 101(b)(1... U.S. citizen seeking the child's immigration can document that the citizen (and his or her...

  13. 8 CFR 204.3 - Orphan cases under section 101(b)(1)(F) of the Act (non-Convention cases).

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... effective date, as defined in 8 CFR 204.301, on behalf of a child who is habitually resident in a Convention... paragraph (a)(2) of this section, a child who meets the definition of orphan contained in section 101(b)(1... U.S. citizen seeking the child's immigration can document that the citizen (and his or her...

  14. 8 CFR 204.3 - Orphan cases under section 101(b)(1)(F) of the Act (non-Convention cases).

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... effective date, as defined in 8 CFR 204.301, on behalf of a child who is habitually resident in a Convention... paragraph (a)(2) of this section, a child who meets the definition of orphan contained in section 101(b)(1... U.S. citizen seeking the child's immigration can document that the citizen (and his or her...

  15. 8 CFR 204.3 - Orphan cases under section 101(b)(1)(F) of the Act (non-Convention cases).

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... effective date, as defined in 8 CFR 204.301, on behalf of a child who is habitually resident in a Convention... paragraph (a)(2) of this section, a child who meets the definition of orphan contained in section 101(b)(1... U.S. citizen seeking the child's immigration can document that the citizen (and his or her...

  16. 8 CFR 204.3 - Orphan cases under section 101(b)(1)(F) of the Act (non-Convention cases).

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... effective date, as defined in 8 CFR 204.301, on behalf of a child who is habitually resident in a Convention... paragraph (a)(2) of this section, a child who meets the definition of orphan contained in section 101(b)(1... U.S. citizen seeking the child's immigration can document that the citizen (and his or her...

  17. Grief-Processing-Based Psychological Intervention for Children Orphaned by AIDS in Central China: A Pilot Study

    ERIC Educational Resources Information Center

    Lin, Xiuyun; Fang, Xiaoyi; Chi, Peilian; Li, Xiaoming; Chen, Wenrui; Heath, Melissa Allen

    2014-01-01

    A group of 124 children orphaned by AIDS (COA), who resided in two orphanages funded by the Chinese government, participated in a study investigating the efficacy of a grief-processing-based psychological group intervention. This psychological intervention program was designed to specifically help COA process their grief and reduce their…

  18. The use of 2D fingerprint methods to support the assessment of structural similarity in orphan drug legislation

    PubMed Central

    2014-01-01

    Background In the European Union, medicines are authorised for some rare disease only if they are judged to be dissimilar to authorised orphan drugs for that disease. This paper describes the use of 2D fingerprints to show the extent of the relationship between computed levels of structural similarity for pairs of molecules and expert judgments of the similarities of those pairs. The resulting relationship can be used to provide input to the assessment of new active compounds for which orphan drug authorisation is being sought. Results 143 experts provided judgments of the similarity or dissimilarity of 100 pairs of drug-like molecules from the DrugBank 3.0 database. The similarities of these pairs were also computed using BCI, Daylight, ECFC4, ECFP4, MDL and Unity 2D fingerprints. Logistic regression analyses demonstrated a strong relationship between the human and computed similarity assessments, with the resulting regression models having significant predictive power in experiments using data from submissions of orphan drug medicines to the European Medicines Agency. The BCI fingerprints performed best overall on the DrugBank dataset while the BCI, Daylight, ECFP4 and Unity fingerprints performed comparably on the European Medicines Agency dataset. Conclusions Measures of structural similarity based on 2D fingerprints can provide a useful source of information for the assessment of orphan drug status by regulatory authorities. PMID:24485002

  19. 78 FR 51732 - The Food and Drug Administration/European Medicines Agency Orphan Product Designation and Grant...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-08-21

    ... valuable information about the FDA and European Medicines Agency (EMA) Orphan Drug Designation programs.... For parking and security information, please refer to http://www.fda.gov/AboutFDA/WorkingatFDA/BuildingsandFacilities/WhiteOakCampusInformation/ucm241740.htm . Contact Person: Eleanor Dixon-Terry, Food...

  20. 75 FR 47602 - Clinical Studies of Safety and Effectiveness of Orphan Products Research Project Grant (R01)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-08-06

    ... HUMAN SERVICES Food and Drug Administration Clinical Studies of Safety and Effectiveness of Orphan... program is to support the clinical development of products for use in rare diseases or conditions where no... provides grants for clinical studies on safety and/or effectiveness that will either result in,...

  1. The orphan gene ybjN conveys pleiotropic effects on multicellular behavior and survival of Escherichia coli

    Technology Transfer Automated Retrieval System (TEKTRAN)

    YbjN, an enterobacteria-specific protein, is a multicopy suppressor of ts9 temperature sensitivity in Escherichia coli. In this study, we further explored the roles of ybjN, an orphan gene in E. coli. First, we demonstrated that ybjN gene was down-regulated about 10-fold in ts9 strain compared to th...

  2. Strategies for Supporting Orphans and Vulnerable Children: An Exploratory Study of an Exemplary Model of Care in Kenya

    ERIC Educational Resources Information Center

    Mears, Melynda; Singletary, Jon; Rogers, Rob

    2011-01-01

    This qualitative study explored the extent to which programs in a religiously affiliated agency in Kenya incorporate 12 internationally sanctioned strategies for supporting orphans and vulnerable children in Sub-Saharan Africa (Olson, Knight, & Foster, 2006). The results indicated that all 12 strategies were being employed, though to varying…

  3. How Zimbabwean AIDS Orphans Negotiate Their Personal Identities within the Fields of Home and School in a Stigmatising Society

    ERIC Educational Resources Information Center

    Kwenda, Chiwimbiso M.

    2009-01-01

    This study is based on field data originally collected for a PhD research project in a small district of Zimbabwe. The study attempts to answer the question about how AIDS orphaned children in a selected context in Zimbabwe construct their concept of self as members of their changed and recomposing families, and as members of their school and…

  4. Length of Institutionalization, Contact with Relatives and Previous Hospitalizations as Predictors of Social and Emotional Behavior in Young Ugandan Orphans

    ERIC Educational Resources Information Center

    Nielsen, Ashley; Coleman, Priscilla K.; Guinn, Matthew; Robb, Clifford

    2004-01-01

    The objectives of this study were to describe the socially based emotions and behaviors of 33 orphans in Uganda and to examine social history correlates of variability in the outcome measures. The toddlers were generally not very aggressive or prosocially oriented, and they displayed rather limited affect. More time was spent alone than with…

  5. Comprehensive Analysis of Mouse Bitter Taste Receptors Reveals Different Molecular Receptive Ranges for Orthologous Receptors in Mice and Humans.

    PubMed

    Lossow, Kristina; Hübner, Sandra; Roudnitzky, Natacha; Slack, Jay P; Pollastro, Federica; Behrens, Maik; Meyerhof, Wolfgang

    2016-07-15

    One key to animal survival is the detection and avoidance of potentially harmful compounds by their bitter taste. Variable numbers of taste 2 receptor genes expressed in the gustatory end organs enable bony vertebrates (Euteleostomi) to recognize numerous bitter chemicals. It is believed that the receptive ranges of bitter taste receptor repertoires match the profiles of bitter chemicals that the species encounter in their diets. Human and mouse genomes contain pairs of orthologous bitter receptor genes that have been conserved throughout evolution. Moreover, expansions in both lineages generated species-specific sets of bitter taste receptor genes. It is assumed that the orthologous bitter taste receptor genes mediate the recognition of bitter toxins relevant for both species, whereas the lineage-specific receptors enable the detection of substances differently encountered by mice and humans. By challenging 34 mouse bitter taste receptors with 128 prototypical bitter substances in a heterologous expression system, we identified cognate compounds for 21 receptors, 19 of which were previously orphan receptors. We have demonstrated that mouse taste 2 receptors, like their human counterparts, vary greatly in their breadth of tuning, ranging from very broadly to extremely narrowly tuned receptors. However, when compared with humans, mice possess fewer broadly tuned receptors and an elevated number of narrowly tuned receptors, supporting the idea that a large receptor repertoire is the basis for the evolution of specialized receptors. Moreover, we have demonstrated that sequence-orthologous bitter taste receptors have distinct agonist profiles. Species-specific gene expansions have enabled further diversification of bitter substance recognition spectra.

  6. Comprehensive Analysis of Mouse Bitter Taste Receptors Reveals Different Molecular Receptive Ranges for Orthologous Receptors in Mice and Humans.

    PubMed

    Lossow, Kristina; Hübner, Sandra; Roudnitzky, Natacha; Slack, Jay P; Pollastro, Federica; Behrens, Maik; Meyerhof, Wolfgang

    2016-07-15

    One key to animal survival is the detection and avoidance of potentially harmful compounds by their bitter taste. Variable numbers of taste 2 receptor genes expressed in the gustatory end organs enable bony vertebrates (Euteleostomi) to recognize numerous bitter chemicals. It is believed that the receptive ranges of bitter taste receptor repertoires match the profiles of bitter chemicals that the species encounter in their diets. Human and mouse genomes contain pairs of orthologous bitter receptor genes that have been conserved throughout evolution. Moreover, expansions in both lineages generated species-specific sets of bitter taste receptor genes. It is assumed that the orthologous bitter taste receptor genes mediate the recognition of bitter toxins relevant for both species, whereas the lineage-specific receptors enable the detection of substances differently encountered by mice and humans. By challenging 34 mouse bitter taste receptors with 128 prototypical bitter substances in a heterologous expression system, we identified cognate compounds for 21 receptors, 19 of which were previously orphan receptors. We have demonstrated that mouse taste 2 receptors, like their human counterparts, vary greatly in their breadth of tuning, ranging from very broadly to extremely narrowly tuned receptors. However, when compared with humans, mice possess fewer broadly tuned receptors and an elevated number of narrowly tuned receptors, supporting the idea that a large receptor repertoire is the basis for the evolution of specialized receptors. Moreover, we have demonstrated that sequence-orthologous bitter taste receptors have distinct agonist profiles. Species-specific gene expansions have enabled further diversification of bitter substance recognition spectra. PMID:27226572

  7. Child work and labour among orphaned and abandoned children in five low and middle income countries

    PubMed Central

    2011-01-01

    Background The care and protection of the estimated 143,000,000 orphaned and abandoned children (OAC) worldwide is of great importance to global policy makers and child service providers in low and middle income countries (LMICs), yet little is known about rates of child labour among OAC, what child and caregiver characteristics predict child engagement in work and labour, or when such work infers with schooling. This study examines rates and correlates of child labour among OAC and associations of child labour with schooling in a cohort of OAC in 5 LMICs. Methods The Positive Outcomes for Orphans (POFO) study employed a two-stage random sampling survey methodology to identify 1480 single and double orphans and children abandoned by both parents ages 6-12 living in family settings in five LMICs: Cambodia, Ethiopia, India, Kenya, and Tanzania. Regression models examined child and caregiver associations with: any work versus no work; and with working <21, 21-27, and 28+ hours during the past week, and child labour (UNICEF definition). Results The majority of OAC (60.7%) engaged in work during the past week, and of those who worked, 17.8% (10.5% of the total sample) worked 28 or more hours. More than one-fifth (21.9%; 13% of the total sample) met UNICEF's child labour definition. Female OAC and those in good health had increased odds of working. OAC living in rural areas, lower household wealth and caregivers not earning an income were associated with increased child labour. Child labour, but not working fewer than 28 hours per week, was associated with decreased school attendance. Conclusions One in seven OAC in this study were reported to be engaged in child labour. Policy makers and social service providers need to pay close attention to the demands being placed on female OAC, particularly in rural areas and poor households with limited income sources. Programs to promote OAC school attendance may need to focus on the needs of families as well as the OAC. PMID

  8. Water Masses and Currents in Orphan Basin of the North Atlantic

    NASA Astrophysics Data System (ADS)

    Loder, J.; Yashayaev, I.; Geshelin, Y.

    2006-12-01

    Over the past three years (2004-2006), the Bedford Institute of Oceanography (BIO) has conducted three annual hydrographic surveys and current-meter mooring deployments in Orphan Basin. Located at the southern end of the Labrador Sea, this region is a large continental-margin basin where portions of subpolar outflows such as the Labrador Current, the Deep Western Boundary Current (DWBC) and Labrador Sea Water approach the topographic promontory of Flemish Cap before exiting the Subpolar Gyre. Hydrographic sections across Orphan Basin occupied in June 2004, May 2005 and May 2006 reveal significant basin-wide changes, which are largely in agreement with the changes in the corresponding layers of the central Labrador Sea. Both the intermediate (Labrador Sea Water) and deep (Northeast Atlantic Deep Water) waters of the basin became warmer and saltier over the past three years. In contrast, the bottom waters - representing the densest limb of the DWBC - became ~0.2°C colder and ~0.015 fresher between 2004 and 2005. This change is most likely associated with the passing of a fresh and cold event around the Labrador Sea, observed about a year earlier in May 2004 on the eastern side of the Labrador Sea, yielding an average DWBC speed of ~10cm/s. The 2006 survey mapped a strong cyclonic eddy in the central Orphan Basin with its radial geostrophic velocities reaching 0.6 m/sec between 500 and 1000 m. Another phenomenon seen in the 2006 temperature, salinity, density and dissolved oxygen profiles at a 2900 m deep station is a distinct near-bottom layer (~150 m thick) bound by an extraordinarily sharp transition to a layer above (with a density step of 0.03 over 10 m). This feature indicates complex dynamics in the basin, possibly associated with a change in vorticity when the flow passes the saddle-shaped topography at its northern boundary. The moored current measurements indicate the structure and magnitude of the major throughflows, as well as episodic temporal

  9. Relationship Between Family Economic Resources, Psychosocial Well-being, and Educational Preferences of AIDS-Orphaned Children in Southern Uganda: Baseline Findings

    PubMed Central

    Ssewamala, Fred M.; Nabunya, Proscovia; Ilic, Vilma; Mukasa, Miriam N.; Ddamulira, Christopher

    2015-01-01

    This study examines the relationship between economic resources, psychosocial well-being, and educational preferences of AIDS-orphaned children in southern Uganda. We use baseline data from a sample of 1410 AIDS-orphaned children (defined as children who have lost one or both biological parents to AIDS) enrolled in the Bridges to the Future study, a National Institute of Child Health and Human Development (NICHD) funded study. Analyses from both bivariate and multiple regression analyses indicate the following: 1) despite the well-documented economic and psychosocial challenges AIDS-orphaned children face, many of these children have high educational plans and aspirations; 2) educational aspirations differ by orphanhood status (double orphan vs. single orphan); 3) regardless of orphanhood status, children report similar levels of psychosocial well-being; 4) high levels of family cohesion, positive perceptions of the future, school satisfaction, and lower levels of hopelessness (hopefulness) are associated with high educational aspirations; and 5) reported family economic resources at baseline, all seem to play a role in predicting children's educational preferences and psychosocial well-being. These findings suggest that the focus for care and support of orphaned children should not be limited to addressing their psychosocial needs. Addressing the economic needs of the households in which orphaned children live is equally important. Indeed, in the context of extreme poverty—in which most of the children represented in this study live—addressing structural factors, including poverty, may be a key driver in addressing their psychosocial functioning. PMID:26146601

  10. Challenges and coping strategies of orphaned children in Tanzania who are not adequately cared for by adults.

    PubMed

    Daniel, Marguerite; Mathias, Angela

    2012-10-01

    Orphaned children in poor rural communities sometimes have no adult who is able to care for them or else the adult caregiver is not able to provide adequate care. Tanzania remains one of the poorest countries in the world, and poverty frequently constrains foster care. Although HIV prevalence is declining, AIDS is still a major cause of orphaning. This article explores the challenges and coping strategies accompanying two possible life trajectories for orphaned children without adequate adult care: 1) that they remain in rural areas in child-headed households, or 2) that they are trafficked to an urban area. Antonovsky's salutogenic model is used as the theoretical framework. The data come from two separate phenomenological studies with vulnerable children. In the first study, in-depth interviews were held with 12 orphaned children in a poor rural area; data concerning three child heads of households are included here. In the second study, 15 girls who were trafficked from rural areas to Dar es Salaam gave extended life-history narrations; data are included for nine of the girls who were orphaned. Loss of parents, a lack of cash, and the need to balance school attendance with food production were chronic stressors for the children heading households, while resources included income-generation strategies and the ability to negotiate with teachers for time to cultivate. For the trafficked girls chronic stressors included exploitation, long working hours, little or no pay, isolation and rape. Resources for them, although limited, included faith networks and neighbours; escape from the exploitative situation frequently involved external help. We conclude that given physical and social assets the child-headed households were able to cope with the challenges of caring for themselves and a younger child, but isolation and dependency on employers made it difficult for the trafficked girls to cope with this exploitation. The salutogenic model proved a useful tool in

  11. Rates of trauma spectrum disorders and risks of posttraumatic stress disorder in a sample of orphaned and widowed genocide survivors

    PubMed Central

    Schaal, Susanne; Dusingizemungu, Jean-Pierre; Jacob, Nadja; Elbert, Thomas

    2011-01-01

    Background During the Rwandan genocide of 1994, nearly one million people were killed within a period of 3 months. Objective The objectives of this study were to investigate the levels of trauma exposure and the rates of mental health disorders and to describe risk factors of posttraumatic stress reactions in Rwandan widows and orphans who had been exposed to the genocide. Design Trained local psychologists interviewed orphans (n=206) and widows (n=194). We used the PSS-I to assess posttraumatic stress disorder (PTSD), the Hopkins Symptom Checklist to assess depression and anxiety symptoms, and the M.I.N.I. to assess risk of suicidality. Results Subjects reported having been exposed to a high number of different types of traumatic events with a mean of 11 for both groups. Widows displayed more severe mental health problems than orphans: 41% of the widows (compared to 29% of the orphans) met symptom criteria for PTSD and a substantial proportion of widows suffered from clinically significant depression (48% versus 34%) and anxiety symptoms (59% versus 42%) even 13 years after the genocide. Over one-third of respondents of both groups were classified as suicidal (38% versus 39%). Regression analysis indicated that PTSD severity was predicted mainly by cumulative exposure to traumatic stressors and by poor physical health status. In contrast, the importance given to religious/spiritual beliefs and economic variables did not correlate with symptoms of PTSD. Conclusions While a significant portion of widows and orphans continues to display severe posttraumatic stress reactions, widows seem to constitute a particularly vulnerable survivor group. Our results point to the chronicity of mental health problems in this population and show that PTSD may endure over time if not addressed by clinical intervention. Possible implications of poor mental health and the need for psychological intervention are discussed. PMID:22893816

  12. The paediatric rheumatologist and orphan disease - a story without happy ending.

    PubMed

    Roszkiewicz, Justyna; Biernacka-Zielińska, Małgorzata; Smolewska, Elżbieta

    2016-01-01

    Orphan diseases are not a common challenge in the everyday practice of the rheumatologist. Despite their extremely rare occurrence one of the patients under our care developed one of them - neuronal ceroid lipofuscinosis, the most frequent neurodegenerative disease observed in the paediatric population. We report a case of 2-year-old girl diagnosed with oligoarticular form of juvenile idiopathic arthritis treated in our Department with steroids and methotrexate and staying in the stage of disease remission. During routine checkups at Outpatient Clinic we observed progressive deterioration of girls neurological condition resulting in ataxia, gait disturbances with no rheumatological cause behind and speech impairment. The appearance of the symptoms was accompanied by frequent episodes of epileptic seizures, with little clinical improvement on combined antiepileptic treatment. Magnetic resonance imaging that we performed showed a picture highly suggestive of neuronal ceroid lipofuscinosis - atrophy of the patients cerebrum and cerebellum. Genetic testing conducted resulted in the diagnosis of late infantile neuronal ceroid lipofuscinosis (LINCL).

  13. Identification and evolution of the orphan genes in the domestic silkworm, Bombyx mori.

    PubMed

    Sun, Wei; Zhao, Xin-Wei; Zhang, Ze

    2015-09-14

    Orphan genes (OGs) which have no recognizable homology to any sequences in other species could contribute to the species specific adaptations. In this study, we identified 738 OGs in the silkworm genome. About 31% of the silkworm OGs is derived from transposable elements, and 5.1% of the silkworm OGs emerged from gene duplication followed by divergence of paralogs. Five de novo silkworm OGs originated from non-coding regions. Microarray data suggested that most of the silkworm OGs were expressed in limited tissues. RNA interference experiments suggested that five de novo OGs are not essential to the silkworm, implying that they may contribute to genetic redundancy or species-specific adaptation. Our results provide some new insights into the evolutionary significance of the silkworm OGs.

  14. Searching for a family of orphan sequences with SAMBA, a parallel hardware dedicated to biological applications.

    PubMed

    Guerdoux-Jamet, P; Risler, J L

    1996-01-01

    A significant proportion of coding sequences or open reading frames discovered in the course of sequencing projects do not show any similarity with other sequences deposited with the protein databanks. In such cases the search for similarities must be performed with as many comparison algorithms as possible, so as to increase the chance of finding weak relationships. A specialised parallel hardware (SAMBA) implementing the Smith & Waterman algorithm has been developed at the 'Institut de Recherche en Informatique et Systèmes Aléatoìres' (IRISA). It makes it possible to scan protein databanks at a speed comparable with that of BLAST or FASTA. We report here a study performed with SAMBA on 814 orphan sequences from S cerevisiae and compare the results with those from BLAST and FASTA.

  15. A Fieldable-Prototype Large-Area Gamma-ray Imager for Orphan Source Search

    SciTech Connect

    Ziock, Klaus-Peter; Fabris, Lorenzo; Carr, Dennis; Collins, Jeff; Cunningham, Mark F; Habte Ghebretatios, Frezghi; Karnowski, Thomas Paul; Marchant, William

    2008-01-01

    We have constructed a unique instrument for use in the search for orphan sources. The system uses gamma-ray imaging to "see through" the natural background variations that effectively limit the search range of normal devices to ~10 m. The imager is mounted in a 4.9- m-long trailer and can be towed by a large personal vehicle. Source locations are determined both in range and along the direction of travel as the vehicle moves. A fully inertial platform coupled to a Global Positioning System receiver is used to map the gamma-ray images onto overhead geospatial imagery. The resulting images provide precise source locations, allowing rapid follow-up work. The instrument simultaneously searches both sides of the street to a distance of 50 m (100-m swath) for milliCurieclass sources with near-perfect performance.

  16. An orphan gene is necessary for preaxial digit formation during salamander limb development

    PubMed Central

    Kumar, Anoop; Gates, Phillip B.; Czarkwiani, Anna; Brockes, Jeremy P.

    2015-01-01

    Limb development in salamanders differs from other tetrapods in that the first digits to form are the two most anterior (preaxial dominance). This has been proposed as a salamander novelty and its mechanistic basis is unknown. Salamanders are the only adult tetrapods able to regenerate the limb, and the contribution of preaxial dominance to limb regeneration is unclear. Here we show that during early outgrowth of the limb bud, a small cohort of cells express the orphan gene Prod1 together with Bmp2, a critical player in digit condensation in amniotes. Disruption of Prod1 with a gene-editing nuclease abrogates these cells, and blocks formation of the radius and ulna, and outgrowth of the anterior digits. Preaxial dominance is a notable feature of limb regeneration in the larval newt, but this changes abruptly after metamorphosis so that the formation of anterior and posterior digits occurs together within the autopodium resembling an amniote-like pattern. PMID:26498026

  17. An orphan gene is necessary for preaxial digit formation during salamander limb development.

    PubMed

    Kumar, Anoop; Gates, Phillip B; Czarkwiani, Anna; Brockes, Jeremy P

    2015-10-26

    Limb development in salamanders differs from other tetrapods in that the first digits to form are the two most anterior (preaxial dominance). This has been proposed as a salamander novelty and its mechanistic basis is unknown. Salamanders are the only adult tetrapods able to regenerate the limb, and the contribution of preaxial dominance to limb regeneration is unclear. Here we show that during early outgrowth of the limb bud, a small cohort of cells express the orphan gene Prod1 together with Bmp2, a critical player in digit condensation in amniotes. Disruption of Prod1 with a gene-editing nuclease abrogates these cells, and blocks formation of the radius and ulna, and outgrowth of the anterior digits. Preaxial dominance is a notable feature of limb regeneration in the larval newt, but this changes abruptly after metamorphosis so that the formation of anterior and posterior digits occurs together within the autopodium resembling an amniote-like pattern.

  18. Partial In Vitro Reconstitution of an Orphan Polyketide Synthase Associated with Clinical Cases of Nocardiosis.

    PubMed

    Kuo, James; Lynch, Stephen R; Liu, Corey W; Xiao, Xirui; Khosla, Chaitan

    2016-09-16

    Although a few well-characterized polyketide synthases (PKSs) have been functionally reconstituted in vitro from purified protein components, the use of this strategy to decode "orphan" assembly line PKSs has not been described. To begin investigating a PKS found only in Nocardia strains associated with clinical cases of nocardiosis, we reconstituted in vitro its five terminal catalytic modules. In the presence of octanoyl-CoA, malonyl-CoA, NADPH, and S-adenosyl methionine, this pentamodular PKS system yielded unprecedented octaketide and heptaketide products whose structures were partially elucidated using mass spectrometry and NMR spectroscopy. The PKS has several notable features, including a "split, stuttering" module and a terminal reductive release mechanism. Our findings pave the way for further analysis of this unusual biosynthetic gene cluster whose natural product may enhance the infectivity of its producer strains in human hosts. PMID:27384917

  19. An orphan gene is necessary for preaxial digit formation during salamander limb development.

    PubMed

    Kumar, Anoop; Gates, Phillip B; Czarkwiani, Anna; Brockes, Jeremy P

    2015-01-01

    Limb development in salamanders differs from other tetrapods in that the first digits to form are the two most anterior (preaxial dominance). This has been proposed as a salamander novelty and its mechanistic basis is unknown. Salamanders are the only adult tetrapods able to regenerate the limb, and the contribution of preaxial dominance to limb regeneration is unclear. Here we show that during early outgrowth of the limb bud, a small cohort of cells express the orphan gene Prod1 together with Bmp2, a critical player in digit condensation in amniotes. Disruption of Prod1 with a gene-editing nuclease abrogates these cells, and blocks formation of the radius and ulna, and outgrowth of the anterior digits. Preaxial dominance is a notable feature of limb regeneration in the larval newt, but this changes abruptly after metamorphosis so that the formation of anterior and posterior digits occurs together within the autopodium resembling an amniote-like pattern. PMID:26498026

  20. The paediatric rheumatologist and orphan disease - a story without happy ending.

    PubMed

    Roszkiewicz, Justyna; Biernacka-Zielińska, Małgorzata; Smolewska, Elżbieta

    2016-01-01

    Orphan diseases are not a common challenge in the everyday practice of the rheumatologist. Despite their extremely rare occurrence one of the patients under our care developed one of them - neuronal ceroid lipofuscinosis, the most frequent neurodegenerative disease observed in the paediatric population. We report a case of 2-year-old girl diagnosed with oligoarticular form of juvenile idiopathic arthritis treated in our Department with steroids and methotrexate and staying in the stage of disease remission. During routine checkups at Outpatient Clinic we observed progressive deterioration of girls neurological condition resulting in ataxia, gait disturbances with no rheumatological cause behind and speech impairment. The appearance of the symptoms was accompanied by frequent episodes of epileptic seizures, with little clinical improvement on combined antiepileptic treatment. Magnetic resonance imaging that we performed showed a picture highly suggestive of neuronal ceroid lipofuscinosis - atrophy of the patients cerebrum and cerebellum. Genetic testing conducted resulted in the diagnosis of late infantile neuronal ceroid lipofuscinosis (LINCL). PMID:27504025