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Sample records for acid receptor-related orphan

  1. 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

  2. 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

  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. 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

  5. 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

  6. 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

  7. Hepatocyte nuclear factor-6 stimulates transcription of the alpha-fetoprotein gene and synergizes with the retinoic-acid-receptor-related orphan receptor alpha-4.

    PubMed Central

    Nacer-Cherif, Habib; Bois-Joyeux, Brigitte; Rousseau, Guy G; Lemaigre, Frédéric P; Danan, Jean-Louis

    2003-01-01

    The rat alpha-fetoprotein ( afp ) gene is controlled by three enhancers whose function depends on their interaction with liver-enriched transcription factors. The afp enhancer III, located at -6 kb, is composed of three regions that act in synergy. Two of these regions, called s1 and s2, contain a putative binding site for hepatocyte nuclear factor-6 (HNF-6). This factor is the prototype of the ONECUT family of cut-homoeodomain proteins and is a known regulator of liver gene expression in adults and during development. We show here that the two splicing isoforms of HNF-6 bind to a site in the s1 region and in the s2 region. The core sequence of the s1 site corresponds to none of the known HNF-6 binding sites. Nevertheless, the binding properties of the s1 site are identical with those of the s2 site and of previously characterized HNF-6 binding sequences. The HNF-6 consensus should therefore be rewritten as DRRTCVATND. Binding of HNF-6 to the s1 and s2 sites requires both the cut and the homoeo domains, is co-operative and induces DNA bending. HNF-6 strongly stimulates the activity of the afp enhancer III in transient transfection experiments. This effect requires the stereo-specific alignment of the two HNF-6 sites. Moreover, HNF-6 stimulates the enhancer in synergy with the retinoic-acid-receptor-related orphan receptor alpha (RORalpha), which binds to a neighbouring site in the s1 region. Thus expression of the afp gene requires functional interactions between HNF-6 molecules and between HNF-6 and RORalpha. PMID:12379144

  8. Inhibitory effects of azole-type fungicides on interleukin-17 gene expression via retinoic acid receptor-related orphan receptors α and γ

    SciTech Connect

    Kojima, Hiroyuki; Muromoto, Ryuta; Takahashi, Miki; Takeuchi, Shinji; Takeda, Yukimasa; Jetten, Anton M.; Matsuda, Tadashi

    2012-03-15

    The retinoic acid receptor-related orphan receptors α and γ (RORα and RORγ), are key regulators of helper T (Th)17 cell differentiation, which is involved in the innate immune system and autoimmune disorders. However, it remains unclear whether environmental chemicals, including pesticides, have agonistic and/or antagonistic activity against RORα/γ. In this study, we investigated the RORα/γ activity of several azole-type fungicides, and the effects of these fungicides on the gene expression of interleukin (IL)-17, which mediates the function of Th17 cells. In the ROR-reporter gene assays, five azole-type fungicides (imibenconazole, triflumizole, hexaconazole, tetraconazole and imazalil) suppressed RORα- and/or RORγ-mediated transcriptional activity as did benzenesulphonamide T0901317, a ROR inverse agonist and a liver X receptor (LXR) agonist. In particular, imibenconazole, triflumizole and hexaconazole showed RORγ inverse agonistic activity at concentrations of 10{sup −6} M. However, unlike T0901317, these fungicides failed to show any LXRα/β agonistic activity. Next, five azole-type fungicides, showing ROR inverse agonist activity, were tested on IL-17 mRNA expression in mouse T lymphoma EL4 cells treated with phorbol myristate acetate and ionomycin. The quantitative RT-PCR analysis revealed that these fungicides suppressed the expression of IL-17 mRNA without effecting RORα and RORγ mRNA levels. In addition, the inhibitory effect of imibenconazole as well as that of T0901317 was absorbed in RORα/γ-knocked down EL4 cells. Taken together, these results suggest that some azole-type fungicides inhibit IL-17 production via RORα/γ. This also provides the first evidence that environmental chemicals can act as modulators of IL-17 expression in immune cells. -- Highlights: ► Nuclear receptors, RORα and RORγ, are key regulators of Th17 cell differentiation. ► Five azole-type fungicides act as RORα/γ inverse agonists. ► These fungicides

  9. Retinoic acid receptor-related orphan receptor (ROR) alpha4 is the predominant isoform of the nuclear receptor RORalpha in the liver and is up-regulated by hypoxia in HepG2 human hepatoma cells.

    PubMed Central

    Chauvet, Caroline; Bois-Joyeux, Brigitte; Danan, Jean-Louis

    2002-01-01

    The retinoic acid receptor-related orphan receptor alpha (RORalpha) is critically involved in many physiological functions in several organs. We find that the main RORalpha isoform in the mouse liver is the RORalpha4 isoform, in terms of both mRNA and protein levels, while the RORalpha1 isoform is less abundant. Because hypoxia is a major feature of liver physiology and pathology, we examined the effect of this stress on Rora gene expression and RORalpha transcriptional activity. HepG2 human hepatoma cells were cultured for 24 h under normoxia (20% O2) or hypoxia (10, 2, and 0.1% O2) and the abundance of the Rora transcripts measured by Northern blot and semi-quantitative RT-PCR. Hypoxic HepG2 cells contained more Rora mRNA than controls. This was also observed in rat hepatocytes in primary culture. Cobalt chloride and desferrioxamine also increased the amount of Rora mRNA in HepG2 cells. It is likely that these treatments increase the amount of the RORalpha4 protein in HepG2 cells as evidenced by Western blotting in the case of desferrioxamine. Transient transfection experiments indicated that hypoxia, cobalt chloride, and desferrioxamine all stimulate RORalpha transcriptional activity in HepG2 cells. Hence, we believe that RORalpha participates in the control of gene transcription in hepatic cells and modulates gene expression in response to hypoxic stress. PMID:12023888

  10. 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

  11. The orphan nuclear receptor estrogen receptor-related receptor gamma negatively regulates BMP2-induced osteoblast differentiation and bone formation.

    PubMed

    Jeong, Byung-Chul; Lee, Yong-Soo; Park, Yun-Yong; Bae, In-Ho; Kim, Don-Kyu; Koo, Seung-Hoi; Choi, Hong-Ran; Kim, Sun-Hun; Franceschi, Renny T; Koh, Jeong-Tae; Choi, Hueng-Sik

    2009-05-22

    Estrogen receptor-related receptor gamma (ERRgamma/ERR3/NR3B3) is a member of the orphan nuclear receptor with important functions in development and homeostasis. Recently it has been reported that ERRalpha is involved in osteoblast differentiation and bone formation. In the present study we examined the role of ERRgamma in osteoblast differentiation. Here, we showed that ERRgamma is expressed in osteoblast progenitors and primary osteoblasts, and its expression is increased temporarily by BMP2. Overexpression of ERRgamma reduced BMP2-induced alkaline phosphatase activity and osteocalcin production as well as calcified nodule formation, whereas inhibition of ERRgamma expression significantly enhanced BMP2-induced osteogenic differentiation and mineralization, suggesting that endogenous ERRgamma plays an important role in osteoblast differentiation. In addition, ERRgamma significantly repressed Runx2 transactivity on osteocalcin and bone sialoprotein promoters. We also observed that ERRgamma physically interacts with Runx2 in vitro and in vivo and competes with p300 to repress Runx2 transactivity. Notably, intramuscular injection of ERRgamma strongly inhibited BMP2-induced ectopic bone formation in a dose-dependent manner. Taken together, these results suggest that ERRgamma is a novel negative regulator of osteoblast differentiation and bone formation via its regulation of Runx2 transactivity. PMID:19324883

  12. The Orphan Nuclear Receptor Estrogen Receptor-related Receptor γ Negatively Regulates BMP2-induced Osteoblast Differentiation and Bone Formation*

    PubMed Central

    Jeong, Byung-Chul; Lee, Yong-Soo; Park, Yun-Yong; Bae, In-Ho; Kim, Don-Kyu; Koo, Seung-Hoi; Choi, Hong-Ran; Kim, Sun-Hun; Franceschi, Renny T.; Koh, Jeong-Tae; Choi, Hueng-Sik

    2009-01-01

    Estrogen receptor-related receptor γ (ERRγ/ERR3/NR3B3) is a member of the orphan nuclear receptor with important functions in development and homeostasis. Recently it has been reported that ERRα is involved in osteoblast differentiation and bone formation. In the present study we examined the role of ERRγ in osteoblast differentiation. Here, we showed that ERRγ is expressed in osteoblast progenitors and primary osteoblasts, and its expression is increased temporarily by BMP2. Overexpression of ERRγ reduced BMP2-induced alkaline phosphatase activity and osteocalcin production as well as calcified nodule formation, whereas inhibition of ERRγ expression significantly enhanced BMP2-induced osteogenic differentiation and mineralization, suggesting that endogenous ERRγ plays an important role in osteoblast differentiation. In addition, ERRγ significantly repressed Runx2 transactivity on osteocalcin and bone sialoprotein promoters. We also observed that ERRγ physically interacts with Runx2 in vitro and in vivo and competes with p300 to repress Runx2 transactivity. Notably, intramuscular injection of ERRγ strongly inhibited BMP2-induced ectopic bone formation in a dose-dependent manner. Taken together, these results suggest that ERRγ is a novel negative regulator of osteoblast differentiation and bone formation via its regulation of Runx2 transactivity. PMID:19324883

  13. 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

  14. Polo-like kinase 2 gene expression is regulated by the orphan nuclear receptor estrogen receptor-related receptor gamma (ERRgamma).

    PubMed

    Park, Yun-Yong; Kim, Seok-Ho; Kim, Yong Joo; Kim, Sun Yee; Lee, Tae-Hoon; Lee, In-Kyu; Park, Seung Bum; Choi, Hueng-Sik

    2007-10-12

    Estrogen receptor-related receptor gamma (ERRgamma) is a member of the nuclear receptor family of transcriptional activators. To date, the target genes and physiological functions of ERRgamma are not well understood. In the current study, we identify that Plk2 is a novel target of ERRgamma. Northern blot analysis showed that overexpression of ERRgamma induced Plk2 expression in cancer cell lines. ERRgamma activated the Plk2 gene promoter, and deletion and mutational analysis of the Plk2 promoter revealed that the ERRgamma-response region is located between nucleotides (nt) -2327 and -2229 and -441 and -432 (relative to the transcriptional start site at +1). Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) analysis demonstrated that ERRgamma binds directly to the Plk2 promoter. Overexpression of ERRgamma in the presence of the mitotic inhibitor nocodazole significantly decreased apoptosis, and induced S-phase cell cycle progression through the induction of Plk2 expression. Taken together, these results demonstrated that Plk2 is a novel target of ERRgamma, and suggest that this interaction is crucial for cancer cell proliferation. PMID:17706602

  15. Identification of a Binding Site for Unsaturated Fatty Acids in the Orphan Nuclear Receptor Nurr1.

    PubMed

    de Vera, Ian Mitchelle S; Giri, Pankaj K; Munoz-Tello, Paola; Brust, Richard; Fuhrmann, Jakob; Matta-Camacho, Edna; Shang, Jinsai; Campbell, Sean; Wilson, Henry D; Granados, Juan; Gardner, William J; Creamer, Trevor P; Solt, Laura A; Kojetin, Douglas J

    2016-07-15

    Nurr1/NR4A2 is an orphan nuclear receptor, and currently there are no known natural ligands that bind Nurr1. A recent metabolomics study identified unsaturated fatty acids, including arachidonic acid and docosahexaenoic acid (DHA), that interact with the ligand-binding domain (LBD) of a related orphan receptor, Nur77/NR4A1. However, the binding location and whether these ligands bind other NR4A receptors were not defined. Here, we show that unsaturated fatty acids also interact with the Nurr1 LBD, and solution NMR spectroscopy reveals the binding epitope of DHA at its putative ligand-binding pocket. Biochemical assays reveal that DHA-bound Nurr1 interacts with high affinity with a peptide derived from PIASγ, a protein that interacts with Nurr1 in cellular extracts, and DHA also affects cellular Nurr1 transactivation. This work is the first structural report of a natural ligand binding to a canonical NR4A ligand-binding pocket and indicates a natural ligand can bind and affect Nurr1 function. PMID:27128111

  16. 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

  17. Bile acids inhibit duodenal secretin expression via orphan nuclear receptor small heterodimer partner (SHP).

    PubMed

    Lam, Ian P Y; Lee, Leo T O; Choi, Hueng-Sik; Alpini, Gianfranco; Chow, Billy K C

    2009-07-01

    Small heterodimer partner (SHP) is an orphan nuclear receptor in which gene expression can be upregulated by bile acids. It regulates its target genes by repressing the transcriptional activities of other nuclear receptors including NeuroD, which has been shown to regulate secretin gene expression. Here, we evaluated the regulation on duodenal secretin gene expression by SHP and selected bile acids, cholic acid (CA) and chenodeoxycholic acid (CDCA). In vitro treatment of CDCA or fexaramine elevated the SHP transcript level and occupancy on secretin promoter. The increase in the SHP level, induced by bile acid treatment or overexpression, reduced secretin gene expression, whereas this gene inhibitory effect was reversed by silencing of endogenous SHP. In in vivo studies, double-immunofluorescence staining demonstrated the coexpression of secretin and SHP in mouse duodenum. Feeding mice with 1% CA-enriched rodent chow resulted in upregulation of SHP and a concomitant decrease in secretin transcript and protein levels in duodenum compared with the control group fed with normal chow. A diet enriched with 5% cholestyramine led to a decrease in SHP level and a corresponding increase in secretin expression. Overall, this study showed that bile acids via SHP inhibit duodenal secretin gene expression. Because secretin is a key hormone that stimulates bile flow in cholangiocytes, this pathway thus provides a novel means to modulate secretin-stimulated choleresis in response to intraduodenal bile acids. PMID:19372104

  18. The orphan GPCR, Gpr161, regulates the retinoic acid and canonical Wnt pathways during neurulation.

    PubMed

    Li, Bo I; Matteson, Paul G; Ababon, Myka F; Nato, Alejandro Q; Lin, Yong; Nanda, Vikas; Matise, Tara C; Millonig, James H

    2015-06-01

    The vacuolated lens (vl) mouse mutation arose on the C3H/HeSnJ background and results in lethality, neural tube defects (NTDs) and cataracts. The vl phenotypes are due to a deletion/frameshift mutation in the orphan GPCR, Gpr161. A recent study using a null allele demonstrated that Gpr161 functions in primary cilia and represses the Shh pathway. We show the hypomorphic Gpr161(vl) allele does not severely affect the Shh pathway. To identify additional pathways regulated by Gpr161 during neurulation, we took advantage of naturally occurring genetic variation in the mouse. Previously Gpr161(vl-C3H) was crossed to different inbred backgrounds including MOLF/EiJ and the Gpr161(vl) mutant phenotypes were rescued. Five modifiers were mapped (Modvl: Modifier of vl) including Modvl5(MOLF). In this study we demonstrate the Modvl5(MOLF) congenic rescues the Gpr161(vl)-associated lethality and NTDs but not cataracts. Bioinformatics determined the transcription factor, Cdx1, is the only annotated gene within the Modvl5 95% CI co-expressed with Gpr161 during neurulation and not expressed in the eye. Using Cdx1 as an entry point, we identified the retinoid acid (RA) and canonical Wnt pathways as downstream targets of Gpr161. QRT-PCR, ISH and IHC determined that expression of RA and Wnt genes are down-regulated in Gpr161(vl/vl) but rescued by the Modvl5(MOLF) congenic during neurulation. Intraperitoneal RA injection restores expression of canonical Wnt markers and rescues Gpr161(vl/vl) NTDs. These results establish the RA and canonical Wnt as pathways downstream of Gpr161 during neurulation, and suggest that Modvl5(MOLF) bypasses the Gpr161(vl) mutation by restoring the activity of these pathways. PMID:25753732

  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. 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

  1. 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.

  2. A review of methods for the analysis of orphan and difficult pesticides: glyphosate, glufosinate, quaternary ammonium and phenoxy acid herbicides, and dithiocarbamate and phthalimide fungicides.

    PubMed

    Raina-Fulton, Renata

    2014-01-01

    This article reviews the chromatography/MS methodologies for analysis of pesticide residues of orphan and difficult chemical classes in a variety of sample matrixes including water, urine, blood, and food. The review focuses on pesticide classes that are not commonly included in multiresidue analysis methods such as highly polar or ionic herbicides including glyphosate, glufosinate, quaternary ammonium, and phenoxy acid herbicides, and some of their major degradation or metabolite products. In addition, dithiocarbamate and phthalimide fungicides, which are thermally unstable and have stability issues in some solvents or sample matrixes, are also examined due to their special needs in residue analysis. PMID:25145125

  3. 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. PMID:26349500

  4. Practical applications of sulfate-reducing bacteria to control acid mine drainage at the Lilly/Orphan Boy Mine near Elliston, Montana

    SciTech Connect

    Canty, M.

    1994-12-31

    The overall purpose of this document is to provide a detailed technical description of a technology, biological sulfate reduction, which is being demonstrated under the Mine Waste Technology Pilot Program, and provide the technology evaluation process undertaken to select this technology for demonstration. In addition, this document will link the use of the selected technology to an application at a specific site. The purpose of this project is to develop technical information on the ability of biological sulfate reduction to slow the process of acid generation and, thus, improve water quality at a remote mine site. Several technologies are screened for their potential to treat acid mine water and to function as a source control for a specific acid-generating situation: a mine shaft and associated underground workings flooded with acid mine water and discharging a small flow from a mine opening. The preferred technology is the use of biological sulfate reduction. Sulfate-reducing bacteria are capable of reducing sulfate to sulfide, as well as increasing the pH and alkalinity of water affected by acid generation. Soluble sulfide reacts with the soluble metals in solution to form insoluble metal sulfides. The environment needed for efficient sulfate-reducing bacteria growth decreases acid production by reducing the dissolved oxygen in water and increasing pH. A detailed technical description of the sulfate-reducing bacteria technology, based on an extensive review of the technical literature, is presented. The field demonstration of this technology to be performed at the Lilly/Orphan Boy Mine is also described. Finally, additional in situ applications of biological sulfate reduction are presented.

  5. 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

  6. Prospero-related homeobox 1 (Prox1) functions as a novel modulator of retinoic acid-related orphan receptors α- and γ-mediated transactivation

    PubMed Central

    Takeda, Yukimasa; Jetten, Anton M.

    2013-01-01

    In this study, we identify Prospero-related homeobox 1 (Prox1) as a novel co-repressor of the retinoic acid-related orphan receptors, RORα and RORγ. Prox1 interacts directly with RORγ and RORα and negatively regulates their transcriptional activity. The AF2 domain of RORs is essential for the interaction, whereas Prox1 interacts with RORs through either its 28 amino acids N-terminal region or its C-terminal prospero-like domain. RORγ antagonists stabilize the interaction between RORγ and Prox1. The homeodomain and the interaction through the prospero-like domain of Prox1 are critical for its repression of ROR transcriptional activity. Chromatin immunoprecipitation analysis demonstrated that in liver, Prox1 is recruited to the ROR response element sites of the clock genes, brain and muscle Arnt-like protein 1 (Bmal1), neuronal PAS domain protein 2 (Npas2) and cryptochrome 1 (Cry1), as part of the same complex as RORs. Knockdown of Prox1 by siRNAs in human hepatoma Huh-7 cells increased the expression of RORγ and several ROR-target genes, along with increased histone acetylation at these ROR response element sites. Chromatin immunoprecipitation sequencing analysis suggests that Prox1 is a potential ROR target gene in liver, which is supported by the regulation of the rhythmic expression of Prox1 by RORγ. Our data suggest that Prox1 is part of a feedback loop that negatively regulates the transcriptional control of clock and metabolic networks by RORs. PMID:23723244

  7. Requirement of novel amino acid fragments of orphan nuclear receptor TR3/Nur77 for its functions in angiogenesis

    PubMed Central

    Grant, Marianne A.; Peng, Jin; Ye, Taiyang; Zhao, Dezheng; Zeng, Huiyan

    2015-01-01

    Pathological angiogenesis is a hallmark of many diseases. We demonstrated that TR3/Nur77 is an excellent target for pro-angiogenesis and anti-angiogenesis therapies. Here, we report that TR3 transcriptionally regulates endothelial cell migration, permeability and the formation of actin stress fibers that is independent of RhoA GTPase. 1) Amino acid residues 344-GRR-346 and de-phosphorylation of amino acid residue serine 351 in the DNA binding domain, and 2) phosphorylation of amino acid residues in the 41-61 amino acid fragment of the transactivation domain, of TR3 are required for its induction of the formation of actin stress fibers, cell proliferation, migration and permeability. The 41-61 amino acid fragment contains one of the three potential protein interaction motifs in the transactivation domain of TR3, predicted by computational modeling and analysis. These studies further our understanding of the molecular mechanism, by which TR3 regulates angiogenesis, identify novel therapeutic targeted sites of TR3, and set the foundation for the development of high-throughput screening assays to identify compounds targeting TR3/Nur77 for pro-angiogenesis and anti-angiogenesis therapies. PMID:26155943

  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]. PMID:16001315

  9. Orphan GPCRs and neuromodulation

    PubMed Central

    Civelli, Olivier

    2012-01-01

    Most G protein-coupled receptors (GPCRs) started as orphan GPCRs. Matching them to known neuromodulators led to the elucidation of the broad diversity of the neuroreceptor families. Moreover, orphan GPCRs have also been used as targets to discover novel neuromodulators. These discoveries have had profound impact on our understanding of brain function. Here, I present an overview of how some of the novel neuropeptides have enlarged our comprehension of responses that direct sleep/wakefulness, the onset of obesity and the feeding response. I also discuss other advances gained from orphan GPCR studies such as the concept of specificity in neuromodulation or of receptors acting as sensors instead of synaptic transmitters. Finally, I suggest that the recently-discovered neuromodulators may hold the keys to our understanding of higher brain functions and psychiatric disorders. PMID:23040803

  10. 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

  11. 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

  12. Retinoid acid-related orphan receptor γ, RORγ, participates in diurnal transcriptional regulation of lipid metabolic genes

    PubMed Central

    Takeda, Yukimasa; Kang, Hong Soon; Lih, Fred B.; Jiang, Hongfeng; Blaner, William S.; Jetten, Anton M.

    2014-01-01

    The hepatic circadian clock plays a pivotal role in regulating major aspects of energy homeostasis and lipid metabolism. In this study, we show that RORγ robustly regulates the rhythmic expression of several lipid metabolic genes, including the insulin-induced gene 2a, Insig2a, elongation of very long chain fatty acids-like 3, Elovl3 and sterol 12α-hydroxylase, Cyp8b1, by enhancing their expression at ZT20-4. The time-dependent increase in their expression correlates with the rhythmic expression pattern of RORγ. The enhanced recruitment of RORγ to ROREs in their promoter region, increased histone acetylation, and reporter and mutation analysis support the concept that RORγ regulates the transcription of several lipid metabolic genes directly by binding ROREs in their promoter regulatory region. Consistent with the disrupted expression of a number of lipid metabolic genes, loss of RORγ reduced the level of several lipids in liver and blood in a ZT-preferred manner. Particularly the whole-body bile acid pool size was considerably reduced in RORγ−/− mice in part through its regulation of several Cyp genes. Similar observations were made in liver-specific RORγ-deficient mice. Altogether, our study indicates that RORγ functions as an important link between the circadian clock and the transcriptional regulation of several metabolic genes. PMID:25143535

  13. Insulin receptor-related receptor as an extracellular alkali sensor

    PubMed Central

    Deyev, Igor E.; Sohet, Fabien; Vassilenko, Konstantin P.; Serova, Oxana V.; Popova, Nadezhda V.; Zozulya, Sergey A.; Burova, Elena B.; Houillier, Pascal; Rzhevsky, Dmitry I.; Berchatova, Anastasiya A.; Murashev, Arkady N.; Chugunov, Anton O.; Efremov, Roman G.; Nikol’sky, Nikolai N.; Bertelli, Eugenio; Eladari, Dominique; Petrenko, Alexander G.

    2011-01-01

    SUMMARY The insulin receptor-related receptor (IRR), an orphan receptor tyrosine kinase of the insulin receptor family, can be activated by alkaline media both in vitro and in vivo at pH>7.9. The alkali-sensing property of IRR is conserved in frog, mouse and human. IRR activation is specific, dose-dependent, quickly reversible and demonstrates positive cooperativity. It also triggers receptor conformational changes and elicits intracellular signaling. The pH sensitivity of IRR is primarily defined by its L1F extracellular domains. IRR is predominantly expressed in organs that come in contact with mildly alkaline media. In particular, IRR is expressed in the cell subsets of the kidney that secrete bicarbonate into urine. Disruption of IRR in mice impairs the renal response to alkali loading attested by development of metabolic alkalosis and decreased urinary bicarbonate excretion in response to this challenge. We therefore postulate that IRR is an alkali sensor that functions in the kidney to manage metabolic bicarbonate excess. PMID:21641549

  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 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

  16. The Orphan Lenses Project

    NASA Astrophysics Data System (ADS)

    Moustakas, Leonidas A.; Brownstein, J.; Fadely, R.; Fassnacht, C. D.; Gavazzi, R.; Goodsall, T.; Griffith, R. L.; Keeton, C. R.; Kneib, J. P.; Koekemoer, A.; Koopmans, L. V. E.; Marshall, P. J.; Merten, J.; Metcalf, R. B.; Oguri, M.; Papovich, C.; Rein, H.; Ryan, R.; Stewart, K. R.; Treu, T.

    2012-01-01

    Strong gravitational lenses are uniquely suited for the study of dark matter structure and substructure within massive halos of many scales, act as gravitational telescopes for distant faint objects, and can give powerful and competitive cosmological constraints. Some 300 lenses have been identified in the literature in one form or another; many others have been found, but perhaps have not warranted dedicated publications. The Orphan Lenses project aims to be a master compilation of all strong gravitational lenses that are known, and a community repository for candidate lenses. A clear and uniform database of basic properties and gravitational lens models is being developed, which will be available online and through a smartphone interactive application. I will present the project, and scientific highlights with this dataset.

  17. Two truncated forms of rat insulin receptor-related receptor.

    PubMed

    Itoh, N; Jobo, K; Tsujimoto, K; Ohta, M; Kawasaki, T

    1993-08-25

    The insulin receptor-related receptor (IRR) (1271 amino acids) is expected to have unique functions as a novel member of the insulin receptor family. In this paper, we report two alternatively spliced variants of rat IRR mRNA, which are predicted to encode two truncated forms of IRR, sIRR-1 (410 amino acids) and sIRR-2 (469 amino acids). The amino acid sequence of sIRR-1 is identical to the N-terminal 410-amino acid sequence of IRR. sIRR-2 has an additional 59-amino acid insertion in the C-terminal region. Both truncated forms retain the N-terminal and cysteine-rich domains but lack the transmembrane and intracellular tyrosine kinase domains, indicating that the truncated forms are the secreted forms. The translation products of the truncated form mRNAs were detected in the stomach and kidney by Western analysis. However, the physiological significance of the secreted forms remains to be elucidated. PMID:7688734

  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. Deoxyribonucleic acid methyl transferases 3a and 3b associate with the nuclear orphan receptor COUP-TFI during gene activation.

    PubMed

    Gallais, Rozenn; Demay, Florence; Barath, Peter; Finot, Laurence; Jurkowska, Renata; Le Guével, Rémy; Gay, Frédérique; Jeltsch, Albert; Métivier, Raphaël; Salbert, Gilles

    2007-09-01

    Transcriptional activation of silent genes can require the erasure of epigenetic marks such as DNA methylation at CpGs (cytosine-guanine dinucleotide). Active demethylation events have been observed, and associated processes are repeatedly suspected to involve DNA glycosylases such as mCpG binding domain protein 4, thymine DNA glycosylase (TDG), Demeter, and repressor of silencing 1. A complete characterization of the molecular mechanisms occurring in metazoan is nonetheless awaited. Here, we report that activation of the endogenous vitronectin gene in P19 cells by the nuclear receptor chicken ovalbumin upstream promoter-transcription factor I (COUP-TFI) is observed in parallel with the recruitment of TDG and p68 RNA helicase, two components of a putative demethylation complex. Interestingly, when activated, the vitronectin gene was loaded with DNA methyltransferases 3a and 3b (Dnmt3a/b), and a strand-biased decrease in CpG methylation was detected. Dnmt3a was further found to associate with COUP-TFI and TDG in vivo, and cotransfection experiments demonstrated that Dnmt3a/b can enhance COUP-TFI-mediated activation of a methylated reporter gene. These results suggest that Dnmt3a/b could cooperate with the orphan receptor COUP-TFI to regulate transcription of the vitronectin gene. PMID:17579209

  20. 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

  1. Orphan nuclear receptors in breast cancer pathogenesis and therapeutic response.

    PubMed

    Riggins, Rebecca B; Mazzotta, Mary M; Maniya, Omar Z; Clarke, Robert

    2010-09-01

    Nuclear receptors comprise a large family of highly conserved transcription factors that regulate many key processes in normal and neoplastic tissues. Most nuclear receptors share a common, highly conserved domain structure that includes a carboxy-terminal ligand-binding domain. However, a subgroup of this gene family is known as the orphan nuclear receptors because to date there are no known natural ligands that regulate their activity. Many of the 25 nuclear receptors classified as orphan play critical roles in embryonic development, metabolism, and the regulation of circadian rhythm. Here, we review the emerging role(s) of orphan nuclear receptors in breast cancer, with a particular focus on two of the estrogen-related receptors (ERRalpha and ERRgamma) and several others implicated in clinical outcome and response or resistance to cytotoxic or endocrine therapies, including the chicken ovalbumin upstream promoter transcription factors, nerve growth factor-induced B, DAX-1, liver receptor homolog-1, and retinoic acid-related orphan receptor alpha. We also propose that a clearer understanding of the function of orphan nuclear receptors in mammary gland development and normal mammary tissues could significantly improve our ability to diagnose, treat, and prevent breast cancer. PMID:20576803

  2. 78 FR 35117 - Orphan Drug Regulations

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-12

    ..., 2011 (76 FR 64868), FDA issued a proposed rule to amend the Orphan Drug Regulations (part 316 (21 CFR... orphan drug program. As described in the proposed rule (76 FR 64868), FDA believes these revisions will... serve the intent of the Orphan Drug Act, as explained in the proposed rule (76 FR 64868 at 64869...

  3. ORPHAN ENDOGENOUS LIPIDS AND ORPHAN GPCRS: A GOOD MATCH

    PubMed Central

    Bradshaw, Heather B; Lee, Sung Ha; McHugh, Douglas

    2009-01-01

    A large and growing family of over 70 endogenous lipids of the basic structure N-acyl amide has been identified during the last 10 years. Only a few of these lipids have been characterized for biological activity, however, those that have shown a wide range of activity may act at G-protein coupled receptors (GPCRs). Like orphan GPCRs that are identified as being in the genome and expressed in tissue, the majority of these endogenous lipids many produced throughout the body, some predominately in nervous tissue, remain orphaned. Here, we give a brief history of these orphan lipids and highlight the activity of N-arachidonoyl glycine, and farnesyl pyrophosphate at the orphan receptors GPR18 and GPR92 respectively as well as summarizing the biological and pharmacological data for the recently identified N-palmitoyl glycine that suggests activity at a novel GPCR. Working to deorphanize both lipids and GPCRs together provides a unique opportunity for a greater understanding of cellular signaling and a challenge to find them all a home. PMID:19379823

  4. 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

  5. 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…

  6. Finding Sequences for over 270 Orphan Enzymes

    PubMed Central

    Shearer, Alexander G.; Altman, Tomer; Rhee, Christine D.

    2014-01-01

    Despite advances in sequencing technology, there are still significant numbers of well-characterized enzymatic activities for which there are no known associated sequences. These ‘orphan enzymes’ represent glaring holes in our biological understanding, and it is a top priority to reunite them with their coding sequences. Here we report a methodology for resolving orphan enzymes through a combination of database search and literature review. Using this method we were able to reconnect over 270 orphan enzymes with their corresponding sequence. This success points toward how we can systematically eliminate the remaining orphan enzymes and prevent the introduction of future orphan enzymes. PMID:24826896

  7. 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. PMID:26768506

  8. Are payers treating orphan drugs differently?

    PubMed Central

    Cohen, Joshua P.; Felix, Abigail

    2014-01-01

    Background Some orphan drugs can cost hundreds of thousands of dollars annually per patient. As a result, payer sensitivity to the cost of orphan drugs is rising, particularly in light of increased numbers of new launches in recent years. In this article, we examine payer coverage in the United States, England and Wales, and the Netherlands of outpatient orphan drugs approved between 1983 and 2012, as well as the 11 most expensive orphan drugs. Methods We collected data from drug regulatory agencies as well as payers and drug evaluation authorities. Results We found that orphan drugs have more coverage restrictions than non-orphan drugs in all three jurisdictions. From an economic perspective, the fact that a drug is an orphan product or has a high per-unit price per se should not imply a special kind of evaluation by payers, or necessarily the imposition of more coverage restrictions. Conclusion Payers should consider the same set of decision criteria that they do with respect to non-orphan drugs: disease severity, availability of treatment alternatives, level of unmet medical need, and cost-effectiveness, criteria that justifiably may be taken into account and traded off against one another in prescribing and reimbursement decisions for orphan drugs.

  9. 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

  10. 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.

  11. Identification and characterization of estrogen receptor-related receptor alpha and gamma in human glioma and astrocytoma cells.

    PubMed

    Gandhari, Mukesh K; Frazier, Chester R; Hartenstein, Julia S; Cloix, Jean-Francois; Bernier, Michel; Wainer, Irving W

    2010-02-01

    The purpose of this study was to examine expression and function of estrogen receptor-related receptors (ERRs) in human glioma and astrocytoma cell lines. These estrogen receptor-negative cell lines expressed ERRalpha and ERRgamma proteins to varying degree in a cell context dependent manner, with U87MG glioma cells expressing both orphan nuclear receptors. Cell proliferation assays were performed in the presence of ERR isoform-specific agonists and antagonists, and the calculated EC(50) and IC(50) values were consistent with previous reported values determined in other types of cancer cell lines. Induction of luciferase expression under the control of ERR isoform-specific promoters was also observed in these cells. These results indicate that ERRalpha and ERRgamma are differentially expressed in these tumor cell lines and likely contribute to agonist-dependent ERR transcriptional activity. PMID:19822186

  12. Identification and characterization of estrogen receptor-related receptor alpha and gamma in human glioma and astrocytoma cells

    PubMed Central

    Gandhari, Mukesh K; Frazier, Chester R; Hartenstein, Julia S; Cloix, Jean-Francois; Bernier, Michel; Wainer, Irving W.

    2009-01-01

    The purpose of this study was to examine expression and function of estrogen receptor-related receptors (ERRs) in human glioma and astrocytoma cell lines. These estrogen receptor-negative cell lines expressed ERRα and ERRγ proteins to varying degree in a cell context dependent manner, with U87MG glioma cells expressing both orphan nuclear receptors. Cell proliferation assays were performed in the presence of ERR isoform-specific agonists and antagonists, and the calculated EC50 and IC50 values were consistent with previous reported values determined in other types of cancer cell lines. Induction of luciferase expression under the control of ERR isoform-specific promoters was also observed in these cells. These results indicate that ERRα and ERRγ are differentially expressed in these tumor cell lines and likely contribute to agonist-dependent ERR transcriptional activity. PMID:19822186

  13. 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

  14. 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

  15. 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...

  16. 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...

  17. 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...

  18. 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...

  19. 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...

  20. [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

  1. Depression among AIDS-orphaned children higher than among other orphaned children in southern India

    PubMed Central

    2014-01-01

    Background Systematic data on mental health issues among orphaned children are not readily available in India. This study explored depression and its associated risk factors among orphaned children in Hyderabad city in south India. Methods 400 orphaned children drawn equally from AIDS and non-AIDS orphan groups aged 12–16 years residing in orphanages in and around Hyderabad city in southern India were recruited to assess depression and associated risk factors using the Center for Epidemiologic Studies-Depression Scale (CES-DC). Variation in the intensity of depression was assessed using multiple classification analysis (MCA). Results 397 (99%) orphans provided complete interviews in the study of whom 306 (76.5%) were aged 12 to 14 years, and 206 (51.8%) were paternal orphans. Children orphaned by AIDS were significantly more likely to report being bullied by friends or relatives (50.3%) and report experiencing discrimination (12.6%) than those orphaned due to other reasons (p < 0.001). The overall prevalence of depression score >15 with CES-DC was 74.1% (95% CI 69.7-78.4) with this being significantly higher for children orphaned by AIDS (84.4%, 95% CI 79.4 – 89.5) than those due to other reasons (63.6%, 95% CI 56.9 – 70.4). Mean depression score was significantly higher for children orphaned by AIDS (34.6) than the other group (20.6; p < 0.001). Among the children orphaned by AIDS, the bulk of depression score was clustered in 12–14 years age groups whereas in the children orphaned by other reasons it was clustered in the 15–16 years age group (p = 0.001). MCA analysis showed being a child orphaned by AIDS had the highest effect on the intensity of depression (Beta = 0.473). Conclusions Children orphaned by AIDS had significantly higher depressive symptoms than the other orphaned children. These findings could be used for further planning of mental health interventions to meet the mental health needs of orphaned children, that could

  2. Expression and functional study of estrogen receptor-related receptors in human prostatic cells and tissues.

    PubMed

    Cheung, C P; Yu, Shan; Wong, K B; Chan, L W; Lai, Fernand M M; Wang, Xianghong; Suetsugi, Masatomo; Chen, Shiuan; Chan, Franky L

    2005-03-01

    Estrogen receptor-related receptors (ERRs; alpha, beta, gamma) are orphan nuclear receptors and constitutively active without binding to estrogen. Like estrogen receptors (ERs), ERRs bind to estrogen receptor elements and estrogen receptor element-related repeats. Growing evidence suggests that ERRs can cross-talk with ERs in different cell types via competition for DNA sites and coactivators. We hypothesize that ERRs might play regulatory roles in normal and neoplastic prostatic cells by sharing similar ER-mediated pathways or acting independently. In this study, we investigated mRNA and protein expression patterns of three ERR members in normal human prostate epithelial cells, established cell lines, cancer xenografts, and prostatic tissues. Additionally, effects of transient transfection of ERRs on prostatic cell proliferation and ER expression were also examined. RT-PCR showed that ERRalpha and ERRgamma transcripts were detected in most cell lines and xenografts, whereas ERRbeta was detected in normal epithelial cells and few immortalized cell lines but not in most cancer lines. Similar results were demonstrated in clinical prostatic specimens. Western blottings and immunohistochemistry confirmed similar expression patterns that ERR proteins were detected as nuclear proteins in epithelial cells, whereas their expressions became reduced or undetected in neoplastic prostatic cells. Transient transfection confirmed that ERRs were expressed in prostatic cells as nuclear proteins and transcriptionally active in the absence of estradiol. Transfection results showed that overexpression of ERRs inhibited cell proliferation and repressed ERalpha transcription in PC-3 cells. Our study shows that ERRs, which are coexpressed with ERs in prostatic cells, could regulate cell growth and modulate ER-mediated pathways via interference on ERalpha transcription in prostatic cells. PMID:15598686

  3. 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…

  4. Orphan drug development across Europe: bottlenecks and opportunities.

    PubMed

    Heemstra, Harald E; de Vrueh, Remco L A; van Weely, Sonja; Büller, Hans A; Leufkens, Hubert G M

    2008-08-01

    With the assignment of the 500th European Union orphan drug designation in 2007, the Regulation on Orphan Medicinal Products truly begins to show its potential for delivering new medicines to patients with rare diseases. Here, we analysed European orphan drug development at a national level and unveil a strong relationship between orphan drug development and pharmaceutical innovation performance in Europe. Moreover, we identify gaps in transition from science into orphan drug development as important bottlenecks that exist in several European countries. Our findings underline the importance of innovation-based policies to enhance the development of orphan drugs in Europe. PMID:18583178

  5. Retinoid-related orphan receptor gamma t (RORγt) inhibitors from Vitae Pharmaceuticals (WO2015116904) and structure proposal for their Phase I candidate VTP-43742.

    PubMed

    Gege, Christian

    2016-06-01

    Retinoic acid receptor-related orphan nuclear receptor gamma t (RORγt or RORC2) is a key transcription factor for the differentiation of naïve proinflammatory CD4(+) T cells and the production of T helper-17 (TH17) cells. Inhibiting RORγt activity is thought to be beneficial in targeting a variety of inflammatory and autoimmune disorders, however current candidates remain to be validated in the clinic. Recently Vitae Pharmaceuticals successfully finished its Phase 1 single ascending dose clinical study with their proprietary RORγt inverse agonist VTP-43742. On the basis of the reported promising results, Vitae Pharmaceuticals could currently be considered as having the leading clinical candidate in the RORγt inverse agonist category. This prompts the interest on the exact chemical structure of their clinical candidate. The first relevant patent application (WO2014179564) from Vitae Pharmaceuticals describes RORγt inverse agonists with a 5,6-dihydro-4H-pyrrolo[3,4-d]thiazole core, while in the second and latest patent application (WO2015116904) this element has changed towards a 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine core. By combining information from Vitae's patent applications and trustworthy online information, the potential elucidation of the chemical structure of clinical candidate VTP-43742 is described. PMID:26895086

  6. 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

  7. 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

  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 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

  9. 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

  10. 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

  11. Coming of age: orphan genes in plants.

    PubMed

    Arendsee, Zebulun W; Li, Ling; Wurtele, Eve Syrkin

    2014-11-01

    Sizable minorities of protein-coding genes from every sequenced eukaryotic and prokaryotic genome are unique to the species. These so-called ‘orphan genes’ may evolve de novo from non-coding sequence or be derived from older coding material. They are often associated with environmental stress responses and species-specific traits or regulatory patterns. However, difficulties in studying genes where comparative analysis is impossible, and a bias towards broadly conserved genes, have resulted in underappreciation of their importance. We review here the identification, possible origins, evolutionary trends, and functions of orphans with an emphasis on their role in plant biology. We exemplify several evolutionary trends with an analysis of Arabidopsis thaliana and present QQS as a model orphan gene. PMID:25151064

  12. Advancements in therapeutically targeting orphan GPCRs.

    PubMed

    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

  13. 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…

  14. 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…

  15. 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,…

  16. EU orphan regulation--ten years of application.

    PubMed

    Michaux, Geneviève

    2010-01-01

    In April 2000, European Regulation (EC) No 141/2000 on Orphan Medicinal Products, which, following the U.S. example, had been adopted to boost the research, development, and marketing of medicinal products for rare diseases, became effective. Ten years later, figures prove that, with an average of more than 70 orphan designations per year, the European orphan regulation is a success. To date, the key issue is no longer research and development but effective market access. Less than 10% of the orphan designated products are approved for marketing and even less products are actually placed on the European national markets due to pricing and reimbursement obstacles. The article examines the European orphan regime, focusing on its two cornerstones--orphan designation and exclusivity--and highlighting the concepts that are still unclear and the issues that have not yet been addressed. The European Orphan Regulation has been proved to work well, but it would be even more successful if orphan designation was easier and orphan incentives were more attractive. The article concludes on the changes to be made to the European orphan legal regime that would encourage even more the research and development of orphan products. PMID:24479246

  17. Rwanda. AIDS orphans: problems and solutions.

    PubMed

    Descombes, M

    1993-01-01

    An estimated 300,000 of Rwanda's population of 7.5 million are infected with HIV. This includes 130,000 women and 20,000 children. Due to AIDS-related mortality, there are an estimated 62,000 orphans in the country, with 150,000 expected by 1997. War, adverse economic conditions, and ignorance of the minimal or nonexistent risk of being infected by these children, however, constrain extended biological and foster families from accepting these orphans into their homes. These children are very much alone and need to be placed in warm, caring households. Caritas Rwanda with the help of the Rwandan Ministry of Health launched the Family Homes Project in 1992 as an extension of the organization's general program of caring for AIDS-affected families in Rwanda in place since 1989. The program offers psychological counseling and assistance with regard to food, basic medicines, the payment of school fees, and funeral expenses. Family homes are structures designed to give orphans a background as similar as possible to that of the family which they have lost. Each harbors 7-10 children typically up to age 16 cared for by a woman who is also the biological mother of some of them. Caritas buys and equips an house in the Kigali suburbs or in one of the provincial towns. The mother is then provided a budget to pay for the daily household expenses of food, clothing, maintenance, water, and electricity. HIV-positive children lead in this setting, as far as their health permits, the same life as their healthy peers. When a serious health problem arises, the orphans are treated at the medical and social center, or the hospital if needed. Caritas Rwanda plans to open a care center staffed with a nurse and an additional outside social worker for orphans who require permanent treatment. Only several hundred children are presently in the program, but Rwanda has set an objective of assisting, by 1997, 50% of its AIDS orphans. PMID:12179314

  18. 21 CFR 316.26 - Amendment to orphan-drug designation.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Amendment to orphan-drug designation. 316.26... (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Designation of an Orphan Drug § 316.26 Amendment to orphan-drug designation. (a) At any time prior to approval of a marketing application for a designated orphan drug,...

  19. 21 CFR 316.21 - Verification of orphan-drug status.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Verification of orphan-drug status. 316.21 Section...) DRUGS FOR HUMAN USE ORPHAN DRUGS Designation of an Orphan Drug § 316.21 Verification of orphan-drug status. (a) So that FDA can determine whether a drug qualifies for orphan-drug designation under...

  20. 21 CFR 316.25 - Refusal to grant orphan-drug designation.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Refusal to grant orphan-drug designation. 316.25... (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Designation of an Orphan Drug § 316.25 Refusal to grant orphan-drug designation. (a) FDA will refuse to grant a request for orphan-drug designation if any of...

  1. 21 CFR 316.29 - Revocation 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 Revocation of orphan-drug designation. 316.29... (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Designation of an Orphan Drug § 316.29 Revocation of orphan-drug designation. (a) FDA may revoke orphan-drug designation for any drug if the agency finds that: (1) The...

  2. Depression among carers of AIDS-orphaned and other-orphaned children in Umlazi Township, South Africa.

    PubMed

    Kuo, Caroline; Operario, Don; Cluver, Lucie

    2012-01-01

    South Africa faces the challenge of supporting the well-being of adults caring for growing numbers of AIDS-orphaned children. These adults play a critical role in responses to the epidemic, but little information exists in regard to their mental health needs. This paper reports on findings from n=1599 adults, recruited through representative household sampling, who serve as primary carers for children in Umlazi Township, an HIV-endemic community. Overall, 22% of participants were carers of AIDS-orphaned children, 11% were carers of other-orphaned children and 67% were carers of non-orphaned children. Prevalence of depression was 30.3%. Orphan carers, regardless of whether they cared for AIDS-orphaned or other-orphaned children, were significantly more likely than carers of non-orphaned children to meet the clinical threshold for depression (35.2% vs. 27.9%, p < 0.01). In multivariate logistic regressions, food insecurity and being a female carer were identified as additional risk factors for greater depression. In contrast, households with access to running water and households dependent on salaries as the main source of income were identified as protective factors for disparities in depression. Mental health interventions are urgently needed to address an increased risk for depression among all orphan carers, not just those caring for AIDS-orphaned children. PMID:22081931

  3. 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

  4. 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.

  5. 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

  6. 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

  7. Emerging roles of orphan nuclear receptors in cancer.

    PubMed

    Baek, Sung Hee; Kim, Keun Il

    2014-01-01

    A growing body of evidence suggests that a subset of orphan nuclear receptors are amplified and prognostic for some human cancers. However, the specific roles of these orphan nuclear receptors in tumor progression and their utility as drug targets are not fully understood. In this review, we summarize recent progress in elucidating the direct and indirect involvement of orphan nuclear receptors in cancer as well as their therapeutic potential in a variety of human cancers. Furthermore, we contrast the role of orphan nuclear receptors in cancer with the known roles of estrogen receptor and androgen receptor in hormone-dependent cancers. PMID:24215441

  8. 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

  9. 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

  10. 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

  11. 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…

  12. Defining the Orphan Functions of Lysine Acetyltransferases

    PubMed Central

    2016-01-01

    Long known for their role in histone acetylation, recent studies have demonstrated that lysine acetyltransferases also carry out distinct “orphan” functions. These activities impact a wide range of biological phenomena including metabolism, RNA modification, nuclear morphology, and mitochondrial function. Here, we review the discovery and characterization of orphan lysine acetyltransferase functions. In addition to highlighting the evidence and biological role for these functions in human disease, we discuss the part emerging chemical tools may play in investigating this versatile enzyme superfamily. PMID:25591746

  13. 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.

  14. Promoter hypomethylation of RAR-related orphan receptor α 1 is correlated with unfavorable clinicopathological features in patients with colorectal cancer.

    PubMed

    Kano, Hisao; Takayama, Tadatoshi; Midorikawa, Yutaka; Nagase, Hiroki

    2016-07-19

    Retinoic acid receptor-related orphan receptor α (RORA) is a tumor-specific differentially methylated region. RORA mRNA expression is frequently downregulated in colorectal cancer (CRC) due to promoter methylation, and this methylation is correlated with the development of CRC. Here we investigated the correlation between the methylation status of the RORA promoter region and clinical CRC stages. The methylation status of RORA isoform 1 (RORA1) and isoform 4 (RORA4) promoters was investigated in 43 paired CRC specimens and adjacent normal tissues by quantitative DNA methylation analysis using the Sequenom MassARRAY system and bisulfite sequencing. The relationship between the methylation status of the RORA1 promoter and the CRC pathological stage was analyzed. RORA1 expression was evaluated using quantitative PCR. Sixteen of 43 CRC specimens (37%) and three CRC cell lines (Caco2, HT29, and HCT116) showed increased levels of methylation in the RORA1 promoter region compared with adjacent normal tissues, whereas no methylation was observed in the RORA4 promoter. Quantitative PCR showed downregulation of RORA1 expression both in CRC samples and cell lines. Furthermore, the RORA1 promoter hypomethylation status showed a significant correlation with unfavorable CRC stages (stages III and IV) compared with favorable stages (stages I and II, p = 0.014). Hypomethylation of the RORA1 promoter may have important clinical implications in unfavorable CRC development, and therefore, the methylation status of the RORA1 promoter may constitute a useful biomarker to determine an indication for postoperative therapy such as adjuvant chemotherapy in highly advanced CRC patients. PMID:27301432

  15. 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…

  16. 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…

  17. Orphan Strontium-87 in Abyssal Peridotites: Daddy Was a Granite

    NASA Astrophysics Data System (ADS)

    Snow, Jonathan E.; Hart, Stanley R.; Dick, Henry J. B.

    1993-12-01

    The 87Sr/86Sr 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," 87Sr appears to be separated from its radioactive parent. Such observations were widely held to be analytical artifacts. Study of several occurrences of orphan 87Sr shows that the orphan component in abyssal peridotite is located in the alteration products of olivine and enstatite in the peridotite. The orphan 87Sr is most likely introduced by infiltration of low-temperature (<200^circC) 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 87Sr and other radiogenic isotopes may provide a tracer for low-temperature seawater penetrating into the oceanic crust.

  18. 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

  19. 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

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

    PubMed

    Thomas, Kevin J A

    2010-12-01

    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

  1. 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…

  2. 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

  3. 21 CFR 316.28 - Publication of orphan-drug designations.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Publication of orphan-drug designations. 316.28... (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Designation of an Orphan Drug § 316.28 Publication of orphan-drug designations. Each month FDA will update a publically available list of drugs designated as...

  4. 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...

  5. 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...

  6. 21 CFR 316.20 - Content and format of a request for orphan-drug designation.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Content and format of a request for orphan-drug... SERVICES (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Designation of an Orphan Drug § 316.20 Content and format of a request for orphan-drug designation. (a) A sponsor that submits a request for...

  7. 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...

  8. 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... SERVICES (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Designation of an Orphan Drug § 316.30 Annual reports of holder of orphan-drug designation. Within 14 months after the date on which a drug was...

  9. Orphan Stars Found in Long Galaxy Tail

    NASA Astrophysics Data System (ADS)

    2007-09-01

    Astronomers have found evidence that stars have been forming in a long tail of gas that extends well outside its parent galaxy. This discovery suggests that such "orphan" stars may be much more prevalent than previously thought. The comet-like tail was observed in X-ray light with NASA's Chandra X-ray Observatory and in optical light with the Southern Astrophysical Research (SOAR) telescope in Chile. The feature extends for more than 200,000 light years and was created as gas was stripped from a galaxy called ESO 137-001 that is plunging toward the center of Abell 3627, a giant cluster of galaxies. "This is one of the longest tails like this we have ever seen," said Ming Sun of Michigan State University, who led the study. "And, it turns out that this is a giant wake of creation, not of destruction." Chandra X-ray Image of ESO 137-001 and Tail in Abell 3627 Chandra X-ray Image of ESO 137-001 and Tail in Abell 3627 The observations indicate that the gas in the tail has formed millions of stars. Because the large amounts of gas and dust needed to form stars are typically found only within galaxies, astronomers have previously thought it unlikely that large numbers of stars would form outside a galaxy. "This isn't the first time that stars have been seen to form between galaxies," said team member Megan Donahue, also of MSU. "But the number of stars forming here is unprecedented." The evidence for star formation in this tail includes 29 regions of ionized hydrogen glowing in optical light, thought to be from newly formed stars. These regions are all downstream of the galaxy, located in or near the tail. Two Chandra X-ray sources are near these regions, another indication of star formation activity. The researchers believe the orphan stars formed within the last 10 million years or so. The stars in the tail of this fast-moving galaxy, which is some 220 million light years away, would be much more isolated than the vast majority of stars in galaxies. H-alpha Image of

  10. 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

  11. Physical and sexual abuse in orphaned compared to non-orphaned children in sub-Saharan Africa: A systematic review and meta-analysis

    PubMed Central

    Nichols, J.; Embleton, L.; Mwangi, A.; Morantz, G.; Vreeman, R.; Ayaya, S.; Ayuku, D.; Braitstein, P.

    2013-01-01

    This systematic review assessed the quantitative literature to determine whether orphans are more likely to experience physical and/or sexual abuse compared to non-orphans in sub-Saharan Africa (SSA). It also evaluated the quality of evidence and identified research gaps. Our search identified 10 studies, all published after 2005, from Zimbabwe, South Africa, Kenya and Uganda. The studies consisted of a total 17,336 participants (51% female and 58% non-orphans). Of those classified as orphans (n = 7,315), 73% were single orphans, and 27% were double orphans. The majority of single orphans were paternal orphans (74%). Quality assessment revealed significant variability in the quality of the studies, although most scored higher for general design than dimensions specific to the domain of orphans and abuse. Combined estimates of data suggested that, compared to non-orphans, orphans are not more likely to experience physical abuse (combined OR = 0.96, 95% CI [0.79, 1.16]) or sexual abuse (combined OR = 1.25, 95% CI [0.88, 1.78]). These data suggest that orphans are not systematically at higher risk of experiencing physical or sexual abuse compared to non-orphans in sub-Saharan Africa. However, because of inconsistent quality of data and reporting, these findings should be interpreted with caution. Several recommendations are made for improving data quality and reporting consistency on this important issue. PMID:24210283

  12. 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

  13. The xenobiotic-sensing nuclear receptors pregnane X receptor, constitutive androstane receptor, and orphan nuclear receptor hepatocyte nuclear factor 4alpha in the regulation of human steroid-/bile acid-sulfotransferase.

    PubMed

    Echchgadda, Ibtissam; Song, Chung S; Oh, Taesung; Ahmed, Mohamed; De La Cruz, Isidro John; Chatterjee, Bandana

    2007-09-01

    The nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are the primary transcription factors coordinating induced expression of the enzymes and proteins directing oxidative, conjugative, and transport phases of endobiotic and xenobiotic metabolism, whereas hepatocyte nuclear factor 4alpha (HNF4alpha), a regulator of hepatic lipid homeostasis, can modify the PXR/CAR response. Steroid- and bile acid-sulfotransferase (SULT2A1) promotes phase II metabolism through its sulfonating action on certain endobiotics, including steroids and bile acids, and on diverse xenobiotics, including therapeutic drugs. This study describes characterization of a PXR- and CAR-inducible composite element in the human SULT2A1 promoter and its synergistic interaction with HNF4alpha. Inverted and direct repeats of AG(G/T)TCA (IR2 and DR4), both binding to PXR and CAR, define the composite element. Differential recognition of the composite element by PXR and CAR is evident because single-site mutation at either IR2 or DR4 in the natural gene abolished the PXR response, whereas mutations at both repeats were necessary to abrogate completely the CAR response. The composite element conferred xenobiotic response to a heterologous promoter, and the cognate ligands induced PXR and CAR recruitment to the chromatin-associated response region. An HNF4alpha element adjacent to the -30 position enhanced basal promoter activity. Although functioning as a synergizer, the HNF4alpha element was not essential for the PXR/CAR response. An emerging role of SULT2A1 in lipid and caloric homeostasis suggests that illumination on the regulatory interactions driving human SULT2A1 expression may reveal new avenues to control certain metabolic disorders. PMID:17595319

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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- ...

  19. Ethical considerations in orphan drug approval and use.

    PubMed

    Kesselheim, A S

    2012-08-01

    The Orphan Drug Act seeks to meet a utilitarian goal of advancing therapeutic options for patients with rare diseases. However, data show that orphan drugs are often approved with more limited premarket testing than that carried out for nonorphan drugs and consequently expose patients to more risk and less certain efficacy. Therefore, the ethical principles of justice and beneficence may require attention to informed consent among patients receiving the drugs and greater investment in postmarket surveillance and confirmational testing. PMID:22814660

  20. [Hope for patients with rare diseases--"orphan" drugs].

    PubMed

    Kuzelová, M; Kubácková, K; Palágyi, M; Smíd, M

    2006-01-01

    Rare diseases are defined as those affected less than five in every 10 000 person in European Union. The purpose of this paper is to present activities, which make possible to stimulate research development and marketing of appropriate medicine for tretment of rare disease, named "Orphan" medicinal products. EU "Orphan" medicinal products legislation which entered into force in April 2000 is described. Definition of "Orphan" medicinal products as well as the procedure of designation and placing the products into the Community register is presented. Those incentives to industry are described, which are already five years very well implemented oh the European level mostly on the pre-authorisation phase of "Orphan" medicinal products development, but also in the registration process as well as the post-authorisation phase. Finaly, the first twenty "Orphan" medicinal products, which have been given positive opinion in the Community for the grant of a marketing authorisation till April 2005 are mentioned in this work. The real availability of "Orphan" medicinal products in the particular EU member states is analysed. PMID:16639930

  1. 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

  2. [On the forensic relevance of orphan diseases].

    PubMed

    Ondruschka, Benjamin; Schneider, Eckhardt; Hädrich, Carsten; Dreßler, Jan; Bayer, Ronny

    2015-01-01

    A 40-year-old woman died shortly after complaining of non-specific symptoms after a pharmacist had accidentally given her the wrong medication. The woman's partner was not familiar with her medical history and the medical file had to be obtained from the family doctor. Autopsy findings and histological examination confirmed the clinically diagnosed autoimmune polyglandular syndrome without a tangible cause of death. Poisoning could not be demonstrated and no relation between the dosage error and death could be established. Laboratory tests revealed diabetic coma with ketoacidosis as the cause of death, which was probably caused by a prolonged lack of insulin administration. In addition to the clarification of legal issues, the complete post-mortem examination of orphan diseases is also relevant for achieving a better understanding of differential diagnostic aspects and complex pathophysiological contexts. Moreover, the genetic background often underlying such diseases should be a reason to inform the family of the deceased about the autopsy results. Only then can secondary preventive measures be taken in time. PMID:26548033

  3. Low density lipoprotein receptor related protein 1 variant interacts with saturated fatty acids in Puerto Ricans

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Low density lipoprotein related receptor protein 1 (LRP1) is a multi-functional endocytic receptor that is highly expressed in adipocytes and the hypothalamus. Animal models and in vitro studies support a role for LRP1 in adipocyte metabolism and leptin signaling, but genetic polymorphisms have not ...

  4. 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.

  5. Pediatric bronchiectasis: No longer an orphan disease.

    PubMed

    Goyal, Vikas; Grimwood, Keith; Marchant, Julie; Masters, I Brent; Chang, Anne B

    2016-05-01

    Bronchiectasis is described classically as a chronic pulmonary disorder characterized by a persistent productive cough and irreversible dilatation of one or more bronchi. However, in children unable to expectorate, cough may instead be wet and intermittent and bronchial dilatation reversible in the early stages. Although still considered an orphan disease, it is being recognized increasingly as causing significant morbidity and mortality in children and adults in both affluent and developing countries. While bronchiectasis has multiple etiologies, the final common pathway involves a complex interplay between the host, respiratory pathogens and environmental factors. These interactions lead to a vicious cycle of repeated infections, airway inflammation and tissue remodelling resulting in impaired airway clearance, destruction of structural elements within the bronchial wall causing them to become dilated and small airway obstruction. In this review, the current knowledge of the epidemiology, pathobiology, clinical features, and management of bronchiectasis in children are summarized. Recent evidence has emerged to improve our understanding of this heterogeneous disease including the role of viruses, and how antibiotics, novel drugs, antiviral agents, and vaccines might be used. Importantly, the management is no longer dependent upon extrapolating from the cystic fibrosis experience. Nevertheless, substantial information gaps remain in determining the underlying disease mechanisms that initiate and sustain the pathophysiological pathways leading to bronchiectasis. National and international collaborations, standardizing definitions of clinical and research end points, and exploring novel primary prevention strategies are needed if further progress is to be made in understanding, treating and even preventing this often life-limiting disease. Pediatr Pulmonol. 2016;51:450-469. © 2016 Wiley Periodicals, Inc. PMID:26840008

  6. 76 FR 3910 - Agency Information Collection Activities; Proposed Collection; Comment Request; Orphan Drugs...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-21

    ... HUMAN SERVICES Food and Drug Administration Agency Information Collection Activities; Proposed Collection; Comment Request; Orphan Drugs; Common European Medicines Agency/Food and Drug Administration Application Form for Orphan Medicinal Product Designation (Form FDA 3671) AGENCY: Food and Drug...

  7. 78 FR 35277 - Agency Information Collection Activities; Proposed Collection; Comment Request; Orphan Drugs...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-12

    ... HUMAN SERVICES Food and Drug Administration Agency Information Collection Activities; Proposed Collection; Comment Request; Orphan Drugs; Common European Medicines Agency/Food and Drug Administration Application Form for Orphan Medicinal Product Designation (Form FDA 3671) AGENCY: Food and Drug...

  8. 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 orphan-drug status. (a) So that FDA can determine...

  9. 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.

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

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 5 2011-04-01 2011-04-01 false Content and format of a request for orphan-drug designation. 316.20 Section 316.20 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 § 316.20 Content...

  11. 21 CFR 316.28 - Publication of orphan-drug designations.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 5 2012-04-01 2012-04-01 false Publication of orphan-drug designations. 316.28 Section 316.28 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Designation of an Orphan Drug § 316.28 Publication of...

  12. 21 CFR 316.28 - Publication of orphan-drug designations.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 5 2013-04-01 2013-04-01 false Publication of orphan-drug designations. 316.28 Section 316.28 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Designation of an Orphan Drug § 316.28 Publication of...

  13. 21 CFR 316.28 - Publication of orphan-drug designations.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 5 2014-04-01 2014-04-01 false Publication of orphan-drug designations. 316.28 Section 316.28 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Designation of an Orphan Drug § 316.28 Publication of...

  14. 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…

  15. 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

  16. 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... issues relating to orphan works and mass digitization under U.S. copyright law. DATES: Comments are due... relating to orphan works and mass digitization under U.S. copyright law. Due to the number and...

  17. 76 FR 29183 - Exclusion of Orphan Drugs for Certain Covered Entities Under 340B Program

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-20

    ... (relating to treatment of sexually transmitted diseases) or section 317(j)(2) (relating to treatment of... 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...

  18. Low-Density Lipoprotein Receptor-Related Protein-1 Protects Against Hepatic Insulin Resistance and Hepatic Steatosis.

    PubMed

    Ding, Yinyuan; Xian, Xunde; Holland, William L; Tsai, Shirling; Herz, Joachim

    2016-05-01

    Low-density lipoprotein receptor-related protein-1 (LRP1) is a multifunctional uptake receptor for chylomicron remnants in the liver. In vascular smooth muscle cells LRP1 controls reverse cholesterol transport through platelet-derived growth factor receptor β (PDGFR-β) trafficking and tyrosine kinase activity. Here we show that LRP1 regulates hepatic energy homeostasis by integrating insulin signaling with lipid uptake and secretion. Somatic inactivation of LRP1 in the liver (hLRP1KO) predisposes to diet-induced insulin resistance with dyslipidemia and non-alcoholic hepatic steatosis. On a high-fat diet, hLRP1KO mice develop a severe Metabolic Syndrome secondary to hepatic insulin resistance, reduced expression of insulin receptors on the hepatocyte surface and decreased glucose transporter 2 (GLUT2) translocation. While LRP1 is also required for efficient cell surface insulin receptor expression in the absence of exogenous lipids, this latent state of insulin resistance is unmasked by exposure to fatty acids. This further impairs insulin receptor trafficking and results in increased hepatic lipogenesis, impaired fatty acid oxidation and reduced very low density lipoprotein (VLDL) triglyceride secretion. PMID:27322467

  19. Bombesin-Like Receptor 3: Physiology of a Functional Orphan.

    PubMed

    Xiao, Cuiying; Reitman, Marc L

    2016-09-01

    Bombesin-like receptor 3 (BRS-3) is an X-linked orphan Gq-coupled receptor that regulates food intake, metabolic rate, body temperature, heart rate, blood pressure, and insulin secretion. Most BRS-3 actions occur via the brain, through mechanisms including regulating sympathetic outflow. Ablation of Brs3 causes obesity, while synthetic agonists produce weight loss. PMID:27055378

  20. [Orphan Drugs: Underrated Opportunities for The Developers in Europe].

    PubMed

    Tillet, Yves; Maillols-Perroy, Anne-Catherine

    2015-01-01

    In Europe, rules relating to the designation and the protection of orphan drug are derived from regulation (EC) 141/2000 of the European Parliament and Council of 16 December 1999, specified by the implementing Regulation (EC) 847/2000. According to these regulations, obtaining the status of orphan drugs implies, in particular, to demonstrate the absence of any satisfying alternative treatment, or, by default, the significant benefit offered by the concerned drug. In the same sense, medicinal product similar to an original orphan medicinal product but safer, more effective or otherwise clinically superior, will benefit from a derogation to the rules on the 10 years market exclusivity usually provided for these products. This article analyses the concept of significant benefit, namely, the clinically relevant advantage or a major contribution to patient care, in particular in the case of similar drugs, as well as the elements to be provided by the sponsor in order to justify this benefit, and the options under which, where there are few or a lack of clinical data on a concerned orphan medicinal products, the demonstration of the significant benefit can rely on assumptions. PMID:25997721

  1. 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…

  2. 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,…

  3. 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…

  4. 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.…

  5. 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,…

  6. 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....

  7. 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....

  8. 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.

  9. Oncogenic conversion of a novel orphan nuclear receptor by chromosome translocation.

    PubMed

    Labelle, Y; Zucman, J; Stenman, G; Kindblom, L G; Knight, J; Turc-Carel, C; Dockhorn-Dworniczak, B; Mandahl, N; Desmaze, C; Peter, M

    1995-12-01

    A recurrent t(9;22) (q22;q12) chromosome translocation has been described in extraskeletal myxoid chondrosarcoma (EMC). Fluorescent in situ hybridization experiments performed on one EMC tumour indicated that the chromosome 22 breakpoint occurred in the EWS gene. Northern blot analysis revealed an aberrant EWS transcript which is cloned by a modified RT-PCR procedure. This transcript consists of an in-frame fusion of the 5' end of EWS to a previously unidentified gene, which was named TEC. This fusion transcript was detected in six of eight EMC studied, and three different junction types between the two genes were found. In all junction types, the putative translation product contained the amino-terminal transactivation domain of EWS linked to the entire TEC protein. Homology analysis showed that the predicted TEC protein contains a DNA-binding domain characteristic of nuclear receptors. The highest identity scores were observed with the NURR1 family of orphan nuclear receptors. These receptors are involved in the control of cell proliferation and differentiation by modulating the response to growth factors and retinoic acid. This work provides, after the PML/RAR alpha gene fusion, the second example of the oncogenic conversion of a nuclear receptor and the first example involving the orphan subfamily. Analysis of the disturbance induced by the EWS/TEc protein in the nuclear receptor network and their target genes may lead to new approaches for EMC treatment. PMID:8634690

  10. Socio-economic status and socio-emotional health of orphans in South Africa.

    PubMed

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

    2015-02-01

    This paper investigates the relationship between socio-economic status and emotional well-being of orphans in Mangaung, South Africa. Five hundred orphans aged 7-11 years participated in the cross-sectional study between 2009 and 2012. Data was collected by trained fieldworkers, who conducted face-to-face interviews and questionnaires with the orphans, their teachers and caregivers, and the heads of the households where the orphans resided. The caregivers, children and teachers all completed the Strengths and Difficulties Questionnaire in order to measure the orphans' mental health, while heads of household provided information about socio-economic indicators. STATA version 12 was used to perform multivariate data analyses to identify socio-economic factors associated with the mental health of orphans. Food security, access to medical services and a male caregiver were factors associated with better emotional well-being of orphans, whereas other variables such as household asset index and monthly household expenditure were not linked with the orphans' mental health. Two of the three variables (food security and access to medical services) associated with better emotional well-being of orphans are also government interventions to assist orphans. Further research is needed to determine whether other government programs also impact the emotional well-being of orphans. PMID:24968757

  11. Constraints to educational opportunities of orphans: a community-based study from northern Uganda.

    PubMed

    Oleke, C; Blystad, A; Fylkesnes, K; Tumwine, J K

    2007-03-01

    The objective of this article is to assess constraints on educational opportunities of orphans cared for within the extended family system in Lira district, northern Uganda. The data were collected through: review of school census records; ethnographic fieldwork; in-depth interviews with 21 community leaders, 45 heads of households caring for orphans and 35 orphans. Focus group discussions were held with men and women caring for orphans, community leaders and orphans. A household survey was conducted in 402 households caring for orphans. We found that very poor widows living on less than half a dollar per day head 48% of the households caring for orphans. The elderly heads of households were 3 times more likely to have all the children in their household in schools than the younger ones. Furthermore, the widowed and single heads of households were more likely to have all orphans in school than the married, and households that received external support offered better educational opportunities. Poverty, as indicated by lack of food while at school and heavy involvement of orphans in domestic labour, were identified as major constraints on orphans' schooling. There is an urgent need to support orphans' education in northern Uganda beyond the current Universal Primary Education efforts. The most vulnerable households need to be targeted, and the communities need to be sensitized to child labour, school meals and sex abuse. PMID:17453570

  12. Posttraumatic stress symptoms among adults caring for orphaned children in HIV-endemic South Africa.

    PubMed

    Kuo, Caroline; Reddy, Madhavi K; Operario, Don; Cluver, Lucie; Stein, Dan J

    2013-06-01

    There is growing evidence that mental health is a significant issue among families affected by AIDS-related parental deaths. The current study examined posttraumatic stress symptoms and identified risk factors among adults caring for AIDS-orphaned and other-orphaned children in an HIV-endemic South African community. A representative community sample of adults caring for children (N = 1,599) was recruited from Umlazi Township. Of the 116 participants who reported that a traumatic event was still bothering them, 19 % reported clinically significant posttraumatic stress symptoms. Of the 116 participants, caregivers of AIDS-orphaned and other-orphaned children were significantly more likely to meet threshold criteria for PTSD (28 %) compared to caregivers of non-orphaned children (10 %). Household receipt of an old age pension was identified as a possible protective factor for PTSD symptoms among caregivers of orphaned children. Services are needed to address PTSD symptoms among caregivers of orphaned children. PMID:23539187

  13. Posttraumatic Stress Symptoms among Adults Caring for Orphaned Children in HIV-endemic South Africa

    PubMed Central

    Kuo, Caroline; Reddy, Madhavi K.; Operario, Don; Cluver, Lucie; Stein, Dan J.

    2013-01-01

    There is growing evidence that mental health is a significant issue among families affected by AIDS-related parental deaths. The current study examined posttraumatic stress symptoms and identified risk factors among adults caring for AIDS-orphaned and other-orphaned children in an HIV-endemic South African community. A representative community sample of adults caring for children (N = 1,599) was recruited from Umlazi Township. Of the 116 participants who reported that a traumatic event was still bothering them, 19% reported clinically significant posttraumatic stress symptoms. Of the 116 participants, caregivers of AIDS-orphaned and other-orphaned children were significantly more likely to meet threshold criteria for PTSD (28%) compared to caregivers of non-orphaned children (10%). Household receipt of an old age pension was identified as a possible protective factor for PTSD symptoms among caregivers of orphaned children. Services are needed to address PTSD symptoms among caregivers of orphaned children. PMID:23539187

  14. 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

  15. Fast skeletal muscle troponin I is a co-activator of estrogen receptor-related receptor {alpha}

    SciTech Connect

    Li Yuping; Chen Bin; Chen Jian; Lou Guiyu; Chen Shiuan; Zhou Dujin

    2008-05-16

    ERR{alpha} (estrogen receptor-related receptor {alpha}) is a member of the nuclear receptor superfamily. To further our understanding of the detailed molecular mechanism of transcriptional regulation by ERR{alpha}, we searched for ERR{alpha}-interacting proteins using a yeast two-hybrid system by screening a human mammary gland cDNA expression library with the ligand-binding domain (LBD) of ERR{alpha} as the 'bait'. Fast skeletal muscle troponin I (TNNI2), along with several known nuclear receptor co-activators, were isolated. We demonstrated that TNNI2 localizes to the cell nucleus and interacts with ERR{alpha} in co-immunoprecipitation experiments. GST pull-down assays also revealed that TNNI2 interacts directly with ERR{alpha}. Through luciferase reporter gene assays, TNNI2 was found to enhance the transactivity of ERR{alpha}. Combining mutagenesis and yeast two-hybrid assays, we mapped the ERR{alpha}-interacting domain on TNNI2 to a region encompassing amino acids 1-128. These findings reveal a new function for TNNI2 as a co-activator of ERR{alpha}.

  16. Perceptions of children and community members concerning the circumstances of orphans in rural Zimbabwe.

    PubMed

    Foster, G; Makufa, C; Drew, R; Mashumba, S; Kambeu, S

    1997-08-01

    Focus group discussions and interviews were held with 40 orphans, 25 caretakers and 33 other community workers from a rural area near Mutare, Zimbabwe. Orphan concerns included feeling different from other children, stress, stigmatization, exploitation, schooling, lack of visits and neglect of support responsibilities by relatives. Many community members, while recognizing their limitations due to poverty, were already actively helping orphans and caretakers. Extended family networks are the primary resource for orphans, though some relatives exploit orphans or fail to fulfil their responsibilities. Interventions are suggested which support community coping mechanisms by strengthening the capacities of families to care for orphans. Outside organizations can develop partnerships with community groups, helping them to respond to the impact of AIDS, by building upon existing concern for orphan families. They can help affected communities to develop orphan support activities which encourage caring responses by community leaders and relatives and which discourage property-grabbing and orphan neglect. Material support channelled through community groups to destitute families at critical times can strengthen family coping mechanisms. Income-generating activities should build upon communities' existing capabilities and benefit the most vulnerable orphan households. Some communities are responding to the AIDS disaster by adaptations to cope with devastating changes taking place in their communities. PMID:9337884

  17. 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

  18. Multifactorial induction of an orphan PKS-NRPS gene cluster in Aspergillus terreus.

    PubMed

    Gressler, Markus; Zaehle, Christoph; Scherlach, Kirstin; Hertweck, Christian; Brock, Matthias

    2011-02-25

    Mining the genome of the pathogenic fungus Aspergillus terreus revealed the presence of an orphan polyketide-nonribosomal-peptide synthetase (PKS-NRPS) gene cluster. Induced expression of the transcriptional activator gene adjacent to the PKS-NRPS gene was not sufficient for the activation of the silent pathway. Monitoring gene expression, metabolic profiling, and using a lacZ reporter strain allowed for the systematic investigation of physiological conditions that eventually led to the discovery of isoflavipucine and dihydroisoflavipucine. Phytotoxin formation is only activated in the presence of certain amino acids, stimulated at alkaline pH, but strictly repressed in the presence of glucose. Global carbon catabolite repression by CreA cannot be abolished by positive-acting factors such as PacC and overrides the pathway activator. Gene inactivation and stable isotope labeling experiments unveiled the molecular basis for flavipucine/fruit rot toxin biosynthesis. PMID:21236704

  19. 77 FR 64555 - Orphan Works and Mass Digitization

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-10-22

    ... Exploitation of Unavailable Books] Art. 134-1 (2012) (Fr.) (``Law 2012-287''), available at http://www.legifrance.gouv.fr/affichTexte.do ;jsessionid=4D8B77A47AA211DE6E336FD22AA18F60.tpdjo09v-- 2?cidTexte... relation to their use of orphan works'' if that use is consistent with the public organization's...

  20. 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.

  1. Rare diseases, orphan drugs, and their regulation in Asia: Current status and future perspectives

    PubMed Central

    Song, Peipei; Gao, Jianjun; Inagaki, Yoshinori; Kokudo, Norihiro; Tang, Wei

    2012-01-01

    Summary Rare diseases are an important public health issue and a challenge to medical care. Specific legislation to encourage research of rare diseases and development of orphan drugs has been adopted in the United States (US), the European Union (EU), and elsewhere. In recent years, much progress has been made in some parts of Asia, including Japan, South Korea, and Taiwan, with the enactment of legislation and accompanying regulation of rare diseases and orphan drugs. China is also actively promoting the regulation of rare diseases and orphan drugs. We describe the current status of the regulation of rare diseases and orphan drugs in Asia and we comparatively analyze the regulation of rare diseases and orphan drugs worldwide in order to examine the challenges to and future perspectives on promoting research on rare diseases and development of orphan drugs in China and other Asian countries. PMID:25343064

  2. 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

  3. 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

  4. Formation of a solar Hα filament from orphan penumbrae

    NASA Astrophysics Data System (ADS)

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

    2016-04-01

    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

  5. Translation of rare disease research into orphan drug development: disease matters.

    PubMed

    Heemstra, Harald E; van Weely, Sonja; Büller, Hans A; Leufkens, Hubert G M; de Vrueh, Remco L A

    2009-12-01

    More than 25 years of orphan drug regulations have yielded several new treatments for patients with rare diseases. Here, we show that successful translation of rare disease research into an orphan drug discovery and development programme is dependent on the disease class, its prevalence and the disease-specific scientific output. Our findings indicate that current orphan drug legislation alone is not sufficient to stimulate orphan drug development for diseases with a very low prevalence. Consequently, additional incentives should focus on stimulating the specific needs of rare disease research at disease class level. PMID:19818412

  6. 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. PMID:22747423

  7. SOCIAL SUPPORT DISPARITIES FOR CAREGIVERS OF AIDS-ORPHANED CHILDREN IN SOUTH AFRICA

    PubMed Central

    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 to caregivers of children orphaned by other causes (n=171) and caregivers of non-orphaned children (n=1,069). Results of multivariate linear regressions indicate that caregivers of AIDS-orphaned children reported significantly lower levels of social support compared to caregivers of other-orphaned children and non-orphaned children independent of socio-demographic covariates. Caregivers of other-orphaned and non-orphaned children reported similar levels of social support. In terms of sources of support, all caregivers were more likely to draw support from family and significant others rather than friends. These findings indicate a need to develop interventions that can increase levels of social support for caregivers of AIDS-orphaned children, particularly networks that include friends and significant others. PMID:22904575

  8. Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor

    PubMed Central

    Liedtke, Wolfgang; Choe, Yong; Martí-Renom, Marc A.; Bell, Andrea M.; Denis, Charlotte S.; Šali, Andrej; Hudspeth, A. J.; Friedman, Jeffrey M.; Heller, Stefan

    2008-01-01

    SUMMARY The detection of osmotic stimuli is essential for all organisms, yet few osmoreceptive proteins are known, none of them in vertebrates. By employing a candidate-gene approach based on genes encoding members of the TRP superfamily of ion channels, we cloned cDNAs encoding the vanilloid receptor-related osmotically activated channel (VR-OAC) from the rat, mouse, human, and chicken. This novel cation-selective channel is gated by exposure to hypotonicity within the physiological range. In the central nevous system, the channel is expressed neurons of the circumventricular organs, neurosensory cells responsive to systemic osmotic pressure. The channel also occurs in other neurosensory cells, including inner-ear hair cells, sensory neurons, and Merkel cells. PMID:11081638

  9. The low density lipoprotein receptor-related protein (LRP) 1 and its function in lung diseases.

    PubMed

    Wujak, L; Markart, P; Wygrecka, M

    2016-07-01

    The low density lipoprotein receptor-related protein (LRP) 1 is a ubiquitously expressed, versatile cell surface transmembrane receptor involved in embryonic development and adult tissue homeostasis. LRP1 binds and endocytoses a broad spectrum of over 40 ligands identified thus far, including lipoproteins, extracellular matrix proteins, proteases and protease/inhibitor complexes and growth factors. Interactions with other membrane receptors and intracellular adaptors/scaffolding proteins allow LRP1 to modulate cell migration, survival, proliferation and (trans) differentiation. Because LRP1 displays a wide-range of interactions and activities, its expression and function is temporally and spatially tightly controlled. It is not, therefore, surprising that deregulation of LRP1 production and/or activity is observed in several diseases. In this review, we will systematically examine the evidence for the role of LRP1 in human pathologies placing special emphasis on LRP1-mediated pathogenesis of the lung. PMID:26926950

  10. 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

  11. 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

  12. Orphan Nuclear Receptors as Targets for Drug Development

    PubMed Central

    Mukherjee, Subhajit

    2012-01-01

    Orphan nuclear receptors regulate diverse biological processes. These important molecules are ligand-activated transcription factors that act as natural sensors for a wide range of steroid hormones and xenobiotic ligands. Because of their importance in regulating various novel signaling pathways, recent research has focused on identifying xenobiotics targeting these receptors for the treatment of multiple human diseases. In this review, we will highlight these receptors in several physiologic and pathophysiologic actions and demonstrate how their functions can be exploited for the successful development of newer drugs. PMID:20372994

  13. Hierarchy length in orphaned colonies of the ant Temnothorax nylanderi

    NASA Astrophysics Data System (ADS)

    Heinze, J.

    2008-08-01

    Workers of the ant Temnothorax nylanderi form dominance orders in orphaned colonies in which only one or a few top-ranking workers begin to produce males from unfertilized eggs. Between one and 11 individuals initiated 80% of all aggression in 14 queenless colonies. As predicted from inclusive fitness models (Molet M, van Baalen M, Monnin T, Insectes Soc 52:247 256, 2005), hierarchy length was found to first increase with colony size and then to level off at larger worker numbers. The frequency and skew of aggression decreased with increasing size, indicating that rank orders are less pronounced in larger colonies.

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

    PubMed

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

    2013-11-01

    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

  15. 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

  16. 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

  17. Care arrangement, grief, and psychological problems among children orphaned by AIDS in China

    PubMed Central

    Zhao, Guoxiang; Li, Xiaoming; Fang, Xiaoyi; Zhao, Junfeng; Yang, Hongmei; Stanton, Bonita

    2007-01-01

    The China Ministry of Health has estimated that there are at least 100,000 AIDS orphans in China. The UNICEF China Office estimates that between 150,000 and 250,000 additional children will be orphaned by AIDS over the next five years. However, limited data are available regarding the socio-demographic characteristics, care arrangement, barriers to appropriate grief resolution and psychological problems among AIDS orphans in China. In this article, we review secondary data and reports from scientific literature, government, non-governmental organizations, and public media regarding children orphaned by AIDS in China to address their living situation, bereavement process, and psychological problems. Our review suggests that AIDS orphans in China are living in a stressful environment with many orphans struggling with psychological problems and unmet basic needs such as food, shelter, education, and medical care. Based on our review, we suggest that future studies should address the psychosocial needs of AIDS orphans in China and develop health promotion programs to mitigate the negative impact of parental death on the physical and psychosocial well-being of these orphans. PMID:18058390

  18. 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…

  19. 21 CFR 316.28 - Publication of orphan-drug designations.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ...-drug designations. Each month FDA will update a publically available list of drugs designated as orphan drugs. A cumulative, updated list of all designated drugs will be provided annually. These will be... 21 Food and Drugs 5 2011-04-01 2011-04-01 false Publication of orphan-drug designations....

  20. 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…

  1. Use of biomarkers in the context of orphan medicines designation in the European Union.

    PubMed

    Tsigkos, Stelios; Llinares, Jordi; Mariz, Segundo; Aarum, Stiina; Fregonese, Laura; Dembowska-Baginska, Bozenna; Elbers, Rembert; Evers, Pauline; Foltanova, Tatiana; Lhoir, Andre; Corrêa-Nunes, Ana; O'Connor, Daniel; Voordouw, Albertha; Westermark, Kerstin; Sepodes, Bruno

    2014-01-01

    The use of biomarkers within the procedures of the Committee of Orphan Medicinal Products (COMP) of the European Medicines Agency (EMA) is discussed herein. The applications for Orphan Medicinal Product designation in the EU are evaluated at two stages. At the time of orphan designation application, the file undergoes an assessment to establish whether the proposed condition is a distinct and serious condition affecting not more than 5 in 10,000 people in the EU, and whether the product is plausible as a therapy for that condition. In cases where therapies already exist, the significant benefit of the candidate product over existing therapies is also evaluated. The orphan criteria are reassessed at the time of marketing authorisation, so that marketing exclusivity for the product in the orphan medical condition can be granted. Within this context, biomarkers have been used in submissions in order to define an orphan condition and to justify that the criteria for orphan designation are met. The current work discusses specific examples from the experience of the COMP, where biomarkers have played a decisive role. Importantly, it identifies the proposal of sub-sets of non-rare conditions based on biomarkers as a challenging issue in the evaluation of applications. In particular two specific requirements for the candidate orphan medicines in relation to the biomarker-based subsets are highlighted: the "plausible link to the condition" and the "exclusion of effects outside the subset". PMID:24461084

  2. Selection of Orphan Rhs Toxin Expression in Evolved Salmonella enterica Serovar Typhimurium

    PubMed Central

    Koskiniemi, Sanna; Garza-Sánchez, Fernando; Sandegren, Linus; Webb, Julia S.; Braaten, Bruce A.; Poole, Stephen J.; Andersson, Dan I.; Hayes, Christopher S.; Low, David A.

    2014-01-01

    Clonally derived bacterial populations exhibit significant genotypic and phenotypic diversity that contribute to fitness in rapidly changing environments. Here, we show that serial passage of Salmonella enterica serovar Typhimurium LT2 (StLT2) in broth, or within a mouse host, results in selection of an evolved population that inhibits the growth of ancestral cells by direct contact. Cells within each evolved population gain the ability to express and deploy a cryptic “orphan” toxin encoded within the rearrangement hotspot (rhs) locus. The Rhs orphan toxin is encoded by a gene fragment located downstream of the “main” rhs gene in the ancestral strain StLT2. The Rhs orphan coding sequence is linked to an immunity gene, which encodes an immunity protein that specifically blocks Rhs orphan toxin activity. Expression of the Rhs orphan immunity protein protects ancestral cells from the evolved lineages, indicating that orphan toxin activity is responsible for the observed growth inhibition. Because the Rhs orphan toxin is encoded by a fragmented reading frame, it lacks translation initiation and protein export signals. We provide evidence that evolved cells undergo recombination between the main rhs gene and the rhs orphan toxin gene fragment, yielding a fusion that enables expression and delivery of the orphan toxin. In this manner, rhs locus rearrangement provides a selective advantage to a subpopulation of cells. These observations suggest that rhs genes play important roles in intra-species competition and bacterial evolution. PMID:24675981

  3. 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…

  4. 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…

  5. 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,…

  6. 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…

  7. 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...

  8. 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…

  9. 42 CFR 10.21 - Exclusion of orphan drugs for certain covered entities.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ..., prescribed, sold, or otherwise used for the rare condition or disease for which that orphan drug was...-accepted indication other than treating the rare disease or condition for which the drug was designated... exclusion of orphan drugs when used to treat the rare disease or condition for which the drug was...

  10. 42 CFR 10.21 - Exclusion of orphan drugs for certain covered entities.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ..., prescribed, sold, or otherwise used for the rare condition or disease for which that orphan drug was...-accepted indication other than treating the rare disease or condition for which the drug was designated... exclusion of orphan drugs when used to treat the rare disease or condition for which the drug was...

  11. 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…

  12. 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

  13. 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

  14. Gender Differences in Maladaptive Cognitive Schema in Orphans in Dakahlia, Egypt

    PubMed Central

    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

  15. Difference in psychosocial well-being between paternal and maternal AIDS orphans in rural China.

    PubMed

    Zhao, Qun; Li, Xiaoming; Fang, Xiaoyi; Zhao, Guoxiang; Zhao, Junfeng; Lin, Xiuyun; Stanton, Bonita

    2010-01-01

    This study compares psychosocial well-being between paternal and maternal orphans in rural China in a sample (n = 459) of children who had lost one parent to HIV and who were in family-based care. Measures included academic marks, education expectation, trusting relationships with current caregivers, self-reported health status, depression, loneliness, posttraumatic stress, and social support. No significant differences were reported between maternal and paternal orphans, except that paternal orphans reported better trusting relationships with caregivers than maternal orphans. Children with a healthy surviving parent reported significantly better scores for depression, loneliness, posttraumatic stress, and social support than children with a sick parent. Analyses showed significance with regard to orphan status on academic marks and trusting relationships with caregivers while controlling for age, gender, surviving parent's health status, and family socioeconomic status. Results underscore the importance of psychosocial support for children whose surviving parent is living with HIV or another illness. PMID:20133172

  16. 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

  17. Orphan drug development: an economically viable strategy for biopharma R&D.

    PubMed

    Meekings, Kiran N; Williams, Cory S M; Arrowsmith, John E

    2012-07-01

    Orphan drug incentives have stimulated research into diseases with significant unmet medical need. Although the targeting of orphan diseases is seen by industry as an attractive strategy, there are limited economic data available to support its use. In this paper we show that the revenue-generating potential of orphan drugs is as great as for non-orphan drugs, even though patient populations for rare diseases are significantly smaller. Moreover, we suggest that orphan drugs have greater profitability when considered in the full context of developmental drivers including government financial incentives, smaller clinical trial sizes, shorter clinical trial times and higher rates of regulatory success. The data support the targeting of rare diseases as an important component of a successful biopharma R&D strategy. PMID:22366309

  18. 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…

  19. 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... of FDA's Office of Orphan Products Development (OPD) grant program. The goal of FDA's OPD grant... Background and Significance section documentation to support the estimated prevalence of the orphan...

  20. 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…

  1. 77 FR 46764 - Clinical Studies of Safety and Effectiveness of Orphan Products Research Project Grant (R01)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-08-06

    ... HUMAN SERVICES Food and Drug Administration Clinical Studies of Safety and Effectiveness of Orphan... of FDA's Office of Orphan Products Development (OPD) grant program. The goal of FDA's OPD grant... Needleman, Office of Orphan Products Development, Food and Drug Administration, 10903 New Hampshire...

  2. 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

  3. Orphan drug legislation: lessons for neglected tropical diseases.

    PubMed

    Villa, Stefano; Compagni, Amelia; Reich, Michael R

    2009-01-01

    In the last 20 years, orphan drug legislation (ODL) has been adopted in several countries around the world (USA, Japan, Australia, and the European Union) and has successfully promoted R&D investments to develop new pharmaceutical products for the treatment of rare diseases. Without these incentives, many life-saving new drugs would have not been developed and produced. For economic reasons, the development of medicines for the treatment of diseases prevalent in the developing world (or tropical diseases) is lagging behind. Among several factors, the low average per-capita income makes pharmaceutical markets in developing countries appear relatively unprofitable and therefore unattractive for R&D-oriented companies. The case of ODL may offer some useful insights and perspectives for the fight against neglected tropical diseases. First, the measures used in ODL may also be effective in boosting R&D for neglected tropical diseases, if appropriately adapted to this market. Second, small-sized companies, which have played a successful role in the development of orphan drugs for rare diseases, may also represent a good business strategy for the case of tropical diseases. PMID:18435430

  4. Children, AIDS and the politics of orphan care in Ethiopia: the extended family revisited.

    PubMed

    Abebe, Tatek; Aase, Asbjorn

    2007-05-01

    The astounding rise in the number of orphans due to the HIV/AIDS epidemic has left many Ethiopian families and communities with enormous childcare problems. Available studies on the capacity and sustainability of the extended family system, which culturally performs the role of care for children in need, suggest two competing theories. The first is grounded in the social rupture thesis and assumes that the traditional system of orphan care is stretched by the impact of the epidemic, and is actually collapsing. By contrast, the second theory counter-suggests that the flexibility and strength of the informal childcare practise, if supported by appropriate interventions, can still support a large number of orphans. Based on a seven-month period of child-focused, qualitative research fieldwork in Ethiopia involving observations; in-depth interviews with orphans (42), social workers (12) and heads of households (18); focus group discussions with orphans (8), elderly people and community leaders (6); and story-writing by children in school contexts, this article explores the trade-offs and social dynamics of orphan care within extended family structures in Ethiopia. It argues that there is a rural-urban divide in the capacity to cater for orphans that emanates from structural differences as well as the socio-cultural and economic values associated with children. The care of orphans within extended family households is also characterised by multiple and reciprocal relationships in care-giving and care-receiving practices. By calling for a contextual understanding of the 'orphan burden', the paper concludes that interventions for orphans may consider care as a continuum in the light of four profiles of extended families, namely rupturing, transient, adaptive, and capable families. PMID:17379371

  5. Identification of estrogen receptor-related receptor gamma as a direct transcriptional target of angiogenin.

    PubMed

    Ang, Jian; Sheng, Jinghao; Lai, Kairan; Wei, Saisai; Gao, Xiangwei

    2013-01-01

    Nuclear translocation of angiogenin (ANG) is essential for the proliferation of its target cells. ANG promotes rRNA synthesis, while whether it regulates mRNA transcription remains unknown. Using the chromatin immunoprecipitation method, we have identified 12 ANG-binding sequences. One of these sequences lies in the estrogen receptor-related receptor gamma (ERRγ) gene which we designated as ANG-Binding Sequence within ERRγ (ABSE). ABSE exhibited ANG-dependent repressor activity in the luciferase reporter system. Down-regulation of ANG increased ERRγ expression, and active gene marker level at the ABSE region. The expression levels of ERRγ targets genes, p21(WAF/CIP) and p27(KIP1), and the occupation of ERRγ on their promoter regions were increased in ANG-deficient cells accordingly. Furthermore, knockdown of ERRγ promoted the proliferation rate in ANG-deficient breast cancer cells. Finally, immunohistochemistry staining showed negative correlation between ANG and ERRγ in breast cancer tissue. Altogether, our study provides evidence that nuclear ANG directly binds to the ABSE of ERRγ gene and inhibits ERRγ transcription to promote breast cancer cell proliferation. PMID:23977052

  6. Identification of Estrogen Receptor-Related Receptor Gamma as a Direct Transcriptional Target of Angiogenin

    PubMed Central

    Ang, Jian; Sheng, Jinghao; Lai, Kairan; Wei, Saisai; Gao, Xiangwei

    2013-01-01

    Nuclear translocation of angiogenin (ANG) is essential for the proliferation of its target cells. ANG promotes rRNA synthesis, while whether it regulates mRNA transcription remains unknown. Using the chromatin immunoprecipitation method, we have identified 12 ANG-binding sequences. One of these sequences lies in the estrogen receptor-related receptor gamma (ERRγ) gene which we designated as ANG-Binding Sequence within ERRγ (ABSE). ABSE exhibited ANG-dependent repressor activity in the luciferase reporter system. Down-regulation of ANG increased ERRγ expression, and active gene marker level at the ABSE region. The expression levels of ERRγ targets genes, p21WAF/CIP and p27KIP1, and the occupation of ERRγ on their promoter regions were increased in ANG-deficient cells accordingly. Furthermore, knockdown of ERRγ promoted the proliferation rate in ANG-deficient breast cancer cells. Finally, immunohistochemistry staining showed negative correlation between ANG and ERRγ in breast cancer tissue. Altogether, our study provides evidence that nuclear ANG directly binds to the ABSE of ERRγ gene and inhibits ERRγ transcription to promote breast cancer cell proliferation. PMID:23977052

  7. Antibodies against low-density lipoprotein receptor-related protein 4 induce myasthenia gravis.

    PubMed

    Shen, Chengyong; Lu, Yisheng; Zhang, Bin; Figueiredo, Dwight; Bean, Jonathan; Jung, Jiung; Wu, Haitao; Barik, Arnab; Yin, Dong-Min; Xiong, Wen-Cheng; Mei, Lin

    2013-12-01

    Myasthenia gravis (MG) is the most common disorder affecting the neuromuscular junction (NMJ). MG is frequently caused by autoantibodies against acetylcholine receptor (AChR) and a kinase critical for NMJ formation, MuSK; however, a proportion of MG patients are double-negative for anti-AChR and anti-MuSK antibodies. Recent studies in these subjects have identified autoantibodies against low-density lipoprotein receptor-related protein 4 (LRP4), an agrin receptor also critical for NMJ formation. LRP4 autoantibodies have not previously been implicated in MG pathogenesis. Here we demonstrate that mice immunized with the extracellular domain of LRP4 generated anti-LRP4 antibodies and exhibited MG-associated symptoms, including muscle weakness, reduced compound muscle action potentials (CMAPs), and compromised neuromuscular transmission. Additionally, fragmented and distorted NMJs were evident at both the light microscopic and electron microscopic levels. We found that anti-LRP4 sera decreased cell surface LRP4 levels, inhibited agrin-induced MuSK activation and AChR clustering, and activated complements, revealing potential pathophysiological mechanisms. To further confirm the pathogenicity of LRP4 antibodies, we transferred IgGs purified from LRP4-immunized rabbits into naive mice and found that they exhibited MG-like symptoms, including reduced CMAP and impaired neuromuscular transmission. Together, these data demonstrate that LRP4 autoantibodies induce MG and that LRP4 contributes to NMJ maintenance in adulthood. PMID:24200689

  8. LDL-receptor-related protein 4 is crucial for formation of the neuromuscular junction.

    PubMed

    Weatherbee, Scott D; Anderson, Kathryn V; Niswander, Lee A

    2006-12-01

    Low-density lipoprotein receptor-related protein 4 (Lrp4) is a member of a family of structurally related, single-pass transmembrane proteins that carry out a variety of functions in development and physiology, including signal transduction and receptor-mediated endocytosis. Lrp4 is expressed in multiple tissues in the mouse, and is important for the proper development and morphogenesis of limbs, ectodermal organs, lungs and kidneys. We show that Lrp4 is also expressed in the post-synaptic endplate region of muscles and is required to form neuromuscular synapses. Lrp4-mutant mice die at birth with defects in both presynaptic and postsynaptic differentiation, including aberrant motor axon growth and branching, a lack of acetylcholine receptor and postsynaptic protein clustering, and a failure to express postsynaptic genes selectively by myofiber synaptic nuclei. Our data show that Lrp4 is required during the earliest events in postsynaptic neuromuscular junction (NMJ) formation and suggest that it acts in the early, nerveindependent steps of NMJ assembly. The identification of Lrp4 as a crucial factor for NMJ formation may have implications for human neuromuscular diseases such as myasthenia syndromes. PMID:17119023

  9. LDL Receptor-Related Protein-1 (LRP1) Regulates Cholesterol Accumulation in Macrophages

    PubMed Central

    Lillis, Anna P.; Muratoglu, Selen Catania; Au, Dianaly T.; Migliorini, Mary; Lee, Mi-Jeong; Fried, Susan K.; Mikhailenko, Irina; Strickland, Dudley K.

    2015-01-01

    Within the circulation, cholesterol is transported by lipoprotein particles and is taken up by cells when these particles associate with cellular receptors. In macrophages, excessive lipoprotein particle uptake leads to foam cell formation, which is an early event in the development of atherosclerosis. Currently, mechanisms responsible for foam cell formation are incompletely understood. To date, several macrophage receptors have been identified that contribute to the uptake of modified forms of lipoproteins leading to foam cell formation, but the contribution of the LDL receptor-related protein 1 (LRP1) to this process is not known. To investigate the role of LRP1 in cholesterol accumulation in macrophages, we generated mice with a selective deletion of LRP1 in macrophages on an LDL receptor (LDLR)-deficient background (macLRP1-/-). After feeding mice a high fat diet for 11 weeks, peritoneal macrophages isolated from Lrp+/+ mice contained significantly higher levels of total cholesterol than those from macLRP1-/- mice. Further analysis revealed that this was due to increased levels of cholesterol esters. Interestingly, macLRP1-/- mice displayed elevated plasma cholesterol and triglyceride levels resulting from accumulation of large, triglyceride-rich lipoprotein particles in the circulation. This increase did not result from an increase in hepatic VLDL biosynthesis, but rather results from a defect in catabolism of triglyceride-rich lipoprotein particles in macLRP1-/- mice. These studies reveal an important in vivo contribution of macrophage LRP1 to cholesterol homeostasis. PMID:26061292

  10. Collagenase-3 binds to a specific receptor and requires the low density lipoprotein receptor-related protein for internalization

    NASA Technical Reports Server (NTRS)

    Barmina, O. Y.; Walling, H. W.; Fiacco, G. J.; Freije, J. M.; Lopez-Otin, C.; Jeffrey, J. J.; Partridge, N. C.

    1999-01-01

    We have previously identified a specific receptor for collagenase-3 that mediates the binding, internalization, and degradation of this ligand in UMR 106-01 rat osteoblastic osteosarcoma cells. In the present study, we show that collagenase-3 binding is calcium-dependent and occurs in a variety of cell types, including osteoblastic and fibroblastic cells. We also present evidence supporting a two-step mechanism of collagenase-3 binding and internalization involving both a specific collagenase-3 receptor and the low density lipoprotein receptor-related protein. Ligand blot analysis shows that (125)I-collagenase-3 binds specifically to two proteins ( approximately 170 kDa and approximately 600 kDa) present in UMR 106-01 cells. Western blotting identified the 600-kDa protein as the low density lipoprotein receptor-related protein. Our data suggest that the 170-kDa protein is a specific collagenase-3 receptor. Low density lipoprotein receptor-related protein-null mouse embryo fibroblasts bind but fail to internalize collagenase-3, whereas UMR 106-01 and wild-type mouse embryo fibroblasts bind and internalize collagenase-3. Internalization, but not binding, is inhibited by the 39-kDa receptor-associated protein. We conclude that the internalization of collagenase-3 requires the participation of the low density lipoprotein receptor-related protein and propose a model in which the cell surface interaction of this ligand requires a sequential contribution from two receptors, with the collagenase-3 receptor acting as a high affinity primary binding site and the low density lipoprotein receptor-related protein mediating internalization.

  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. Orphan Status, HIV Risk Behavior, and Mental Health Among Adolescents in Rural Kenya

    PubMed Central

    Drabkin, Anya S.; Stashko, Allison L.; Broverman, Sherryl A.; Ogwang-Odhiambo, Rose A.; Sikkema, Kathleen J.

    2012-01-01

    Objective To examine orphan status, mental health, social support, and HIV risk among adolescents in rural Kenya. Methods Randomly selected adolescents aged 10–18 years completed surveys assessing sexual activity, sex-related beliefs and self-efficacy, mental health, social support, caregiver–child communication, time since parental death, and economic resources. Analysis of covariance and regression analyses compared orphans and nonorphans; orphan status was tested as a moderator between well-being and HIV risk. Results Orphans reported poorer mental health, less social support, and fewer material resources. They did not differ from nonorphans on HIV risk indicators. Longer time since parental death was associated with poorer outcomes. In moderator analyses, emotional problems and poorer caregiver–youth communication were more strongly associated with lower sex-related self-efficacy for orphans. Conclusions Orphans are at higher risk for psychosocial problems. These problems may affect orphans’ self-efficacy for safer sex practices more than nonorphans. Decreased HIV risk could be one benefit of psychosocial interventions for orphans. PMID:22728899

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

    PubMed

    Ardington, Cally; Leibbrandt, Murray

    2010-04-01

    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

  14. No difference in between-country variability in use of newly approved orphan and non- orphan medicinal products - a pilot study

    PubMed Central

    2009-01-01

    Background Regulators and payers have to strike a balance between the needs of the patient and the optimal allocation of resources. Drugs indicated for rare diseases (orphan medicines) are a special group in this context because of their often high per unit costs. Our objective in this pilot study was to determine, for drugs used in an outpatient setting, how utilisation of centrally authorised drugs varies between countries across a selection of EU member states. Methods We randomly selected five orphan medicines and nine other drugs that were centrally authorised in the European Union between January 2000 and November 2006. We compared utilisation of these drugs in six European Union member states: Austria, Denmark, Finland, Portugal, The Netherlands, and Sweden. Utilisation data were expressed as Defined Daily Doses per 1000 persons per year. Variability in use across countries was determined by calculating the relative standard deviation for the utilisation rates of individual drugs across countries. Results No association between orphan medicine status and variability in use across countries was found (P = 0.52). Drugs with an orphan medicine status were more expensive and had a higher innovation score than drugs without an orphan medicine status. Conclusions The results show that the variability in use of orphan medicines in the different health care systems of the European Union appears to be comparable to the other newly authorised drugs that were included in the analysis. This means that, although strong heterogeneity in access may exist, this heterogeneity is not specific for drugs with an orphan status. PMID:20003427

  15. Orphan Toxin OrtT (YdcX) of Escherichia coli Reduces Growth during the Stringent Response

    PubMed Central

    Islam, Sabina; Benedik, Michael J.; Wood, Thomas K.

    2015-01-01

    Toxin/antitoxin (TA) systems are nearly universal in prokaryotes; toxins are paired with antitoxins which inactivate them until the toxins are utilized. Here we explore whether toxins may function alone; i.e., whether a toxin which lacks a corresponding antitoxin (orphan toxin) is physiologically relevant. By focusing on a homologous protein of the membrane-damaging toxin GhoT of the Escherichia coli GhoT/GhoS type V TA system, we found that YdcX (renamed OrtT for orphan toxin related to tetrahydrofolate) is toxic but is not part of TA pair. OrtT is not inactivated by neighboring YdcY (which is demonstrated to be a protein), nor is it inactivated by antitoxin GhoS. Also, OrtT is not inactivated by small RNA upstream or downstream of ortT. Moreover, screening a genomic library did not identify an antitoxin partner for OrtT. OrtT is a protein and its toxicity stems from membrane damage as evidenced by transmission electron microscopy and cell lysis. Furthermore, OrtT reduces cell growth and metabolism in the presence of both antimicrobials trimethoprim and sulfamethoxazole; these antimicrobials induce the stringent response by inhibiting tetrahydrofolate synthesis. Therefore, we demonstrate that OrtT acts as an independent toxin to reduce growth during stress related to amino acid and DNA synthesis. PMID:25643179

  16. Determination of Alkali-Sensing Parts of the Insulin Receptor-Related Receptor Using the Bioinformatic Approach

    PubMed Central

    Deyev, I. E.; Popova, N. V.; Petrenko, A. G.

    2015-01-01

    IRR (insulin receptor-related receptor) is a receptor tyrosine kinase belonging to the insulin receptor family, which also includes insulin receptor and IGF-IR receptor. We have previously shown that IRR is activated by extracellular fluid with pH > 7.9 and regulates excess alkali excretion in the body. We performed a bioinformatic analysis of the pH-sensitive potential of all three members of the insulin receptor family of various animal species (from frog to man) and their chimeras with swapping of different domains in the extracellular region. An analysis using the AcalPred program showed that insulin receptor family proteins are divided into two classes: one class with the optimal working pH in the acidic medium (virtually all insulin receptor and insulin-like growth factor receptor orthologs, except for the IGF-IR ortholog from Xenopus laevis) and the second class with the optimal working pH in the alkaline medium (all IRR orthologs). The program had predicted that the most noticeable effect on the pH-sensitive property of IRR would be caused by the replacement of the L1 and C domains in its extracellular region, as well as the replacement of the second and third fibronectin repeats. It had also been assumed that replacement of the L2 domain would have the least significant effect on the alkaline sensitivity of IRR. To test the in silico predictions, we obtained three constructs with swapping of the L1C domains, the third L2 domain, and all three domains L1CL2 of IRR with similar domains of the insulin-like growth factor receptor. We found that replacement of the L1C and L1CL2 domains reduces the receptor’s ability to be activated with alkaline pH, thus increasing the half-maximal effective concentration by about 100%. Replacement of the L2 domain increased the half-maximal effective concentration by 40%. Thus, our results indicate the high predictive potential of the AcalPred algorithm, not only for the pH-sensitive enzymes, but also for p

  17. Health of adults caring for orphaned children in an HIV-endemic community in South Africa.

    PubMed

    Kuo, Caroline; Operario, Don

    2011-09-01

    In South Africa, an estimated 2.5 million children have been orphaned by AIDS and other causes of adult mortality. Although there is a growing body of research on the well-being of South African orphaned children, few research studies have examined the health of adult individuals caring for children in HIV-endemic communities. The cross-sectional survey assessed prevalence of general health and functioning (based on Short-Form 36 version 2 scale), depression (based on Center for Epidemiologic Studies-Depression scale), anxiety (using Kessler-10 scale), and post-traumatic stress (using the Harvard Trauma Questionnaire) among a representative community sample of adults caring for children in Umlazi Township, an HIV-endemic community in South Africa. Of 1599 respondents, 33% (n=530) were carers of orphaned children. Results showed that, overall, carers reported poor general health and functioning and elevated levels of depression, anxiety, and post-traumatic stress. Carers of orphaned children reported significantly poorer general health and functioning and higher rates of depression and post-traumatic stress compared with carers of non-orphaned children. In multivariate analyses, orphan carer and non-orphan carer differences in general health were accounted for by age, gender, education, economic assets, and source of income, but differences in depression were independent of these cofactors. Interventions are needed to address physical and mental health of carers in general. Greater health problems among orphan carers appeared to be fully explained by socioeconomic characteristics, which offer opportunities for targeting of programs. More research is needed to understand determinants of mental health disparities among orphan carers, which were not explained by socioeconomic characteristics. PMID:21480009

  18. 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

  19. 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

  20. 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.

  1. Characteristics of orphan drug applications that fail to achieve marketing approval in the USA.

    PubMed

    Heemstra, Harald E; Leufkens, Hubert G M; Rodgers, R P Channing; Xu, Kui; Voordouw, Bettie C G; Braun, M Miles

    2011-01-01

    The US Orphan Drug Act has fostered the development of drugs for patients with rare diseases by granting 'orphan designations', although several orphan drugs for which a marketing application has been submitted to the FDA have failed to obtain approval. This study identified the clinical trial design, the level of experience of the sponsor and the level of interaction with the FDA to be associated with non-approval. Sponsors, therefore, should engage in dialogue with the FDA and thoughtfully design pivotal clinical trials in accordance with FDA guidance documents. PMID:21094692

  2. 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

  3. 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.

  4. 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

  5. Effectiveness, safety and costs of orphan drugs: an evidence-based review

    PubMed Central

    Onakpoya, Igho J; Spencer, Elizabeth A; Thompson, Matthew J; Heneghan, Carl J

    2015-01-01

    Introduction Several orphan drugs have been approved by the European Medicines Agency (EMA) over the past two decades. However, the drugs are expensive, and in some instances, the evidence for effectiveness is not convincing at the time of regulatory approval. Our objective was to evaluate the clinical effectiveness of orphan drugs that have been granted marketing licenses in Europe, determine the annual costs of each drug, compare the costs of branded orphan drugs against their generic equivalents, and explore any relationships between orphan drug disease prevalence and annual costs. Methods We searched the EMA database to identify orphan drugs granted marketing authorisation up to April 2014. Electronic searches were also conducted in PubMed, EMBASE and Google Scholar, to assess data on effectiveness, safety and annual costs. 2 reviewers independently evaluated the levels and quality of evidence, and extracted data. Results We identified 74 orphan drugs, with 54 (73%) demonstrating moderate quality of evidence. 85% showed significant clinical effects, but serious adverse events were reported in 86.5%. Their annual costs were between £726 and £378 000. There was a significant inverse relationship between disease prevalence and annual costs (p=0.01); this was largely due to the influence of the ultra-orphan diseases. We could not determine whether the balance between effectiveness and safety influenced annual costs. For 10 drugs where generic alternatives were available, the branded drugs were 1.4 to 82 000 times more expensive. Conclusions The available evidence suggests that there is inconsistency in the quality of evidence of approved orphan drugs, and there is no clear mechanism for determining their prices. In some cases, far cheaper generic agents appear to be available. A more robust, transparent and standard mechanism for determining annual costs is imperative. PMID:26109112

  6. Strategies for providing care and support to children orphaned by AIDS.

    PubMed

    Drew, R S; Makufa, C; Foster, G

    1998-04-01

    As a result of the severe HIV/AIDS epidemic in sub-Saharan countries such as Zimbabwe, where between 25-30% of the adult population are estimated to be infected, there are a growing number of orphans requiring care and support. Traditionally, orphans have been absorbed within the extended family but this is becoming more difficult because of the large number of young adults dying. The burden of care and support is falling on the very young and the very old. A number of strategies have been introduced to provide this care and support. Institutions, though popular, are very expensive to run, have limited capacity and only really cater for physical needs. Interventions which simply react to those who present to them may not reach the most needy and may encourage dependency. Community-based orphan care has been identified as the best and most cost-effective way of caring for orphans. An example of a community-based orphan visiting programme is presented. In the last six months of 1996, the FOCUS programme's 88 volunteers made a total of 9,634 visits to 3,192 orphans in 798 families at an average cost of US+1.55 per visit. The key elements of such programmes have been identified. They need to be implemented by a community-based organization (CBO) within a defined community. Volunteers should be selected from within the community. They need to be trained and supported as they enumerate orphans, identify the most needy and carry out regular visits. The volunteers should keep records of all their activities. These records can then be used as a basis for monitoring the programme. In order to cope with the increasing number of orphans in resource-poor settings like Zimbabwe, it is essential that such programmes be replicated and scaled up. This not only an economic necessity but is also a way of providing appropriate and effective services to those who need them. PMID:9625890

  7. 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

  8. 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

  9. 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. PMID:24855866

  10. 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. PMID:25767802

  11. The "hidden patient": older relatives raising children orphaned by AIDS.

    PubMed

    Joslin, D; Harrison, R

    1998-01-01

    In the United States today, thousands of grandmothers and other third- and fourth-generation relatives are raising children and adolescents whose primary parent, usually the mothers, has died from acquired immune deficiency syndrome (AIDS) or is too ill to serve as the primary parent. More than 100,000 children below the age of 18 are expected to lose their mothers to AIDS by the year 2000, most in poor communities. Isolated by the demands of caregiving, child care, and the stigma of AIDS on even uninfected family members, this group of older surrogate parents is at risk not only for chronic conditions and stress-related somatic complaints, but for neglected health. Using the gerontological concept of the "hidden patient," this article presents four cases drawn from an exploratory study of the physical and emotional health risks and health behaviors of older adults raising children orphaned by AIDS. External and internal barriers to self-care are described, including lack of child and respite care and health insurance, caregiver depression, and denial of health problems. PMID:9595898

  12. 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

  13. Care arrangements of AIDS orphans and their relationship with children's psychosocial well-being in rural China.

    PubMed

    Hong, Yan; Li, Xiaoming; Fang, Xiaoyi; Zhao, Guoxiang; Zhao, Junfeng; Zhao, Qun; Lin, Xiuyun; Zhang, Liying; Stanton, Bonita

    2011-03-01

    There is an estimated 100,000 children orphaned by AIDS in China, but data on the care arrangement of these orphans are limited. In this study, we examine the relationship between AIDS orphans' care arrangement and their psychosocial well-being among a sample of AIDS orphans in rural China. A total of 296 children who lost both parents to AIDS participated in the study, including 176 in orphanages, 90 in kinship care and 30 in community-based group homes. All participants completed a cross-sectional survey assessing their traumatic symptoms, physical health and schooling. Data reveal that the AIDS orphans in group homes reported the best outcomes in three domains of psychosocial well-being, followed by those in the orphanages and then the kinship care. The differences in psychosocial well-being among the three groups of children persist after controlling for key demographic characteristics. The findings suggest that the appropriate care arrangement for AIDS orphans should be evaluated within the specific social and cultural context where the orphans live. In resource-poor regions or areas stricken hardest by the AIDS epidemic, kinship care may not sufficiently serve the needs of AIDS orphans. Community-based care models, with appropriate government and community support preserving the family style and low child-to-caregiver ratio may constitute an effective and sustainable care model for the best interest of the AIDS orphans in developing countries. PMID:20587602

  14. 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.

  15. Utilizing the Antarctic Master Directory to find orphan datasets

    NASA Astrophysics Data System (ADS)

    Bonczkowski, J.; Carbotte, S. M.; Arko, R. A.; Grebas, S. K.

    2011-12-01

    While most Antarctic data are housed at an established disciplinary-specific data repository, there are data types for which no suitable repository exists. In some cases, these "orphan" data, without an appropriate national archive, are served from local servers by the principal investigators who produced the data. There are many pitfalls with data served privately, including the frequent lack of adequate documentation to ensure the data can be understood by others for re-use and the impermanence of personal web sites. For example, if an investigator leaves an institution and the data moves, the link published is no longer accessible. To ensure continued availability of data, submission to long-term national data repositories is needed. As stated in the National Science Foundation Office of Polar Programs (NSF/OPP) Guidelines and Award Conditions for Scientific Data, investigators are obligated to submit their data for curation and long-term preservation; this includes the registration of a dataset description into the Antarctic Master Directory (AMD), http://gcmd.nasa.gov/Data/portals/amd/. The AMD is a Web-based, searchable directory of thousands of dataset descriptions, known as DIF records, submitted by scientists from over 20 countries. It serves as a node of the International Directory Network/Global Change Master Directory (IDN/GCMD). The US Antarctic Program Data Coordination Center (USAP-DCC), http://www.usap-data.org/, funded through NSF/OPP, was established in 2007 to help streamline the process of data submission and DIF record creation. When data does not quite fit within any existing disciplinary repository, it can be registered within the USAP-DCC as the fallback data repository. Within the scope of the USAP-DCC we undertook the challenge of discovering and "rescuing" orphan datasets currently registered within the AMD. In order to find which DIF records led to data served privately, all records relating to US data within the AMD were parsed. After

  16. 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

  17. 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.

  18. Brief communication: Orphaned Male Chimpanzees die young even after weaning.

    PubMed

    Nakamura, Michio; Hayaki, Hitoshige; Hosaka, Kazuhiko; Itoh, Noriko; Zamma, Koichiro

    2014-01-01

    If a social-living animal has a long life span, permitting different generations to co-exist within a social group, as is the case in many primate species, it can be beneficial for a parent to continue to support its weaned offspring to increase the latter's survival and/or reproductive success. Chimpanzees have an even longer period of dependence on their mothers' milk than do humans, and consequently, offspring younger than 4.5-5 years old cannot survive if the mother dies. Most direct maternal investments, such as maternal transportation of infants and sharing of night shelters (beds or nests), end with nutritional weaning. Thus, it had been assumed that a mother's death was no longer critical to the survival of weaned offspring, in contrast to human children, who continue to depend on parental care long after weaning. However, in theory at least, maternal investment in a chimpanzee son after weaning could be beneficial because in chimpanzees' male-philopatric society, mother and son co-exist for a long time after the offspring's weaning. Using long-term demographic data for a wild chimpanzee population in the Mahale Mountains, Tanzania, we show the first empirical evidence that orphaned chimpanzee sons die younger than expected even if they lose their mothers after weaning. This suggests that long-lasting, but indirect, maternal investment in sons continues several years after weaning and is vital to the survival of the sons. The maternal influence on males in the male-philopatric societies of hominids may be greater than previously believed. PMID:24318948

  19. 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.

  20. Pyrolysis/Steam Reforming Technology for Treatment of TRU Orphan Wastes

    SciTech Connect

    Mason, J. B.; McKibbin, J.; Schmoker, D.; Bacala, P.

    2003-02-27

    Certain transuranic (TRU) waste streams within the Department of Energy (DOE) complex cannot be disposed of at the Waste Isolation Pilot Plant (WIPP) because they do not meet the shipping requirements of the TRUPACT-II or the disposal requirements of the Waste Analysis Plan (WAP) in the WIPP RCRA Part B Permit. These waste streams, referred to as orphan wastes, cannot be shipped or disposed of because they contain one or more prohibited items, such as liquids, volatile organic compounds (VOCs), hydrogen gas, corrosive acids or bases, reactive metals, or high concentrations of polychlorinated biphenyl (PCB), etc. The patented, non-incineration, pyrolysis and steam reforming processes marketed by THOR Treatment Technologies LLC removes all of these prohibited items from drums of TRU waste and produces a dry, inert, inorganic waste material that meets the existing TRUPACT-II requirements for shipping, as well as the existing WAP requirements for disposal of TRU waste at WIPP. THOR Treatment Technologies is a joint venture formed in June 2002 by Studsvik, Inc. (Studsvik) and Westinghouse Government Environmental Services Company LLC (WGES) to further develop and deploy Studsvik's patented THORSM technology within the DOE and Department of Defense (DoD) markets. The THORSM treatment process is a commercially proven system that has treated over 100,000 cu. ft. of nuclear waste from commercial power plants since 1999. Some of this waste has had contact dose rates of up to 400 R/hr. A distinguishing characteristic of the THORSM process for TRU waste treatment is the ability to treat drums of waste without removing the waste contents from the drum. This feature greatly minimizes criticality and contamination issues for processing of plutonium-containing wastes. The novel features described herein are protected by issued and pending patents.

  1. A novel economic intervention to reduce HIV risks among school-going AIDS orphans in rural Uganda.

    PubMed

    Ssewamala, Fred M; Alicea, Stacey; Bannon, William M; Ismayilova, Leyla

    2008-01-01

    This study tested an economic intervention to reduce HIV risks among AIDS-orphaned adolescents. Adolescents (n = 96) were randomly assigned to receive the intervention or usual care for orphans in Uganda. Data obtained at baseline and 12-month follow-up revealed significant differences between the treatment and control groups in HIV prevention attitudes and educational planning. PMID:18155037

  2. 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

    ... HUMAN SERVICES Food and Drug Administration The Food and Drug Administration/European Medicines Agency Orphan Product Designation and Grant Public Workshop AGENCY: Food and Drug Administration, HHS. ACTION: Notice of public workshop. The Food and Drug Administration's (FDA) Office of Orphan Products...

  3. 77 FR 52744 - Food and Drug Administration/European Medicines Agency Orphan Product Designation and Grant Workshop

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-08-30

    ... HUMAN SERVICES Food and Drug Administration Food and Drug Administration/European Medicines Agency Orphan Product Designation and Grant Workshop AGENCY: Food and Drug Administration, HHS. ACTION: Notice of meeting. The Food and Drug Administration's (FDA) Office of Orphan Products Development...

  4. 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…

  5. 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.

  6. 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.

  7. 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

  8. Orphan CpG islands identify numerous conserved promoters in the mammalian genome.

    PubMed

    Illingworth, Robert S; Gruenewald-Schneider, Ulrike; Webb, Shaun; Kerr, Alastair R W; James, Keith D; Turner, Daniel J; Smith, Colin; Harrison, David J; Andrews, Robert; Bird, Adrian P

    2010-09-01

    CpG islands (CGIs) are vertebrate genomic landmarks that encompass the promoters of most genes and often lack DNA methylation. Querying their apparent importance, the number of CGIs is reported to vary widely in different species and many do not co-localise with annotated promoters. We set out to quantify the number of CGIs in mouse and human genomes using CXXC Affinity Purification plus deep sequencing (CAP-seq). We also asked whether CGIs not associated with annotated transcripts share properties with those at known promoters. We found that, contrary to previous estimates, CGI abundance in humans and mice is very similar and many are at conserved locations relative to genes. In each species CpG density correlates positively with the degree of H3K4 trimethylation, supporting the hypothesis that these two properties are mechanistically interdependent. Approximately half of mammalian CGIs (>10,000) are "orphans" that are not associated with annotated promoters. Many orphan CGIs show evidence of transcriptional initiation and dynamic expression during development. Unlike CGIs at known promoters, orphan CGIs are frequently subject to DNA methylation during development, and this is accompanied by loss of their active promoter features. In colorectal tumors, however, orphan CGIs are not preferentially methylated, suggesting that cancer does not recapitulate a developmental program. Human and mouse genomes have similar numbers of CGIs, over half of which are remote from known promoters. Orphan CGIs nevertheless have the characteristics of functional promoters, though they are much more likely than promoter CGIs to become methylated during development and hence lose these properties. The data indicate that orphan CGIs correspond to previously undetected promoters whose transcriptional activity may play a functional role during development. PMID:20885785

  9. 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.

  10. 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.

  11. 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

  12. Perceived social support and the psychological well-being of AIDS orphans in urban Kenya.

    PubMed

    Okawa, Sumiyo; Yasuoka, Junko; Ishikawa, Naoko; Poudel, Krishna C; Ragi, Allan; Jimba, Masamine

    2011-09-01

    Parental deaths due to AIDS seriously affect the psychological well-being of children. Social support may provide an effective resource in the care of vulnerable children in resource-limited settings. However, few studies have examined the relationships between social support and psychological well-being among AIDS orphans. This cross-sectional study was conducted to explore associations between perceived social support (PSS) and the psychological well-being of AIDS orphans, and to identify socio-demographic factors that are associated with PSS. Data were collected from 398 pairs of AIDS orphans (aged 10-18 years) and their caregivers in Nairobi, Kenya. The participants provided information on their socio-demographic characteristics, the children's PSS, and the children's psychological status (based on measures of depressive symptoms and self-esteem). Of the 398 pairs, 327 were included in the analysis. PSS scores of AIDS orphans showed significant correlations with depressive symptoms (ρ =-0.31, p<0.001) and self-esteem (ρ=0.32, p<0.001). Socio-demographic factors, such as HIV-positive status of children (β=3.714, p=0.014) and cohabitation with siblings (β=3.044, p=0.016), were also associated with higher PSS scores. In particular, HIV-infected children (n=37) had higher scores of PSS from a special person (β=2.208, p=0.004), and children living with biological siblings (n=269) also had higher scores of PSS from both a special person (β=1.411, p=0.029) and friends (β=1.276, p=0.039). In conclusion, this study showed that PSS is positively associated with the psychological well-being of AIDS orphans. Siblings and special persons can be effective sources of social support for AIDS orphans, which help to promote their psychological well-being. PMID:21500024

  13. Does the Orphan Disadvantage “Spill Over?” An analysis of whether living in an area with a higher concentration of orphans is associated with children’s school enrollment in sub-Saharan Africa

    PubMed Central

    Smith-Greenaway, Emily; Heckert, Jessica

    2013-01-01

    BACKGROUND Despite considerable concern regarding the social consequences of sub-Saharan Africa’s high orphan prevalence, no research investigates how living in a community densely populated with orphans is more broadly associated with children’s—including nonorphans’—acquisition of human capital. OBJECTIVE We provide a new look at the implications of widespread orphanhood in sub-Saharan Africa by examining whether living in an area with a high concentration of orphans is associated with children’s likelihood of school enrollment. METHODS We use data from the Demographic and Health Survey (DHS) and the Multiple Indicators Cluster Survey (MICS) to estimate multilevel logistic regression models to assess whether living in a setting with a higher concentration of orphans is associated with school enrollment among 383,010 children in 336 provinces in 34 sub-Saharan African countries. RESULTS Orphan concentration has a curvilinear association with children’s school enrollment in western and eastern Africa: the initially positive association becomes negative at higher levels. In central and southern Africa, orphan concentration has a positive linear association with children’s school enrollment. CONCLUSION In western and eastern Africa, the negative association between living in a setting more densely populated with orphans and children’s school enrollment provides suggestive evidence that the orphan disadvantage “spills over” in the communities most heavily affected. Conversely, in central and southern Africa, the positive association between living in a setting more densely populated with orphans and children’s school enrollment highlights the resiliency of these relatively wealthier communities with high levels of orphans. Although longitudinal research is needed to confirm these findings and clarify the underlying mechanisms, this study lays the groundwork for a new body of research aimed at understanding the broader social implications of

  14. 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

  15. 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

  16. Educational Outcomes for Orphan Girls in Rural Zimbabwe: Effects of a School Support Intervention.

    PubMed

    Iritani, Bonita J; Cho, Hyunsan; Rusakaniko, Simbarashe; Mapfumo, John; Hartman, Shane; Hallfors, Denise Dion

    2016-03-01

    Educational achievement has important implications for the health and well-being of young women in sub-Saharan Africa. The authors assessed the effects of providing school support on educational outcomes of orphan girls in rural Zimbabwe. Data were from a randomized controlled trial offering the intervention group comprehensive schooling support and controls no treatment initially and then fees only. Results indicated comprehensive support reduced school dropout and absence but did not improve test scores. Providing support to orphan girls is promising for addressing World Health Organization Millennium Development Goals, but further research is needed about contextual factors affecting girls' school participation and learning. PMID:25692731

  17. Expression of a Drosophila melanogaster acetylcholine receptor-related gene in the central nervous system

    SciTech Connect

    Wadsworth, S.C.; Rosenthal, L.S.; Kammermeyer, K.L.; Potter, M.B.; Nelson, D.J.

    1988-02-01

    The authors isolated Drosophila melanogaster genomic sequences with nucleotide and amino acid sequence homology to subunits of vertebrate acetylcholine receptor by hybridization with a Torpedo acetylcholine receptor subunit cDNA probe. Five introns are present in the portion of the Drosophila gene encoding the unprocessed protein and are positionally conserved relative to the human acetylcholine receptor alpha-subunit gene. The Drosophila genomic clone hybridized to salivary gland polytene chromosome 3L within region 64B and was termed AChR64B. A 3-kilobasae poly(A)-containing transcript complementary to the AChR64B clone was readily detectable by RNA blot hybridizations during midembryogenesis, during metamorphosis, and in newly enclosed adults. AChR64B transcripts were localized to the cellular regions of the central nervous system during embryonic, larval, pupal, and adult stages of development. During metamorphosis, a temporal relationship between the morphogenesis of the optic lobe and expression of AChR64B transcripts was observed.

  18. 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…

  19. 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,…

  20. The role of globalization in drug development and access to orphan drugs: orphan drug legislation in the US/EU and in Latin America.

    PubMed

    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

  1. 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

  2. Expression of low density lipoprotein receptor-related protein 4 (Lrp4) gene in the mouse germ cells.

    PubMed

    Yamaguchi, Yasuka L; Tanaka, Satomi S; Kasa, Miyuki; Yasuda, Kunio; Tam, Patrick P L; Matsui, Yasuhisa

    2006-08-01

    The low density lipoprotein receptor-related protein 4 gene (Lrp4) was identified by subtractive screening of cDNAs of the migratory primordial germ cells (PGCs) of E8.5-9.5 embryo and E3.5 blastocysts. Lrp4 is expressed in PGCs in the hindgut and the dorsal mesentery of E9.5 embryos, and in germ cells in the genital ridges of male and female E10.5-13.5 embryos. Lrp4 is also expressed in spermatogonia of the neonatal and adult testes and in the immature oocytes and follicular cells of the adult ovary. The absence of Lrp4 expression in the blastocyst, embryonic stem cells and embryonic germ cells suggests the Lrp4 is a molecular marker that distinguishes the germ cells from embryo-derived pluripotent stem cells. PMID:16434236

  3. Interaction of the apolipoprotein E receptors low density lipoprotein receptor-related protein and sorLA/LR11.

    PubMed

    Spoelgen, R; Adams, K W; Koker, M; Thomas, A V; Andersen, O M; Hallett, P J; Bercury, K K; Joyner, D F; Deng, M; Stoothoff, W H; Strickland, D K; Willnow, T E; Hyman, B T

    2009-02-18

    In this study, we examined protein-protein interactions between two neuronal receptors, low density lipoprotein receptor-related protein (LRP) and sorLA/LR11, and found that these receptors interact, as indicated by three independent lines of evidence: co-immunoprecipitation experiments on mouse brain extracts and mouse neuronal cells, surface plasmon resonance analysis with purified human LRP and sorLA, and fluorescence lifetime imaging microscopy (FLIM) on rat primary cortical neurons. Immunocytochemistry experiments revealed widespread co-localization of LRP and sorLA within perinuclear compartments of rat primary neurons, while FLIM analysis showed that LRP-sorLA interactions take place within a subset of these compartments. PMID:19047013

  4. Convergent Signaling Pathways Controlled by LRP1 (Receptor-related Protein 1) Cytoplasmic and Extracellular Domains Limit Cellular Cholesterol Accumulation.

    PubMed

    El Asmar, Zeina; Terrand, Jérome; Jenty, Marion; Host, Lionel; Mlih, Mohamed; Zerr, Aurélie; Justiniano, Hélène; Matz, Rachel L; Boudier, Christian; Scholler, Estelle; Garnier, Jean-Marie; Bertaccini, Diego; Thiersé, Danièle; Schaeffer, Christine; Van Dorsselaer, Alain; Herz, Joachim; Bruban, Véronique; Boucher, Philippe

    2016-03-01

    The low density lipoprotein receptor-related protein 1 (LRP1) is a ubiquitously expressed cell surface receptor that protects from intracellular cholesterol accumulation. However, the underlying mechanisms are unknown. Here we show that the extracellular (α) chain of LRP1 mediates TGFβ-induced enhancement of Wnt5a, which limits intracellular cholesterol accumulation by inhibiting cholesterol biosynthesis and by promoting cholesterol export. Moreover, we demonstrate that the cytoplasmic (β) chain of LRP1 suffices to limit cholesterol accumulation in LRP1(-/-) cells. Through binding of Erk2 to the second of its carboxyl-terminal NPXY motifs, LRP1 β-chain positively regulates the expression of ATP binding cassette transporter A1 (ABCA1) and of neutral cholesterol ester hydrolase (NCEH1). These results highlight the unexpected functions of LRP1 and the canonical Wnt5a pathway and new therapeutic potential in cholesterol-associated disorders including cardiovascular diseases. PMID:26792864

  5. 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…

  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. 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

  8. 21 CFR 316.20 - Content and format of a request for orphan-drug designation.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... agent including title, address, and telephone number; the generic and trade name, if any, of the drug or... 21 Food and Drugs 5 2012-04-01 2012-04-01 false Content and format of a request for orphan-drug designation. 316.20 Section 316.20 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND...

  9. 21 CFR 316.20 - Content and format of a request for orphan-drug designation.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... agent including title, address, and telephone number; the generic and trade name, if any, of the drug or... 21 Food and Drugs 5 2013-04-01 2013-04-01 false Content and format of a request for orphan-drug designation. 316.20 Section 316.20 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND...

  10. 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…

  11. 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.…

  12. 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…

  13. The orphaning experience: descriptions from Ugandan youth who have lost parents to HIV/AIDS.

    PubMed

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

    2010-01-01

    The HIV/AIDS epidemic has continued to pose significant challenges to countries in Sub-Saharan Africa. Millions of African children and youth have lost parents to HIV/AIDS leaving a generation of orphans to be cared for within extended family systems and communities. The experiences of youth who have lost parents to the HIV/AIDS epidemic provide an important ingress into this complex, evolving, multi-dimensional phenomenon. A fundamental qualitative descriptive study was conducted to develop a culturally relevant and comprehensive description of the experiences of orphanhood from the perspectives of Ugandan youth. A purposeful sample of 13 youth who had lost one or both parents to HIV/AIDS and who were affiliated with a non-governmental organization providing support to orphans were interviewed. Youth orphaned by HIV/AIDS described the experience of orphanhood beginning with parental illness, not death. Several losses were associated with the death of a parent including lost social capitol, educational opportunities and monetary assets. Unique findings revealed that youth experienced culturally specific stigma and conflict which was distinctly related to their HIV/AIDS orphan status. Exploitation within extended cultural family systems was also reported. Results from this study suggest that there is a pressing need to identify and provide culturally appropriate services for these Ugandan youth prior to and after the loss of a parent(s). PMID:20205893

  14. 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

  15. 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…

  16. 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…

  17. 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…

  18. 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…

  19. 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…

  20. 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…

  1. 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…

  2. 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...

  3. 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…

  4. 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...

  5. 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

  6. 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…

  7. The Socioemotional Development of Orphans in Orphanages and Traditional Foster Care in Iraqi Kurdistan.

    ERIC Educational Resources Information Center

    Ahmad, Abdulbaghi; Mohamad, Kirmanj

    1996-01-01

    A one-year follow-up study of children who had lost both parents and were placed in orphanages (n=19) or foster homes (n=18) in Iraqi Kurdistan investigated the orphans' situation and development. The children in orphanages were found to have higher frequency of post-traumatic stress disorder than the foster care children. (Author/CR)

  8. 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…

  9. 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

  10. 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

  11. Orphans and Vulnerable Children in Kenya: Results From a Nationally Representative Population-Based Survey

    PubMed Central

    Lee, Veronica C.; Muriithi, Patrick; Gilbert-Nandra, Ulrike; Kim, Andrea A.; Schmitz, Mary E.; Odek, James; Mokaya, Rose; Galbraith, Jennifer S.

    2016-01-01

    Background In Kenya, it is estimated that there are approximately 3.6 million children aged <18 years who have been orphaned or who are vulnerable. We examined the data from the second Kenya AIDS Indicator Survey (KAIS 2012) to determine the number and profile of orphans and vulnerable children (OVC) in Kenya who were aged <18 years. Methods KAIS 2012 was a nationally representative, population-based household survey. We analyzed the data for all the children from birth to age 17 years who resided in an eligible household so as to determine whether their parents were alive or had been very ill to define their OVC status. Results We estimated that there were 2.6 million OVC in Kenya in 2012, of whom 1.8 million were orphans and 750,000 were vulnerable. Among orphans, 15% were double orphans. Over one-third of all the OVC were aged between 10 and 14 years. Households with ≥1 OVC (12% of all households) were usually in the lowest 2 wealth quintiles, and 22% of OVC households had experienced moderate or severe hunger. Receipt of OVC support services was low for medical (3.7%), psychological (4.1%), social (1.3%), and material support (6.2%); educational support was slightly more common (11.5%). Orphanhood among children aged <15 years increased from 1993 to 2003 (P < 0.01) but declined from 2003 to 2012 (P < 0.01). Conclusions The 2.6 million OVC constitute a significant proportion of Kenya’s population aged <18 years. Special attention should be paid to OVC to prevent further vulnerability and ensure their well-being and development as they transition into adulthood. PMID:24732824

  12. 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.

  13. Establishing medical plausibility in the context of orphan medicines designation in the European Union.

    PubMed

    Tsigkos, Stelios; Mariz, Segundo; Llinares, Jordi; Fregonese, Laura; Aarum, Stiina; Naumann-Winter, Frauke; Frauke, Naumann-Winter; Westermark, Kerstin; Sepodes, Bruno

    2014-01-01

    In the European Union, sponsors have the responsibility to demonstrate the "intention to diagnose, prevent or treat" a serious and rare condition before the Committee of Orphan Medicinal Products (COMP), for a medicinal product to meet the criteria for Orphan Designation. This requirement is commonly referred to as "medical plausibility" and the justification of this intention is assessed on the merits of each application by the COMP, which deliberates over the scientific evaluation of the evidence submitted. The scientific assessment of the applications for orphan designation by the Committee is based on the review of non-clinical (such as in vitro and in vivo) and/or clinical data submitted by the sponsor. Several challenges regarding the evidence provided emerge when the sponsor is applying for a designation at an early stage of development. Herein we discuss specific examples from the experience of the COMP, in order to elaborate on the type and level of evidence generally considered necessary for the purpose of justification of the intention to treat an orphan condition. Importantly, it is pointed out that bridging of data from other products, irrespectively of how comparable they may be, or from settings not directly associated with the condition as applied for designation, is by and large not a successful exercise and may only be exceptionally considered. It is further exemplified that, as reflected in the updated 'Guideline on the format and context of the applications for designation' and the guidance document 'Recommendation on elements required to support the medical plausibility and the assumption of significant benefit for an orphan designation' available on the EMA website, the sponsor should provide data with the specific product as applied for in specific models of the condition or in patients affected by the same condition subject of each application. PMID:25475155

  14. 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

  15. Effect of an Orphan Response Regulator on Streptococcus mutans Sucrose-Dependent Adherence and Cariogenesis

    PubMed Central

    Idone, Vincent; Brendtro, Stacy; Gillespie, Robert; Kocaj, Steve; Peterson, Erica; Rendi, Mara; Warren, Wayne; Michalek, Suzanne; Krastel, Kirsten; Cvitkovitch, Dennis; Spatafora, Grace

    2003-01-01

    Streptococcus mutans is the principal acidogenic component of dental plaque that demineralizes tooth enamel, leading to dental decay. Cell-associated glucosyltransferases catalyze the sucrose-dependent synthesis of sticky glucan polymers that, together with glucan binding proteins, promote S. mutans adherence to teeth and cell aggregation. We generated an S. mutans Tn916 transposon mutant, GMS315, which is defective in sucrose-dependent adherence and significantly less cariogenic than the UA130 wild-type progenitor in germfree rats. The results of sodium dodecyl sulfate-polyacrylamide gel electrophoresis, Western blotting, and N-terminal sequence analysis confirmed the absence of a 155-kDa glucosyltransferase S (Gtf-S) from GMS315 protein profiles. Mapping of the unique transposon insertion in GMS315 revealed disruption of a putative regulatory region located upstream of gcrR, a gene previously described by Sato et al. that shares significant amino acid identity with other bacterial response regulators (Y. Sato, Y. Yamamoto, and H. Kizaki, FEMS Microbiol. Lett. 186: 187-191, 2000). The gcrR regulator, which we call “tarC,” does not align with any of the 13 proposed two-component signal transduction systems derived from in silico analysis of the S. mutans genome, but rather represents one of several orphan response regulators in the genome. The results of Northern hybridization and/or real-time reverse transcription-PCR experiments reveal increased expression of both Gtf-S and glucan binding protein C (GbpC) in a tarC knockout mutant (GMS900), thereby supporting the notion that TarC acts as a negative transcriptional regulator. In addition, we noted that GMS900 has altered biofilm architecture relative to the wild type and is hypocariogenic in germfree rats. Taken collectively, these findings support a role for signal transduction in S. mutans sucrose-dependent adherence and aggregation and implicate TarC as a potential target for controlling S. mutans

  16. Orphan nuclear receptor oestrogen-related receptor γ (ERRγ) plays a key role in hepatic cannabinoid receptor type 1-mediated induction of CYP7A1 gene expression.

    PubMed

    Zhang, Yaochen; Kim, Don-Kyu; Lee, Ji-Min; Park, Seung Bum; Jeong, Won-Il; Kim, Seong Heon; Lee, In-Kyu; Lee, Chul-Ho; Chiang, John Y L; Choi, Hueng-Sik

    2015-09-01

    Bile acids are primarily synthesized from cholesterol in the liver and have important roles in dietary lipid absorption and cholesterol homoeostasis. Detailed roles of the orphan nuclear receptors regulating cholesterol 7α-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis, have not yet been fully elucidated. In the present study, we report that oestrogen-related receptor γ (ERRγ) is a novel transcriptional regulator of CYP7A1 expression. Activation of cannabinoid receptor type 1 (CB1 receptor) signalling induced ERRγ-mediated transcription of the CYP7A1 gene. Overexpression of ERRγ increased CYP7A1 expression in vitro and in vivo, whereas knockdown of ERRγ attenuated CYP7A1 expression. Deletion analysis of the CYP7A1 gene promoter and a ChIP assay revealed an ERRγ-binding site on the CYP7A1 gene promoter. Small heterodimer partner (SHP) inhibited the transcriptional activity of ERRγ and thus regulated CYP7A1 expression. Overexpression of ERRγ led to increased bile acid levels, whereas an inverse agonist of ERRγ, GSK5182, reduced CYP7A1 expression and bile acid synthesis. Finally, GSK5182 significantly reduced hepatic CB1 receptor-mediated induction of CYP7A1 expression and bile acid synthesis in alcohol-treated mice. These results provide the molecular mechanism linking ERRγ and bile acid metabolism. PMID:26348907

  17. LDL Receptor-related Protein 1 Regulates the Abundance of Diverse Cell-signaling Proteins in the Plasma Membrane Proteome

    PubMed Central

    Gaultier, Alban; Simon, Gabriel; Niessen, Sherry; Dix, Melissa; Takimoto, Shinako; Cravatt, Benjamin F.; Gonias, Steven L.

    2010-01-01

    LDL receptor-related protein 1 (LRP1) is an endocytic receptor, reported to regulate the abundance of other receptors in the plasma membrane, including uPAR and tissue factor. The goal of this study was to identify novel plasma membrane proteins, involved in cell-signaling, which are regulated by LRP1. Membrane protein ectodomains were prepared from RAW 264.7 cells in which LRP1 was silenced and control cells using protease K. Peptides were identified by LC-MS/MS. By analysis of spectral counts, 31 transmembrane and secreted proteins were regulated in abundance at least 2-fold when LRP1 was silenced. Validation studies confirmed that semaphorin4D (Sema4D), plexin domain-containing protein-1 (Plxdc1), and neuropilin-1 were more abundant in the membranes of LRP1 gene-silenced cells. Regulation of Plxdc1 by LRP1 was confirmed in CHO cells, as a second model system. Plxdc1 co-immunoprecipitated with LRP1 from extracts of RAW 264.7 cells and mouse liver. Although Sema4D did not co-immunoprecipitate with LRP1, the cell-surface level of Sema4D was increased by RAP, which binds to LRP1 and inhibits binding of other ligands. These studies identify Plxdc1, Sema4D, and neuropilin-1 as novel LRP1-regulated cell-signaling proteins. Overall, LRP1 emerges as a generalized regulator of the plasma membrane proteome. PMID:20919742

  18. Directed differentiation of postnatal hippocampal neural stem cells generates nuclear receptor related-1 protein- and tyrosine hydroxylase-expressing cells

    PubMed Central

    Ding, Yinxiu; Zhang, Zixin; Ma, Jiangbo; Xia, Hechun; Wang, Yin; Liu, Yinming; Ma, Quanrui; Sun, Tao; Liu, Juan

    2016-01-01

    Parkinson's disease (PD) is a severe neurodegenerative disorder. Although the detailed underlying molecular mechanism remains to be elucidated, the major pathological feature of PD is the loss of dopaminergic (DA) neurons of the substantia nigra. The use of donor stem cells to replace DA neurons may be a key breakthrough in the treatment of PD. In the present study, the growth kinetics of hippocampal neural stem cells (Hip-NSCs) isolated from postnatal mice and cultured in vitro were observed, specifically the generation of cells expressing DA neuronal markers nuclear receptor related-1 protein (Nurr1) and tyrosine hydroxylase (TH). It was revealed that Hip-NSCs differentiated primarily into astrocytes when cultured in serum-containing medium. However, in low serum conditions, the number of βIII tubulin-positive neurons increased markedly. The proportion of Nurr1-positive cells and TH-positive neurons, significantly increased with increasing duration of directed differentiation of Hip-NSCs (P=0.0187 and 0.0254, respectively). The results of the present study reveal that Hip-NSCs may be induced to differentiate in vitro into neurons expressing Nurr1 and TH, known to be critical regulators of DA neuronal fate. Additionally, their expression may be necessary to facilitate neuronal maturation in vitro. These data suggest that Hip-NSCs may serve as a source of DA neurons for cell therapy in patients diagnosed with PD. PMID:27432537

  19. Glucocorticoid-Induced Tumour Necrosis Factor Receptor-Related Protein: A Key Marker of Functional Regulatory T Cells

    PubMed Central

    Ronchetti, Simona; Ricci, Erika; Petrillo, Maria Grazia; Cari, Luigi; Migliorati, Graziella; Nocentini, Giuseppe; Riccardi, Carlo

    2015-01-01

    Glucocorticoid-induced tumour necrosis factor receptor-related protein (GITR, TNFRSF18, and CD357) is expressed at high levels in activated T cells and regulatory T cells (Tregs). In this review, we present data from mouse and human studies suggesting that GITR is a crucial player in the differentiation of thymic Tregs (tTregs), and expansion of both tTregs and peripheral Tregs (pTregs). The role of GITR in Treg expansion is confirmed by the association of GITR expression with markers of memory T cells. In this context, it is not surprising that GITR appears to be a marker of active Tregs, as suggested by the association of GITR expression with other markers of Treg activation or cytokines with suppressive activity (e.g., IL-10 and TGF-β), the presence of GITR+ cells in tissues where Tregs are active (e.g., solid tumours), or functional studies on Tregs. Furthermore, some Treg subsets including Tr1 cells express either low or no classical Treg markers (e.g., FoxP3 and CD25) and do express GITR. Therefore, when evaluating changes in the number of Tregs in human diseases, GITR expression must be evaluated. Moreover, GITR should be considered as a marker for isolating Tregs. PMID:25961057

  20. The low density lipoprotein receptor-related protein 1: Unique tissue-specific functions revealed by selective gene knockout studies

    PubMed Central

    Lillis, Anna P.; Van Duyn, Lauren B.; Murphy-Ullrich, Joanne E.; Strickland, Dudley K.

    2008-01-01

    The low-density lipoprotein (LDL) receptor-related protein (originally called LRP, but now referred to as LRP1) is a large endocytic receptor that is widely expressed in several tissues. LRP1 is a member of the LDL receptor family that plays diverse roles in various biological processes including lipoprotein metabolism, degradation of proteases, activation of lysosomal enzymes and cellular entry of bacterial toxins and viruses. Deletion of the LRP1 gene leads to lethality in mice, revealing a critical, but as of yet, undefined role in development. Tissue-specific gene deletion studies reveal an important contribution of LRP1 in the vasculature, central nervous system, in macrophages and in adipocytes. Three important properties of LRP1 dictate its diverse role in physiology: first, its ability to recognize more than thirty distinct ligands; second, its ability to bind a large number of cytoplasmic adaptor proteins via determinants located on its cytoplasmic domain in a phosphorylation-specific manner; and third, its ability to associate with and modulate the activity of other transmembrane receptors such as integrins and receptor tyrosine kinases. PMID:18626063

  1. The low-density lipoprotein receptor-related protein 1 and amyloid-β clearance in Alzheimer’s disease

    PubMed Central

    Kanekiyo, Takahisa; Bu, Guojun

    2014-01-01

    Accumulation and aggregation of amyloid-β (Aβ) peptides in the brain trigger the development of progressive neurodegeneration and dementia associated with Alzheimer’s disease (AD). Perturbation in Aβ clearance, rather than Aβ production, is likely the cause of sporadic, late-onset AD, which accounts for the majority of AD cases. Since cellular uptake and subsequent degradation constitute a major Aβ clearance pathway, the receptor-mediated endocytosis of Aβ has been intensely investigated. Among Aβ receptors, the low-density lipoprotein receptor-related protein 1 (LRP1) is one of the most studied receptors. LRP1 is a large endocytic receptor for more than 40 ligands, including apolipoprotein E, α2-macroglobulin and Aβ. Emerging in vitro and in vivo evidence demonstrates that LRP1 is critically involved in brain Aβ clearance. LRP1 is highly expressed in a variety of cell types in the brain including neurons, vascular cells and glial cells, where LRP1 functions to maintain brain homeostasis and control Aβ metabolism. LRP1-mediated endocytosis regulates cellular Aβ uptake by binding to Aβ either directly or indirectly through its co-receptors or ligands. Furthermore, LRP1 regulates several signaling pathways, which also likely influences Aβ endocytic pathways. In this review, we discuss how LRP1 regulates the brain Aβ clearance and how this unique endocytic receptor participates in AD pathogenesis. Understanding of the mechanisms underlying LRP1-mediated Aβ clearance should enable the rational design of novel diagnostic and therapeutic strategies for AD. PMID:24904407

  2. Treating psychological trauma among Rwandan orphans is associated with a reduction in HIV risk-taking behaviors: A pilot study.

    PubMed

    Talbot, Annie; Uwihoreye, Chaste; Kamen, Charles; Grant, Philip; McGlynn, Lawrence; Mugabe, Isaac; Nshimyumukiza, Martin; Dongier, Pierre; Slamowitz, Debbie; Padilla, Cindy; Uvamahoro, Jaqueline; Musayidire, Irene; Mukarubuga, Ancilla; Zolopa, Andrew

    2013-12-01

    The nongovernmental organization, Uyisenga N'Manzi (UNM), provides Rwandan orphans of genocide and HIV/AIDS with education, social, and mental health services. Many orphans in UNM report symptoms of psychological trauma. The primary study objective was to evaluate a multidisciplinary program integrating HIV prevention with an existing package of mental health services. We randomly selected 120 orphans between ages 15-25 years served by UNM and evaluated sexually-transmitted infections, HIV risk-taking behaviors and knowledge, and mental health at baseline, 5, 9, and 12 months. Increased trauma symptoms at baseline were associated with poorer coping skills and social functioning, and increased psychological distress and HIV risk-taking behavior. Following the 12-month intervention, trauma symptoms declined significantly, with those accessing counseling services showing greatest improvement. Orphans with the highest trauma scores benefited most from the intervention. In this at-risk population, addressing mental health issues in the context of HIV prevention is critical. PMID:24245594

  3. 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

  4. Anti-cas spacers in orphan CRISPR4 arrays prevent uptake of active CRISPR-Cas I-F systems.

    PubMed

    Almendros, Cristóbal; Guzmán, Noemí M; García-Martínez, Jesús; Mojica, Francisco J M

    2016-01-01

    Archaea and bacteria harbour clustered regularly interspaced short palindromic repeats (CRISPR) loci. These arrays encode RNA molecules (crRNA), each containing a sequence of a single repeat-intervening spacer. The crRNAs guide CRISPR-associated (Cas) proteins to cleave nucleic acids complementary to the crRNA spacer, thus interfering with targeted foreign elements. Notably, pre-existing spacers may trigger the acquisition of new spacers from the target molecule by means of a primed adaptation mechanism. Here, we show that naturally occurring orphan CRISPR arrays that contain spacers matching sequences of the cognate (absent) cas genes are able to elicit both primed adaptation and direct interference against genetic elements carrying those genes. Our findings show the existence of an anti-cas mechanism that prevents the transfer of a fully equipped CRISPR-Cas system. Hence, they suggest that CRISPR immunity may be undesired by particular prokaryotes, potentially because they could limit possibilities for gaining favourable sequences by lateral transfer. PMID:27573106

  5. 'Older women', customary obligations and orphan foster caregiving: the case of queen mothers in Manya Klo, Ghana.

    PubMed

    Drah, Bright B

    2014-06-01

    Female orphan caregivers in countries heavily affected by HIV in sub-Saharan Africa are often presented as a homogenous group of vulnerable 'older women' that struggles to support orphans. There is a dearth of data on the different kinds of women and how their social characteristics impact their survival strategies and caregiving responsibilities. This study examines the link between the social characteristics of queen mothers in Manya Klo in Ghana and their roles as caregivers. The research findings suggest that queen mothers have become the primary caregivers of orphans, even though they do not have the wherewithal to provide for these orphans. The lack of kin support to queen mothers exacerbates their physical and economic vulnerabilities. They engage in less dignifying economic activities and pay less attention to their own needs in order to meet their customary obligations as orphan caregivers. The growing influence of queen mothers as caregivers for orphans, however, is a reflection of some of the changes that are occurring in customary foster care arrangements. Policy makers and interventionists require in depth understanding of queen mothers and their peculiar circumstances in order to strengthen their roles as leaders and caregivers. PMID:24737050

  6. 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

  7. Poverty and psychological health among AIDS-orphaned children in Cape Town, South Africa.

    PubMed

    Cluver, Lucie; Gardner, Frances; Operario, Don

    2009-06-01

    This study examined associations between AIDS-orphanhood status, poverty indicators, and psychological problems (depression, anxiety, post-traumatic stress, peer problems, delinquency, conduct problems) among children and adolescents in townships surrounding Cape Town, South Africa. One thousand and twenty-five children and adolescents completed standardized and culturally sensitive cross-sectional surveys. Children orphaned by AIDS had more psychological problems including depression, peer problems, post-traumatic stress, and conduct problems. Specific poverty indicators including food security, access to social welfare grants, employment in the household and access to school were associated with better psychological health. Poverty indicators mediated associations of AIDS-orphanhood with psychological problems. Food security showed the most consistent association with reduced psychological problems. Poverty alleviation measures have the potential to improve psychological health for AIDS-orphaned children in South African townships. PMID:19806489

  8. 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

  9. 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

  10. 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

  11. Preventing HIV By Providing Support for Orphan Girls to Stay in School: Does Religion Matter?

    PubMed Central

    Hallfors, Denise D.; Cho, Hyunsan; Iritani, Bonita J.; Mapfumo, John; Mpofu, Elias; Luseno, Winnie K.; January, James

    2012-01-01

    Objective The paper examines the influence of religion on attitudes, behaviors, and HIV infection among rural adolescent women in Zimbabwe. Design We analyzed data from a 2007-2010 randomized controlled trial in rural eastern Zimbabwe testing whether school support can prevent HIV risk behaviors and related attitudes among rural adolescent orphan girls; supplementary data from the 2006 Zimbabwe Demographic and Health Survey (ZDHS) were also analyzed. The present study design is largely cross-sectional, using the most recent available survey data from the clinical trial to examine the association between religious affiliation and religiosity on school dropout, marriage, and related attitudes, controlling for intervention condition, age and orphan type. The ZDHS data examined the effect of religious denomination on marriage and HIV status among young rural women, controlling for age. Results Apostolic Church affiliation greatly increased the likelihood of early marriage compared to reference Methodist Church affiliation (odds ratio=4.5). Greater religiosity independently reduced the likelihood of school dropout, increased gender equity attitudes and disagreement with early sex, and marginally reduced early marriage. Young rural Apostolic women in the ZDHS were nearly four times as likely to marry as teenagers compared to Protestants, and marriage doubled the likelihood of HIV infection. Conclusions Findings contradict an earlier seminal study that Apostolics are relatively protected from HIV compared to other Christian denominations. Young Apostolic women are at increased risk of HIV infection through early marriage. The Apostolic Church is a large and growing denomination in sub-Saharan Africa that discourages medical testing and treatment in favor of faith healing. Since this can increase the risk of undiagnosed HIV infection for young married women and their infants in high prevalence areas, further study is urgently needed to confirm this emerging public health

  12. 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.

  13. 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. PMID:12319864

  14. Hunting the Parent of the Orphan Stream: Identifying Stream Members from Low-resolution Spectroscopy

    NASA Astrophysics Data System (ADS)

    Casey, Andrew R.; Da Costa, Gary; Keller, Stefan C.; Maunder, Elizabeth

    2013-02-01

    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 GSR = 82.1 ± 1.4 km s-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, σ([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.

  15. A journey of hope: lessons learned from studies on rare diseases and orphan drugs.

    PubMed

    Wästfelt, M; Fadeel, B; Henter, J-I

    2006-07-01

    Rare diseases are frequently life-threatening or chronically debilitating and the impact on the quality of life of affected patients and their family members is thus significant. However, drug development for these conditions has been limited by a lack of understanding of the underlying mechanisms of disease and the relative unavailability of subjects for clinical trials, as well as the prohibitive cost of investing in a novel pharmaceutical agent with poor market potential. Nevertheless, the introduction of Orphan Drug legislations has provided important incentives for the development of orphan drugs (i.e. drugs that have been abandoned or 'orphaned' by major drug companies). Moreover, recent studies on rare diseases, including inherited immunodeficiencies and metabolic disorders, have served not only to alleviate the plight of patients with rare diseases, but also yielded valuable information on biological processes of relevance for other, more common conditions. These lessons, along with the crucial importance of cooperation between academic institutions, pharmaceutical companies, patient advocacy groups and society in the elucidation of rare diseases, are highlighted in the present review. PMID:16789973

  16. 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.

  17. The Impact of School Subsidies on HIV-Related Outcomes among Adolescent Female Orphans

    PubMed Central

    Hallfors, Denise Dion; Cho, Hyunsan; Rusakaniko, Simbarashe; Mapfumo, John; Iritani, Bonita; Zhang, Lei; Luseno, Winnie; Miller, Ted

    2014-01-01

    Objectives We examine effects of school support as a structural HIV prevention intervention for adolescent female orphans in Zimbabwe after 5 years. Methods 328 orphan adolescent girls were followed in a clustered randomized control trial from 2007 to 2010. The experimental group received school fees, uniforms, and school supplies and were assigned a school-based “helper.” In 2011-12, the control group received delayed partial treatment of school fees only. At the final data point in 2012, survey, HIV, and HSV-2 biomarker data were collected from approximately 88% of the sample. Bivariate and multivariate analyses were conducted on endpoint outcomes, controlling for age, religious affiliation, and baseline SES. Results The two groups did not differ on HIV or HSV-2 biomarkers. The comprehensive five-year intervention continued to reduce the likelihood of marriage, improve school retention, improve SES (food security), and marginally maintain gains in quality of life, even after providing school fees to the control group. Conclusions Paying school fees and expenses resulted in significant improvements in life outcomes for orphan adolescent girls. Biological evidence of HIV infection prevention, however, was not observed. Our study adds to the growing body of research on school support as HIV prevention for girls in sub-Saharan Africa, but as yet, no clear picture of effectiveness has emerged. PMID:25530603

  18. Low-density Lipoprotein Receptor-related Proteins in a Novel Mechanism of Axon Guidance and Peripheral Nerve Regeneration.

    PubMed

    Landowski, Lila M; Pavez, Macarena; Brown, Lachlan S; Gasperini, Robert; Taylor, Bruce V; West, Adrian K; Foa, Lisa

    2016-01-15

    The low-density lipoprotein receptor-related protein receptors 1 and 2 (LRP1 and LRP2) are emerging as important cell signaling mediators in modulating neuronal growth and repair. We examined whether LRP1 and LRP2 are able to mediate a specific aspect of neuronal growth: axon guidance. We sought to identify LRP1 and LRP2 ligands that could induce axonal chemoattraction, which might have therapeutic potential. Using embryonic sensory neurons (rat dorsal root ganglia) in a growth cone turning assay, we tested a range of LRP1 and LRP2 ligands for the ability to guide growth cone navigation. Three ligands were chemorepulsive: α-2-macroglobulin, tissue plasminogen activator, and metallothionein III. Conversely, only one LRP ligand, metallothionein II, was found to be chemoattractive. Chemoattraction toward a gradient of metallothionein II was calcium-dependent, required the expression of both LRP1 and LRP2, and likely involves further co-receptors such as the tropomyosin-related kinase A (TrkA) receptor. The potential for LRP-mediated chemoattraction to mediate axonal regeneration was examined in vivo in a model of chemical denervation in adult rats. In these in vivo studies, metallothionein II was shown to enhance epidermal nerve fiber regeneration so that it was complete within 7 days compared with 14 days in saline-treated animals. Our data demonstrate that both LRP1 and LRP2 are necessary for metallothionein II-mediated chemotactic signal transduction and that they may form part of a signaling complex. Furthermore, the data suggest that LRP-mediated chemoattraction represents a novel, non-classical signaling system that has therapeutic potential as a disease-modifying agent for the injured peripheral nervous system. PMID:26598525

  19. Orphans of the HIV epidemic: the challenges from toddlerhood to adolescence and beyond

    PubMed Central

    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

  20. 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

  1. 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…

  2. 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

  3. 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

  4. 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. PMID:21926421

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

    PubMed Central

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

    2015-01-01

    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

  7. 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

  8. Impact of Domestic Care Environment on Trauma and Posttraumatic Stress Disorder among Orphans in Western Kenya

    PubMed Central

    Atwoli, Lukoye; Ayuku, David; Hogan, Joseph; Koech, Julius; Vreeman, Rachel Christine; Ayaya, Samuel; Braitstein, Paula

    2014-01-01

    Objective The aim of this study was to determine the impact of the domestic care environment on the prevalence of potentially traumatic events (PTEs) and posttraumatic stress disorder (PTSD) among orphaned and separated children in Uasin Gishu County, western Kenya. Methods A total of 1565 (55.5% male) orphaned and separated adolescents aged 10–18 years (mean 13.8 years, sd 2.2), were assessed for PTSD and PTEs including bullying, physical abuse and sexual abuse. In this sample, 746 lived in extended family households, 746 in Charitable Children's Institutions (CCIs), and 73 on the street. Posttraumatic stress symptom (PTSS) scores and PTSD were assessed using the Child PTSD Checklist. Results Bullying was the commonest PTE in all domestic care environments, followed by physical and sexual abuse. All PTEs were commonest among the street youth followed by CCIs. However, sexual abuse was more prevalent in households than in CCIs. Prevalence of PTSD was highest among street youth (28.8%), then households (15.0%) and CCIs (11.5%). PTSS scores were also highest among street youth, followed by CCIs and households. Bullying was associated with higher PTSS scores and PTSD odds than either sexual or physical abuse. Conclusion This study demonstrated differences in distribution of trauma and PTSD among orphaned and separated children in different domestic care environments, with street youth suffering more than those in CCIs or households. Interventions are needed to address bullying and sexual abuse, especially in extended family households. Street youth, a heretofore neglected population, are urgently in need of dedicated mental health services and support. PMID:24625395

  9. Multiple phosphorylation events control chicken ovalbumin upstream promoter transcription factor I orphan nuclear receptor activity.

    PubMed

    Gay, Frédérique; Baráth, Peter; Desbois-Le Péron, Christine; Métivier, Raphaël; Le Guével, Rémy; Birse, Darcy; Salbert, Gilles

    2002-06-01

    Chicken ovalbumin upstream promoter transcription factor I (COUP-TFI) is an orphan member of the nuclear hormone receptor superfamily that comprises key regulators of many biological functions, such as embryonic development, metabolism, homeostasis, and reproduction. Although COUP-TFI can both actively silence gene transcription and antagonize the functions of various other nuclear receptors, the COUP-TFI orphan receptor also acts as a transcriptional activator in certain contexts. Moreover, COUP-TFI has recently been shown to serve as an accessory factor for some ligand-bound nuclear receptors, suggesting that it may modulate, both negatively and positively, a wide range of hormonal responses. In the absence of any identified cognate ligand, the mechanisms involved in the regulation of COUP-TFI activity remain unclear. The elucidation of several putative phosphorylation sites for MAPKs, PKC, and casein kinase II within the sequence of this orphan receptor led us to investigate phosphorylation events regulating the various COUP-TFI functions. After showing that COUP-TFI is phosphorylated in vivo, we provide evidence that in vivo inhibition of either MAPK or PKC signaling pathway leads to a specific and pronounced decrease in COUP-TFI-dependent transcriptional activation of the vitronectin gene promoter. Focusing on the molecular mechanisms underlying the MAPK- and PKC-mediated regulation of COUP-TFI activity, we show that COUP-TFI can be directly targeted by PKC and MAPK. These phosphorylation events differentially modulate COUP-TFI functions: PKC-mediated phosphorylation enhances COUP-TFI affinity for DNA and MAPK-mediated phosphorylation positively regulates the transactivation function of COUP-TFI, possibly through enhancing specific coactivator recruitment. These data provide evidence that COUP-TFI is likely to integrate distinct signaling pathways and raise the possibility that multiple extracellular signals influence biological processes controlled by COUP

  10. 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

  11. 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.

  12. Determinants for successful marketing authorisation of orphan medicinal products in the EU.

    PubMed

    Putzeist, Michelle; Heemstra, Harald E; Garcia, Jordi Llinares; Mantel-Teeuwisse, Aukje K; Gispen-De Wied, Christine C; Hoes, Arno W; Leufkens, Hubert G M

    2012-04-01

    In 2010, the European Regulation for Orphan Medicinal Products (OMPs) was in force for ten years. In this study we assessed possible determinants of applications for OMPs in the EU since 2000 that are associated with a successful marketing authorisation. Our analysis shows that clinical trial characteristics such as demonstrating convincing evidence of a beneficial effect on the primary endpoint, the selection of a clinically relevant endpoint, providing RCT data as pivotal study evidence and the submission of sound dose finding data are critical success factors. In addition, high medical need seems to counterweigh uncertainties about the scientific evidence in the benefit-risk assessment of OMPs. PMID:22094244

  13. Post-traumatic stress symptoms and structure among orphan and vulnerable children and adolescents in Zambia

    PubMed Central

    Familiar, Itziar; Murray, Laura; Gross, Alden; Skavenski, Stephanie; Jere, Elizabeth; Bass, Judith

    2014-01-01

    Background Scant information exists on PTSD symptoms and structure in youth from developing countries. Methods We describe the symptom profile and exposure to trauma experiences among 343 orphan and vulnerable children and adolescents from Zambia. We distinguished profiles of post-traumatic stress symptoms using latent class analysis. Results Average number of trauma-related symptoms (21.6; range 0-38) was similar across sex and age. Latent class model suggested 3 classes varying by level of severity: low (31% of the sample), medium (45% of the sample), and high (24% of the sample) symptomatology. Conclusions Results suggest that PTSD is a continuously distributed latent trait. PMID:25382359

  14. 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

  15. Orphan nuclear receptor small heterodimer partner inhibits transforming growth factor-beta signaling by repressing SMAD3 transactivation.

    PubMed

    Suh, Ji Ho; Huang, Jiansheng; Park, Yun-Yong; Seong, Hyun-A; Kim, Dongwook; Shong, Minho; Ha, Hyunjung; Lee, In-Kyu; Lee, Keesook; Wang, Li; Choi, Hueng-Sik

    2006-12-22

    Orphan nuclear receptor small heterodimer partner (SHP) is an atypical member of the nuclear receptor superfamily; SHP regulates the nuclear receptor-mediated transcription of target genes but lacks a conventional DNA binding domain. In this study, we demonstrate that SHP represses transforming growth factor-beta (TGF-beta)-induced gene expression through a direct interaction with Smad, a transducer of TGF-beta signaling. Transient transfection studies demonstrate that SHP represses Smad3-induced transcription. In vivo and in vitro protein interaction assays revealed that SHP directly interacts with Smad2 and Smad3 but not with Smad4. Mapping of domains mediating the interaction between SHP and Smad3 showed that the entire N-terminal domain (1-159 amino acids) of SHP and the linker domain of Smad3 are involved in this interaction. In vitro glutathione S-transferase pulldown competition experiments revealed the SHP-mediated repression of Smad3 transactivation through competition with its co-activator p300. SHP also inhibits the activation of endogenous TGF-beta-responsive gene promoters, the p21, Smad7, and plasminogen activator inhibitor-1 (PAI-1) promoters. Moreover, adenovirus-mediated overexpression of SHP decreases PAI-1 mRNA levels, and down-regulation of SHP by a small interfering RNA increases both the transactivation of Smad3 and the PAI-1 mRNA levels. Finally, the PAI-1 gene is expressed in SHP(-/-) mouse hepatocytes at a higher level than in normal hepatocytes. Taken together, these data indicate that SHP is a novel co-regulator of Smad3, and this study provides new insights into regulation of TGF-beta signaling. PMID:17074765

  16. Posttraumatic stress in AIDS-orphaned children exposed to high levels of trauma: the protective role of perceived social support.

    PubMed

    Cluver, Lucie; Fincham, Dylan S; Seedat, Soraya

    2009-04-01

    Poor urban children in South Africa are exposed to multiple community traumas, but AIDS-orphaned children are at particular risk for posttraumatic stress. This study examined the hypothesis that social support may moderate the relationship between trauma exposure and posttraumatic stress for this group. Four hundred twenty-five AIDS-orphaned children were interviewed using standardized measures of psychopathology. Compared to participants with low perceived social support, those with high perceived social support demonstrated significantly lower levels of PTSD symptoms after both low and high levels of trauma exposure. This suggests that strong perception of social support from carers, school staff, and friends may lessen deleterious effects of exposure to trauma, and could be a focus of intervention efforts to improve psychological outcomes for AIDS-orphaned children. PMID:19319917

  17. 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. PMID:19662802

  18. Orphan G-protein-coupled receptors: the next generation of drug targets?

    PubMed Central

    Wilson, Shelagh; Bergsma, Derk J; Chambers, Jon K; Muir, Alison I; Fantom, Kenneth G M; Ellis, Catherine; Murdock, Paul R; Herrity, Nicole C; Stadel, Jeffrey M

    1998-01-01

    The pharmaceutical industry has readily embraced genomics to provide it with new targets for drug discovery. Large scale DNA sequencing has allowed the identification of a plethora of DNA sequences distantly related to known G protein-coupled receptors (GPCRs), a superfamily of receptors that have a proven history of being excellent therapeutic targets. In most cases the extent of sequence homology is insufficient to assign these `orphan' receptors to a particular receptor subfamily. Consequently, reverse molecular pharmacological and functional genomic strategies are being employed to identify the activating ligands of the cloned receptors. Briefly, the reverse molecular pharmacological methodology includes cloning and expression of orphan GPCRs in mammalian cells and screening these cells for a functional response to cognate or surrogate agonists present in biological extract preparations, peptide libraries, and complex compound collections. The functional genomics approach involves the use of `humanized yeast cells, where the yeast GPCR transduction system is engineered to permit functional expression and coupling of human GPCRs to the endogenous signalling machinery. Both systems provide an excellent platform for identifying novel receptor ligands. Once activating ligands are identified they can be used as pharmacological tools to explore receptor function and relationship to disease. PMID:9884064

  19. Community-based mental health counseling for children orphaned by AIDS in China.

    PubMed

    Kaufman, Joan A; Zeng, Wu; Wang, Liyao; Zhang, Ying

    2013-01-01

    There is an urgent need to develop scalable approaches to community-based mental health services for children in rural China and other developing countries involving task shifting from clinicians to trained community workers. Evidence is needed about the effectiveness of interventions for children affected by AIDS in rural areas. This article describes an intervention study aimed at developing, implementing, and evaluating a community-based counseling program for the AIDS orphans of Fuyang, Anhui Province, an area of central China where a tainted blood donation scheme infected countless farmers and left many children orphaned by AIDS. In China these children live in rural settings with no access to mental health services. The authors trained a group of community-based counselors to provide group counseling sessions focusing on self-awareness and communication and to provide a basic therapeutic approach for depression and anxiety. The authors conducted a baseline and two follow-up surveys of 39 children who met the clinical diagnostic criteria for anxiety and depression. There was a statistically significant improvement for the children on anxiety, but there was no statistically significant improvement on depression, with greatest gains immediately following the intervention. We demonstrated the feasibility of task shifting for mental health services in this setting. PMID:22880692

  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. 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.

  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. PMID:22215105

  3. 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.

  4. 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

  5. Hypothermic machine preservation facilitates successful transplantation of "orphan" extended criteria donor livers.

    PubMed

    Guarrera, J V; Henry, S D; Samstein, B; Reznik, E; Musat, C; Lukose, T I; Ratner, L E; Brown, R S; Kato, T; Emond, J C

    2015-01-01

    Hypothermic machine preservation (HMP) remains investigational in clinical liver transplantation. It is widely used to preserve kidneys for transplantation with improved results over static cold storage (SCS). At our center, we have used HMP in 31 adults receiving extended criteria donor (ECD) livers declined by the originating United Network for Organ Sharing region ("orphan livers"). These cases were compared to ECD SCS cases in a matched cohort study design. Livers were matched for donor age, recipient age, cold ischemic time, donor risk index and Model for End-Stage Liver Disease (MELD) score. HMP was performed for 3-7 h at 4-8 °C using our previously published protocol. Early allograft dysfunction rates were 19% in the HMP group versus 30% in the control group (p = 0.384). One-year patient survival was 84% in the HMP group versus 80% in the SCS group (p = NS). Post hoc analysis revealed significantly less biliary complications in the HMP group versus the SCS group (4 vs. 13, p = 0.016). Mean hospital stay was significantly shorter in the HMP group (13.64 ± 10.9 vs. 20.14 ± 11.12 days in the SCS group, p = 0.001). HMP provided safe and reliable preservation in orphan livers transplanted at our center. PMID:25521639

  6. 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

  7. 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

  8. The influence of orphan care and other household shocks on health status over time: a longitudinal study of children's caregivers in rural Malawi.

    PubMed

    Littrell, Megan; Boris, Neil W; Brown, Lisanne; Hill, Michael; Macintyre, Kate

    2011-12-01

    In the context of rising rates of orphanhood in AIDS-affected settings, very little is understood about implications for caregiver well-being given increasing and intensifying responsibilities for the care of orphaned children. Emotional distress and self-reported health status as well as shifts in household orphan care, wealth, food security and recent illness and death among household members were measured among a panel of 1219 caregivers in rural Malawi between 2007 and 2009. Logistic regression was used to identify predictors of improved and diminished caregiver health and emotional distress. Results suggest that becoming an orphan caregiver is associated with a shift from good to poor health status (adjusted odds ratio [AOR]=2.29, 95% confidence interval [CI]=1.16-4.54), and that elevated levels of distress and poor health both persist over time in comparison with care for non-orphans only. Once engaged in orphan care, taking on additional orphans is associated with increased emotional distress in relation to not caring for orphans (AOR=3.16, 95% CI=1.30-7.73) as well as in relation to maintaining the same number of orphans in care over time (AOR=2.84, 95% CI=1.04-7.70). In addition, findings illustrate the strong influence of household wealth and food security on caregiver well-being. Food insecurity and poverty that persist or develop over time are associated with increasing distress. Conversely, maintenance or improvement in food security and household wealth are associated with decreases in distress. Providing all aspects of household maintenance and care for children, primary caregivers are key to the extended family solution for orphaned and vulnerable children. Bolstering the foundation of rural African families to ensure care and protection of these children involves targeting support to orphan caregivers but must also include addressing the issues of poverty and food insecurity that pose a wider threat to caregiving capacity. PMID:21711171

  9. Common polymorphisms within the NR4A3 locus, encoding the orphan nuclear receptor Nor-1, are associated with enhanced β-cell function in non-diabetic subjects

    PubMed Central

    Weyrich, Peter; Staiger, Harald; Stančáková, Alena; Schäfer, Silke A; Kirchhoff, Kerstin; Ullrich, Susanne; Ranta, Felicia; Gallwitz, Baptist; Stefan, Norbert; Machicao, Fausto; Kuusisto, Johanna; Laakso, Markku; Fritsche, Andreas; Häring, Hans-Ulrich

    2009-01-01

    Background Neuron-derived orphan receptor (Nor) 1, nuclear receptor (Nur) 77, and nuclear receptor-related protein (Nurr) 1 constitute the NR4A family of orphan nuclear receptors which were recently found to modulate hepatic glucose production, insulin signalling in adipocytes, and oxidative metabolism in skeletal muscle. In this study, we assessed whether common genetic variation within the NR4A3 locus, encoding Nor-1, contributes to the development of prediabetic phenotypes, such as glucose intolerance, insulin resistance, or β-cell dysfunction. Methods We genotyped 1495 non-diabetic subjects from Southern Germany for the five tagging single nucleotide polymorphisms (SNPs) rs7047636, rs1526267, rs2416879, rs12686676, and rs10819699 (minor allele frequencies ≥ 0.05) covering 100% of genetic variation within the NR4A3 locus (with D' = 1.0, r2 ≥ 0.9) and assessed their association with metabolic data derived from the fasting state, an oral glucose tolerance test (OGTT), and a hyperinsulinemic-euglycemic clamp (subgroup, N = 506). SNPs that revealed consistent associations with prediabetic phenotypes were subsequently genotyped in a second cohort (METSIM Study; Finland; N = 5265) for replication. Results All five SNPs were in Hardy-Weinberg equilibrium (p ≥ 0.7, all). The minor alleles of three SNPs, i.e., rs1526267, rs12686676, and rs10819699, consistently tended to associate with higher insulin release as derived from plasma insulin at 30 min(OGTT), AUCC-peptide-to-AUCGluc ratio and the AUCIns30-to-AUCGluc30 ratio with rs12686676 reaching the level of significance (p ≤ 0.03, all; additive model). The association of the SNP rs12686676 with insulin secretion was replicated in the METSIM cohort (p ≤ 0.03, additive model). There was no consistent association with glucose tolerance or insulin resistance in both study cohorts. Conclusion We conclude that common genetic variation within the NR4A3 locus determines insulin secretion. Thus, NR4A3 represents a

  10. Lipoprotein receptor-related protein 1 variants and dietary fatty acids: meta-analysis of European origin and African American studies

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Low-density lipoprotein-related receptor protein 1 (LRP1) is a multi-functional endocytic receptor and signaling molecule that is expressed in adipose and the hypothalamus. Evidence for a role of LRP1 in adiposity is accumulating from animal and in vitro models, but data from human studies are limit...

  11. 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…

  12. 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

  13. Identification of endogenous substrates of orphan cytochrome P450 enzymes through the use of untargeted metabolomics approaches

    PubMed Central

    Cheng, Qian; Guengerich, F. Peter.

    2013-01-01

    Summary Metabolomics provides an invaluable means to interrogate the function of “orphan” enzymes, i.e., those whose endogenous substrates are not known. Here we describe a high performance liquid chromatography-coupled mass spectrometry (HPLC-MS)-based metabolomics approach to identify an endogenous substrate of an orphan cytochrome P450. PMID:23475668

  14. 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...

  15. 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…

  16. 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…

  17. 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…

  18. 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…

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

    PubMed

    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

  20. 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

  1. 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

  2. The 29-kDa proteins phosphorylated ion thrombin-activated human platelets are forms of the estrogen receptor-related 27-kDa heat shock protein

    SciTech Connect

    Mendelsohn, M.E.; Yan Zhu; O'Neill, S. )

    1991-12-15

    Thrombin plays a critical role in platelet activation, hemostasis, and thrombosis. Cellular activation by thrombin leads to the phosphorylation of multiple proteins, most of which are unidentified. The authors have characterized several 29-kDa proteins that are rapidly phosphorylated following exposure of intact human platelets to thrombin. A murine monoclonal antibody raised to an unidentified estrogen receptor-related 29-kDa protein selectively recognized these proteins as well as a more basic, unphosphorylated 27-kDa protein. Cellular activation by thrombin led to a marked shift in the proportion of protein from the 27-kDa unphosphorylated form to the 29-kDa phosphoprotein species. Using this antibody, they isolated and sequenced a human cDNA clone encoding a protein that was identical to the mammalian 27-kDa heat shock protein (HSP27), a protein of uncertain function that is known to be phosphorylated to several forms and to be transcriptionally induced by estrogen. The 29-kDa proteins were confirmed to be phosphorylated forms of HSP27 by immunoprecipitation studies. Thus, the estrogen receptor-related protein is HSP27, and the three major 20-kDa proteins phosphorylated in thrombin-activated platelets are forms of HSP27. These data suggest a role for HSP27 in the signal transduction events of platelet activation.

  3. 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

  4. 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

  5. The orphan G protein coupled receptor 161 is required for left-right patterning

    PubMed Central

    Leung, TinChung; Humbert, Jasper E.; Stauffer, Anna M.; Giger, Kathryn E.; Chen, Hui; Tsai, Huai-Jen; Wang, Chuan; Mirshahi, Tooraj; Robishaw, Janet D.

    2015-01-01

    Gpr161 (also known as RE2) is an orphan G protein-coupled receptor (GPCR) that is expressed during embryonic development in zebrafish. Determining its biological function has proven difficult due to lack of knowledge regarding its natural or synthetic ligands. Here, we show that targeted knockdown of gpr161 disrupts asymmetric gene expression in the lateral plate mesoderm, resulting in aberrant looping of the heart tube. This is associated with elevated Ca2+ levels in cells lining the Kupffer's vesicle and normalization of Ca2+ levels, by over-expression of ncx1 or pmca RNA, is able to partially rescue the cardiac looping defect in gpr161 knockdown embryos. Taken together, these data support a model in which gpr161 plays an essential role in left-right (L-R) patterning by modulating Ca2+ levels in the cells surrounding the Kupffer's vesicle. PMID:18755178

  6. The Orphan Adhesion-GPCR GPR126 Is Required for Embryonic Development in the Mouse

    PubMed Central

    Waller-Evans, Helen; Prömel, Simone; Langenhan, Tobias; Dixon, John; Zahn, Dirk; Colledge, William H.; Doran, Joanne; Carlton, Mark B. L.; Davies, Ben; Aparicio, Samuel A. J. R.; Grosse, Johannes; Russ, Andreas P.

    2010-01-01

    Adhesion-GPCRs provide essential cell-cell and cell-matrix interactions in development, and have been implicated in inherited human diseases like Usher Syndrome and bilateral frontoparietal polymicrogyria. They are the second largest subfamily of seven-transmembrane spanning proteins in vertebrates, but the function of most of these receptors is still not understood. The orphan Adhesion-GPCR GPR126 has recently been shown to play an essential role in the myelination of peripheral nerves in zebrafish. In parallel, whole-genome association studies have implicated variation at the GPR126 locus as a determinant of body height in the human population. The physiological function of GPR126 in mammals is still unknown. We describe a targeted mutation of GPR126 in the mouse, and show that GPR126 is required for embryonic viability and cardiovascular development. PMID:21124978

  7. 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

  8. The pERK of being a target: Kinase regulation of the orphan nuclear receptor ERRγ

    PubMed Central

    Riggins, Rebecca B.

    2015-01-01

    Estrogen-related receptors (ERRs) are orphan members of the nuclear receptor superfamily that are important regulators of mitochondrial metabolism with emerging roles in cancer. In the absence of an endogenous ligand, ERRs are reliant upon other regulatory mechanisms that include protein/protein interactions and post-translational modification, though the cellular and clinical significance of this latter mechanism is unclear. We recently published a study in which we establish estrogen-related receptor gamma (ERRγ) as a target for extracellular signal-regulated kinase (ERK), and show that regulation of ERRγ by ERK has important consequences for the function of this receptor in cellular models of estrogen receptor-positive (ER+) breast cancer. In this Research Highlight, we discuss the implications of these findings from a molecular and clinical perspective. PMID:26005698

  9. 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.

  10. 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

  11. Adopting orphans: comprehensive genetic testing of Mendelian diseases of childhood by next-generation sequencing

    PubMed Central

    Kingsmore, Stephen F; Dinwiddie, Darrell L; Miller, Neil A; Soden, Sarah E; Saunders, Carol J

    2011-01-01

    Orphan diseases are individually uncommon but collectively contribute significantly to pediatric morbidity, mortality and healthcare costs. Current molecular testing for rare genetic disorders is often a lengthy and costly endeavor, and in many cases a molecular diagnosis is never achieved despite extensive testing. Diseases with locus heterogeneity or overlapping signs and symptoms are especially challenging owing to the number of potential targets. Consequently, there is immense need for scalable, economical, rapid, multiplexed diagnostic testing for rare Mendelian diseases. Recent advances in next-generation sequencing and bioinformatic technologies have the potential to change the standard of care for the diagnosis of rare genetic disorders. These advances will be reviewed in the setting of a recently developed test for 592 autosomal recessive and X-linked diseases. PMID:22022947

  12. The role of the orphan nuclear receptor COUP-TFII in tumorigenesis

    PubMed Central

    Xu, Mafei; Qin, Jun; Tsai, Sophia Y; Tsai, Ming-jer

    2015-01-01

    The chicken ovalbumin upstream promoter transcription factors (COUP-TFs), members of the nuclear receptor superfamily, consist of two highly homologous subtypes, COUP-TFI (EAR-3, NR2F1) and COUP-TFII (ARP-1, NR2F2). They are referred to as orphan receptors because the COUP-TF ligands have yet to be identified. Since the discovery of COUP-TFs in 1986, extensive studies have demonstrated their crucial functions in a variety of developmental processes, such as organogenesis, angiogenesis, and metabolic homeostasis. Recently, emerging evidence has highlighted that COUP-TFs, specifically COUP-TFII, play important roles in tumorigenesis. In this review, we will discuss the critical functions of COUP-TFII in the development of the tumor microenvironment, the progression of various cancers, and its underlying mechanisms. PMID:25283503

  13. 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. PMID:25808990

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

    PubMed Central

    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

  15. Cost-Effectiveness of School Support for Orphan Girls to Prevent HIV Infection in Zimbabwe

    PubMed Central

    Miller, Ted; Hallfors, Denise; Cho, Hyunsan; Luseno, Winnie; Waehrer, Geetha

    2013-01-01

    This cost-effectiveness study analyzes the cost per quality-adjusted life year (QALY) gained in a randomized controlled trial that tested school support as a structural intervention to prevent HIV risk factors among Zimbabwe orphan girl adolescents. The intervention significantly reduced early marriage, increased years of schooling completed, and increased health-related quality of life. By reducing early marriage, the literature suggests the intervention reduced HIV infection. The intervention yielded an estimated US$1, 472 in societal benefits and an estimated gain of 0.36 QALYs per orphan supported. It cost an estimated US$6/QALY gained, about 1% of annual per capita income in Zimbabwe. That is well below the maximum price that the World Health Organization (WHO) Commission on Macroeconomics and Health recommends paying for health gains in low and middle income countries. About half the girls in the intervention condition were boarded when they reached high school. For non-boarders, the intervention’s financial benefits exceeded its costs, yielding an estimated net cost savings of $502 per pupil. Without boarding, the intervention would yield net savings even if it were 34% less effective in replication. Boarding was not cost-effective. It cost an additional $1,234 per girl boarded (over the three years of the study, discounted to present value at a 3% discount rate) but had no effect on any of the outcome measures relative to girls in the treatment group who did not board. For girls who did not board, the average cost of approximately three years of school support was US$973. PMID:23334923

  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. QQS orphan gene regulates carbon and nitrogen partitioning across species via NF-YC interactions.

    PubMed

    Li, Ling; Zheng, Wenguang; Zhu, Yanbing; Ye, Huaxun; Tang, Buyun; Arendsee, Zebulun W; Jones, Dallas; Li, Ruoran; Ortiz, Diego; Zhao, Xuefeng; Du, Chuanlong; Nettleton, Dan; Scott, M Paul; Salas-Fernandez, Maria G; Yin, Yanhai; Wurtele, Eve Syrkin

    2015-11-24

    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 metabolic processes affecting carbon and nitrogen partitioning among proteins and carbohydrates, modulating leaf and seed composition in Arabidopsis and soybean. Here the universality of QQS function in modulating carbon and nitrogen allocation is exemplified by a series of transgenic experiments. We show that ectopic expression of QQS increases soybean protein independent of the genetic background and original protein content of the cultivar. Furthermore, transgenic QQS expression increases the protein content of maize, a C4 species (a species that uses 4-carbon photosynthesis), and rice, a protein-poor agronomic crop, both highly divergent from Arabidopsis. We determine that QQS protein binds to the transcriptional regulator AtNF-YC4 (Arabidopsis nuclear factor Y, subunit C4). Overexpression of AtNF-YC4 in Arabidopsis mimics the QQS-overexpression phenotype, increasing protein and decreasing starch levels. NF-YC, a component of the NF-Y complex, is conserved across eukaryotes. The NF-YC4 homologs of soybean, rice, and maize also bind to QQS, which provides an explanation of how QQS can act in species where it does not occur endogenously. These findings are, to our knowledge, the first insight into the mechanism of action of QQS in modulating carbon and nitrogen allocation across species. They have major implications for the emergence and function of orphan genes, and identify a nontransgenic strategy for modulating protein levels in crop species, a trait of great agronomic significance. PMID:26554020

  18. QQS orphan gene regulates carbon and nitrogen partitioning across species via NF-YC interactions

    PubMed Central

    Li, Ling; Zheng, Wenguang; Zhu, Yanbing; Ye, Huaxun; Tang, Buyun; Arendsee, Zebulun W.; Jones, Dallas; Li, Ruoran; Ortiz, Diego; Zhao, Xuefeng; Du, Chuanlong; Nettleton, Dan; Scott, M. Paul; Salas-Fernandez, Maria G.; Yin, Yanhai; Wurtele, Eve Syrkin

    2015-01-01

    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 metabolic processes affecting carbon and nitrogen partitioning among proteins and carbohydrates, modulating leaf and seed composition in Arabidopsis and soybean. Here the universality of QQS function in modulating carbon and nitrogen allocation is exemplified by a series of transgenic experiments. We show that ectopic expression of QQS increases soybean protein independent of the genetic background and original protein content of the cultivar. Furthermore, transgenic QQS expression increases the protein content of maize, a C4 species (a species that uses 4-carbon photosynthesis), and rice, a protein-poor agronomic crop, both highly divergent from Arabidopsis. We determine that QQS protein binds to the transcriptional regulator AtNF-YC4 (Arabidopsis nuclear factor Y, subunit C4). Overexpression of AtNF-YC4 in Arabidopsis mimics the QQS-overexpression phenotype, increasing protein and decreasing starch levels. NF-YC, a component of the NF-Y complex, is conserved across eukaryotes. The NF-YC4 homologs of soybean, rice, and maize also bind to QQS, which provides an explanation of how QQS can act in species where it does not occur endogenously. These findings are, to our knowledge, the first insight into the mechanism of action of QQS in modulating carbon and nitrogen allocation across species. They have major implications for the emergence and function of orphan genes, and identify a nontransgenic strategy for modulating protein levels in crop species, a trait of great agronomic significance. PMID:26554020

  19. Orphan receptor GPR15/BOB is up-regulated in rheumatoid arthritis

    PubMed Central

    Cartwright, Alison; Schmutz, Caroline; Askari, Ayman; Kuiper, Jan-Herman; Middleton, Jim

    2014-01-01

    Chemokine receptors on leukocytes mediate the recruitment and accumulation of these cells within affected joints in chronic inflammatory diseases such as rheumatoid arthritis (RA). Identification of involved receptors offers potential for development of therapeutic interventions. The objective of this study was to investigate the expression of orphan receptor GPR15/BOB in the synovium of RA and non-RA patients and in peripheral blood of RA patients and healthy donors. GPR15/BOB protein and messenger RNA expression were examined in RA and non-RA synovium by immunofluorescence and reverse-transcription polymerase chain reaction (RT-PCR) respectively. GPR15/BOB expression on peripheral blood leukocytes was analysed by flow cytometry and GPR15/BOB messenger RNA was examined in peripheral blood monocytes by RT-PCR. GPR15/BOB protein was observed in CD68+ and CD14+ macrophages in synovia, with greater expression in RA synovia. GPR15/BOB protein was expressed in all patient synovia whereas in non-RA synovia expression was low or absent. Similarly GPR15/BOB messenger RNA was detected in all RA and a minority of non-RA synovia. GPR15/BOB protein was expressed on peripheral blood leukocytes from RA and healthy individuals with increased expression by monocytes and neutrophils in RA. GPR15/BOB messenger RNA expression was confirmed in peripheral blood monocytes. In conclusion GPR15/BOB is expressed by macrophages in synovial tissue and on monocytes and neutrophils in peripheral blood, and expression is up-regulated in RA patients compared to non-RA controls. This orphan receptor on monocytes/macrophages and neutrophils may play a role in RA pathophysiology. PMID:24725539

  20. A Burkholderia cenocepacia orphan LuxR homolog is involved in quorum-sensing regulation.

    PubMed

    Malott, Rebecca J; O'Grady, Eoin P; Toller, Jessica; Inhülsen, Silja; Eberl, Leo; Sokol, Pamela A

    2009-04-01

    Burkholderia cenocepacia utilizes quorum sensing to control gene expression, including the expression of genes involved in virulence. In addition to CepR and CciR, a third LuxR homolog, CepR2, was found to regulate gene expression and virulence factor production. All B. cenocepacia strains examined contained this orphan LuxR homolog, which was not associated with an adjacent N-acyl-homoserine lactone synthase gene. Expression of cepR2 was negatively autoregulated and was negatively regulated by CciR in strain K56-2. Microarray analysis and quantitative reverse transcription-PCR determined that CepR2 did not influence expression of cepIR or cciIR. However, in strain K56-2, CepR2 negatively regulated expression of several known quorum-sensing-controlled genes, including genes encoding zinc metalloproteases. CepR2 exerted positive and negative regulation on genes on three chromosomes, including strong negative regulation of a gene cluster located adjacent to cepR2. In strain H111, which lacks the CciIR quorum-sensing system, CepR2 positively regulated pyochelin production by controlling transcription of one of the operons required for the biosynthesis of the siderophore in an N-acyl-homoserine lactone-independent manner. CepR2 activation of a luxI promoter was demonstrated in a heterologous Escherichia coli host, providing further evidence that CepR2 can function in the absence of signaling molecules. This study demonstrates that the orphan LuxR homolog CepR2 contributes to the quorum-sensing regulatory network in two distinct strains of B. cenocepacia. PMID:19201791

  1. Cost-effectiveness of school support for orphan girls to prevent HIV infection in Zimbabwe.

    PubMed

    Miller, Ted; Hallfors, Denise; Cho, Hyunsan; Luseno, Winnie; Waehrer, Geetha

    2013-10-01

    This cost-effectiveness study analyzes the cost per quality-adjusted life year (QALY) gained in a randomized controlled trial that tested school support as a structural intervention to prevent HIV risk factors among Zimbabwe orphan girl adolescents. The intervention significantly reduced early marriage, increased years of schooling completed, and increased health-related quality of life. By reducing early marriage, the literature suggests the intervention reduced HIV infection. The intervention yielded an estimated US$1,472 in societal benefits and an estimated gain of 0.36 QALYs per orphan supported. It cost an estimated US$6/QALY gained, about 1 % of annual per capita income in Zimbabwe. That is well below the maximum price that the World Health Organization (WHO) Commission on Macroeconomics and Health recommends paying for health gains in low and middle income countries. About half the girls in the intervention condition were boarded when they reached high school. For non-boarders, the intervention's financial benefits exceeded its costs, yielding an estimated net cost savings of $502 per pupil. Without boarding, the intervention would yield net savings even if it were 34 % less effective in replication. Boarding was not cost-effective. It cost an additional $1,234 per girl boarded (over the 3 years of the study, discounted to present value at a 3 % discount rate) but had no effect on any of the outcome measures relative to girls in the treatment group who did not board. For girls who did not board, the average cost of approximately 3 years of school support was US$973. PMID:23334923

  2. Boldness towards novelty and translocation success in captive-raised, orphaned Tasmanian devils.

    PubMed

    Sinn, David L; Cawthen, Lisa; Jones, Susan M; Pukk, Chrissy; Jones, Menna E

    2014-01-01

    Translocation of endangered animals is common, but success is often variable and/or poor. Despite its intuitive appeal, little is known with regards to how individual differences amongst translocated animals influence their post-release survival, growth, and reproduction. We measured consistent pre-release responses to novelty in a familiar environment (boldness; repeatability=0.55) and cortisol response in a group of captive-reared Tasmanian devils, currently listed as "Endangered" by the IUCN. The devils were then released at either a hard- or soft-release site within their mothers' population of origin, and individual growth, movement, reproduction (females only), and survival across 2-8 months post-release was measured. Sex, release method, cohort, behavior, and cortisol response did not affect post-release growth, nor did these factors influence the home range size of orphan devils. Final linear distances moved from the release site were impacted heavily by the release cohort, but translocated devils' movement overall was not different from that in the same-age wild devils. All orphan females of reproductive age were subsequently captured with offspring. Overall survival rates in translocated devils were moderate (∼42%), and were not affected by devil sex, release method, cohort, release weight, or pre-release cortisol response. Devils that survived during the study period were, however, 3.5 times more bold than those that did not (effect size r=0.76). Our results suggest that conservation managers may need to provide developmental conditions in captivity that promote a wide range of behaviors across individuals slated for wild release. PMID:24375492

  3. Functional domains of the human orphan receptor ARP-1/COUP-TFII involved in active repression and transrepression.

    PubMed

    Achatz, G; Hölzl, B; Speckmayer, R; Hauser, C; Sandhofer, F; Paulweber, B

    1997-09-01

    The orphan receptor ARP-1/COUP-TFII, a member of the chicken ovalbumin upstream promoter transcription factor (COUP-TF) subfamily of nuclear receptors, strongly represses transcriptional activity of numerous genes, including several apolipoprotein-encoding genes. Recently it has been demonstrated that the mechanism by which COUP-TFs reduce transcriptional activity involves active repression and transrepression. To map the domains of ARP-1/COUP-TFII required for repressor activity, a detailed deletion analysis of the protein was performed. Chimeric proteins in which various segments of the ARP-1/COUP-TFII carboxy terminus were fused to the GAL4 DNA binding domain were used to characterize its active repression domain. The smallest segment confering active repressor activity to a heterologous DNA binding domain was found to comprise residues 210 to 414. This domain encompasses the region of ARP-1/COUP-TFII corresponding to helices 3 to 12 in the recently published crystal structure of other members of the nuclear receptor superfamily. It includes the AF-2 AD core domain formed by helix 12 but not the hinge region, which is essential for interaction with a corepressor in the case of the thyroid hormone and retinoic acid receptor. Attachment of the nuclear localization signal from the simian virus 40 large T antigen (Flu tag) to the amino terminus of ARP-1/COUP-TFII abolished its ability to bind to DNA without affecting its repressor activity. By using a series of Flu-tagged mutants, the domains required for transrepressor activity of the protein were mapped. They include the DNA binding domain and the segment spanning residues 193 to 399. Transcriptional activity induced by liver-enriched transactivators such as hepatocyte nuclear factor 3 (HNF-3), C/EBP, or HNF-4 was repressed by ARP-1/COUP-TFII independent of the presence of its cognate binding site, while basal transcription or transcriptional activity induced by ATF or Sp1 was not perturbed by the protein. In

  4. Functional domains of the human orphan receptor ARP-1/COUP-TFII involved in active repression and transrepression.

    PubMed Central

    Achatz, G; Hölzl, B; Speckmayer, R; Hauser, C; Sandhofer, F; Paulweber, B

    1997-01-01

    The orphan receptor ARP-1/COUP-TFII, a member of the chicken ovalbumin upstream promoter transcription factor (COUP-TF) subfamily of nuclear receptors, strongly represses transcriptional activity of numerous genes, including several apolipoprotein-encoding genes. Recently it has been demonstrated that the mechanism by which COUP-TFs reduce transcriptional activity involves active repression and transrepression. To map the domains of ARP-1/COUP-TFII required for repressor activity, a detailed deletion analysis of the protein was performed. Chimeric proteins in which various segments of the ARP-1/COUP-TFII carboxy terminus were fused to the GAL4 DNA binding domain were used to characterize its active repression domain. The smallest segment confering active repressor activity to a heterologous DNA binding domain was found to comprise residues 210 to 414. This domain encompasses the region of ARP-1/COUP-TFII corresponding to helices 3 to 12 in the recently published crystal structure of other members of the nuclear receptor superfamily. It includes the AF-2 AD core domain formed by helix 12 but not the hinge region, which is essential for interaction with a corepressor in the case of the thyroid hormone and retinoic acid receptor. Attachment of the nuclear localization signal from the simian virus 40 large T antigen (Flu tag) to the amino terminus of ARP-1/COUP-TFII abolished its ability to bind to DNA without affecting its repressor activity. By using a series of Flu-tagged mutants, the domains required for transrepressor activity of the protein were mapped. They include the DNA binding domain and the segment spanning residues 193 to 399. Transcriptional activity induced by liver-enriched transactivators such as hepatocyte nuclear factor 3 (HNF-3), C/EBP, or HNF-4 was repressed by ARP-1/COUP-TFII independent of the presence of its cognate binding site, while basal transcription or transcriptional activity induced by ATF or Sp1 was not perturbed by the protein. In

  5. Molecular basis for high affinity and selectivity of peptide antagonist, Bantag-1, for the orphan BB3 receptor.

    PubMed

    Nakamura, Taichi; Ramos-Álvarez, Irene; Iordanskaia, Tatiana; Moreno, Paola; Mantey, Samuel A; Jensen, R T

    2016-09-01

    Bombesin-receptor-subtype-3 (BB3 receptor) is a G-protein-coupled-orphan-receptor classified in the mammalian Bombesin-family because of high homology to gastrin-releasing peptide (BB2 receptor)/neuromedin-B receptors (BB1 receptor). There is increased interest in BB3 receptor because studies primarily from knockout-mice suggest it plays roles in energy/glucose metabolism, insulin-secretion, as well as motility and tumor-growth. Investigations into its roles in physiological/pathophysiological processes are limited because of lack of selective ligands. Recently, a selective, peptide-antagonist, Bantag-1, was described. However, because BB3 receptor has low-affinity for all natural, Bn-related peptides, little is known of the molecular basis of its high-affinity/selectivity. This was systematically investigated in this study for Bantag-1 using a chimeric-approach making both Bantag-1 loss-/gain-of-affinity-chimeras, by exchanging extracellular (EC) domains of BB3/BB2 receptor, and using site-directed-mutagenesis. Receptors were transiently expressed and affinities determined by binding studies. Bantag-1 had >5000-fold selectivity for BB3 receptor over BB2/BB1 receptors and substitution of the first EC-domain (EC1) in loss-/gain-of affinity-chimeras greatly affected affinity. Mutagenesis of each amino acid difference in EC1 between BB3 receptor/BB2 receptor showed replacement of His(107) in BB3 receptor by Lys(107) (H107K-BB3 receptor-mutant) from BB2 receptor, decreased affinity 60-fold, and three replacements [H107K, E11D, G112R] decreased affinity 500-fold. Mutagenesis in EC1's surrounding transmembrane-regions (TMs) demonstrated TM2 differences were not important, but R127Q in TM3 alone decreased affinity 400-fold. Additional mutants in EC1/TM3 explored the molecular basis for these changes demonstrated in EC1, particularly important is the presence of aromatic-interactions by His(107), rather than hydrogen-bonding or charge-charge interactions, for determining

  6. Trends In Orphan New Molecular Entities, 1983-2014: Half Were First In Class, And Rare Cancers Were The Most Frequent Target.

    PubMed

    Miller, Kathleen L; Lanthier, Michael

    2016-03-01

    The Orphan Drug Act was enacted in 1983 to stimulate drug development for rare diseases. How well this law has accomplished that goal is an important public health question. This study examined the characteristics of the 209 orphan drugs approved as new molecular entities in the period 1983-2014. As a whole, these drugs were highly innovative and provided substantial gains in reducing unmet medical needs for rare diseases: Over 50 percent of the drugs were first in class, and 78 percent received a priority review. Drugs approved as either therapeutic or supportive therapies for rare cancers represented the highest proportion of these drugs (35 percent). Additionally, in 2010-14 large companies became a strong presence in developing orphan new molecular entities for oncology indications. Overall, new orphan drugs appeared to be highly innovative and provided important advances in care for patients with rare diseases. PMID:26953301

  7. Characterization of a strong repression domain in the hinge region of orphan nuclear receptor hB1F/hLRH-1.

    PubMed

    Xu, Ping-Long; Shan, Shi-Fang; Kong, Yu-Ying; Xie, You-Hua; Wang, Yuan

    2003-10-01

    Human hepatitis B virus enhancer II B1 binding factor (hB1F also known as NR5A2, LRH-1, FTF or CPF) is an orphan nuclear receptor and belongs to the fushi tarazu factor I (FTZ-F1) subfamily. It plays important roles in the transcriptional regulation of a number of genes involved in bile acid biosynthesis pathway, hepatitis B virus (HBV) replication and liver specific regulatory network. Like other nuclear receptors, hB1F is composed of modular functional domains. We characterized a domain in its hinge region that imposes a strong repression on the transcriptional activity of hB1F, which is important for the function of hB1F on regulating the activity of HBV enhancer II/core promoter. Mutations of the core residues in this domain abrogate the repression. Bioinformatic analysis reveals that the amino acid sequence of this region is highly conserved only among members of the FTZ-F1 subfamily. The repression is observed in five cell lines tested, while the degree of the repression varies greatly, which does not parallel with the expression level of the DEAD box protein of 130 kD (DP103), a potential interacting protein of a homologous domain in the steroidogenic factor 1 (SF-1). Moreover, the repression is not affected by the silencing mediator for retinoic acid receptor and thyroid hormone receptor (SMRT) and steroid receptor coactivator 1 (SRC-1). Collectively, these data suggest a novel regulatory mechanism for the transcriptional activity of hB1F. PMID:14515208

  8. Who wants to adopt and who wants to be adopted: a sample of American families and sub-Saharan African orphans.

    PubMed

    Balding, Christopher; Feng, Yan; Atashband, Armita

    2015-12-01

    The debate between pro- and anti-international adoption advocates relies heavily on rhetoric and little on data analysis. To better understand the state of orphans and potential adopters in this debate, we utilize the National Survey of Family Growth (NSFG) and the Demographic and Health Surveys (DHS) to study who adopts internationally and the status of orphaned children in sub-Saharan Africa. According to NSFG data adopters are church going, highly educated, stable families aware of the challenges faced by international adoption, with high rates of infertility and rates of child abuse half the population average. According to the DHS data, orphans in sub-Saharan Africa suffer from significantly higher deprivation, reduced schooling and increased levels of stunting and underweight reported than their cohort. Using this data, we estimate conservatively that that 1 50 000 orphans from our sample of sub-Saharan African countries died from their 5-year birth cohort. Given the large number of families seeking to adopt and the high number of orphan deaths, it seems counterproductive to restrict international adoptions given the significantly lower risks faced by children in adopted families compared with remaining orphaned. PMID:25769738

  9. High Affinity Binding of the Receptor-associated Protein D1D2 Domains with the Low Density Lipoprotein Receptor-related Protein (LRP1) Involves Bivalent Complex Formation: CRITICAL ROLES OF LYSINES 60 AND 191.

    PubMed

    Prasad, Joni M; Young, Patricia A; Strickland, Dudley K

    2016-08-26

    The LDL receptor-related protein 1 (LRP1) is a large endocytic receptor that binds and mediates the endocytosis of numerous structurally diverse ligands. Currently, the basis for ligand recognition by LRP1 is not well understood. LRP1 requires a molecular chaperone, termed the receptor-associated protein (RAP), to escort the newly synthesized receptor from the endoplasmic reticulum to the Golgi. RAP is a three-domain protein that contains the following two high affinity binding sites for LRP1: one is located within domains 1 and 2, and one is located in its third domain. Studies on the interaction of the RAP third domain with LRP1 reveal critical contributions by lysine 256 and lysine 270 for this interaction. From these studies, a model for ligand recognition by this class of receptors has been proposed. Here, we employed surface plasmon resonance to investigate the binding of RAP D1D2 to LRP1. Our results reveal that the high affinity of D1D2 for LRP1 results from avidity effects mediated by the simultaneous interactions of lysine 60 in D1 and lysine 191 in D2 with sites on LRP1 to form a bivalent D1D2-LRP1 complex. When lysine 60 and 191 are both mutated to alanine, the binding of D1D2 to LRP1 is ablated. Our data also reveal that D1D2 is able to bind to a second distinct site on LRP1 to form a monovalent complex. The studies confirm the canonical model for ligand recognition by this class of receptors, which is initiated by pairs of lysine residues that dock into acidic pockets on the receptor. PMID:27402839

  10. Using constitutive activity to define appropriate high-throughput screening assays for orphan g protein-coupled receptors.

    PubMed

    Ngo, Tony; Coleman, James L J; Smith, Nicola J

    2015-01-01

    Orphan G protein-coupled receptors represent an underexploited resource for drug discovery but pose a considerable challenge for assay development because their cognate G protein signaling pathways are often unknown. In this methodological chapter, we describe the use of constitutive activity, that is, the inherent ability of receptors to couple to their cognate G proteins in the absence of ligand, to inform the development of high-throughput screening assays for a particular orphan receptor. We specifically focus on a two-step process, whereby constitutive G protein coupling is first determined using yeast Gpa1/human G protein chimeras linked to growth and β-galactosidase generation. Coupling selectivity is then confirmed in mammalian cells expressing endogenous G proteins and driving accumulation of transcription factor-fused luciferase reporters specific to each of the classes of G protein. Based on these findings, high-throughput screening campaigns can be performed on the already miniaturized mammalian reporter system. PMID:25563179

  11. The prevalence of child-specific utilities in NICE appraisals for paediatric indications: rise of the economic orphans?

    PubMed

    Montgomery, Stephen Maxwell; Kusel, Jeanette

    2016-06-01

    Children are not mini-adults, and thus require studies to be conducted in the population of interest to inform decisions about their care. The paucity of such studies for clinical efficacy lead them to be termed 'therapeutic orphans'. Following the introduction of the 'fourth hurdle' of reimbursement approval on the basis of cost-utility analysis, utility data is now a key requirement for patients to access treatments in England and many other countries. This special report considers whether a paucity of utility valuation studies in children may have made them 'economic orphans' as well and presents results of a review of NICE appraisals as a window on this problem over time. PMID:27082293

  12. Orphan Basin crustal structure from a dense wide-angle seismic profile - Tomographic inversion

    NASA Astrophysics Data System (ADS)

    Watremez, Louise; Lau, K. W. Helen; Nedimović, Mladen R.; Louden, Keith E.; Karner, Garry D.

    2014-05-01

    Orphan Basin is located on the eastern margin of Canada, offshore of Newfoundland and East of Flemish Cap. It is an aborted continental rift formed by multiple episodes of rifting. The crustal structure across the basin has been determined by an earlier refraction study using 15 instruments on a 550 km long line. It shows that the continental crust was extended over an unusually wide region but did not break apart. The crustal structure of the basin thus documents stages in the formation of a magma-poor rifted margin up to crustal breakup. The OBWAVE (Orphan Basin Wide-Angle Velocity Experiment) survey was carried out to image crustal structures across the basin and better understand the processes of formation of this margin. The spacing of the 89 recording stations varies from 3 to 5 km along this 500-km-long line, which was acquired along a pre-existing reflection line. The highest resolution section corresponds to the part of the profile where the crust was expected to be the thinnest. We present the results from a joint tomography inversion of first and Moho reflected arrival times. The high data density allows us to define crustal structures with greater detail than for typical studies and to improve the understanding of the processes leading to the extreme stretching of continental crust. The final model was computed following a detailed parametric study to determine the optimal parameters controlling the ray-tracing and the inversion processes. The final model shows very good resolution. In particular, Monte Carlo standard deviations of crustal velocities and Moho depths are generally < 50 m/s and within 1 km, respectively. In comparison to the velocity models of typical seismic refraction profiles, results from the OBWAVE study show a notable improvement in the resolution of the velocity model and in the level of detail observed using the least a priori information possible. The final model allows us to determine the crustal thinning and variable structures

  13. Securing the metal recycling chain for the steel industry by detecting orphan radioactive sources in scrap metal

    SciTech Connect

    Pesente, S.; Benettoni, M.; Checchia, P.; Conti, E.; Gonella, F.; Nebbia, G.; Vanini, S.; Viesti, G.; Zumerle, G.; Bonomi, G.; Zenoni, A.; Calvini, P.; Squarcia, S.

    2010-08-04

    Experimental tests are reported for the detection of the heavy metal shielding of orphan sources hidden inside scrap metal by using a recently developed muon tomography system. Shielded sources do not trigger alarm in radiation portal commonly employed at the entrance of steel industry using scrap metal. Future systems integrating radiation portals with muon tomography inspection gates will substantially reduce the possibility of accidental melting of radioactive sources securing the use of recycled metal.

  14. Health information, what happens when there isn't any? Information literacy and the challenges for rare and orphan diseases.

    PubMed

    Spring, Hannah

    2014-09-01

    This feature looks at the challenges for information literacy in rare and orphan diseases. In particular, it focuses on the information difficulties faced by those living with a rare condition or awaiting a diagnosis, and also those of the health professionals in charge of their care. The feature also highlights some of the key issues that library and information professionals need to be aware of when providing information support in such circumstances. PMID:25155983

  15. Correlation of Brunhes detrital-layer stratigraphy into the North Atlantic from Orphan Knoll (Labrador Sea)

    NASA Astrophysics Data System (ADS)

    Channell, J. E.; Hodell, D. A.; Romero, O. E.; Hillaire-Marcel, C.; de Vernal, A.; Stoner, J. S.; Mazaud, A.; Roehl, U.

    2011-12-01

    IODP Site U1302-U1303, on the SE flank of Orphan Knoll (Labrador Sea), has a record of detrital layers that extends through most of the Brunhes Chron. The age model is built by tandem matching of relative paleointensity (RPI) and oxygen isotope data (δ18O) from Neogloboquadrina pachyderma (sin.) to reference records, indicating a mean Brunhes sedimentation rate of 14 cm/kyr. Sedimentation back to marine isotope stage (MIS) 18 is characterized by detrital layers that are detected by higher than background gamma-ray attenuation (GRA) density, peaks in X-ray fluorescence (XRF) indicators for detrital carbonate (Ca/Sr) and detrital silicate (Si/Sr), an ice-rafted debris (IRD) proxy (>106 μm), magnetic susceptibility, and magnetic grain-size peaks. The age model enables correlation of Site U1302/03 to IODP Site U1308 (re-drill of DSDP Site 609) in the heart of the central Atlantic IRD belt where an age model and a similar set of detrital-layer proxies have already been derived. Ages of Heinrich layers H1, H2, H4, H5 and H6 are within ~2 kyr at the two sites (H0, H3 and H5a are not observed at Site U1308), and agree with previous work at Orphan Knoll within ~3 kyr. At Site U1308, Brunhes detrital layers are restricted to peak glacials and glacial terminations back to MIS16, however, these same proxies at Site U1302/03 indicate detrital layers distributed throughout the record in both glacial and most interglacial stages. At Site U1302/03, we distinguish Heinrich-type layers in glacial stages, which are associated with IRD (some of which have near-synchronous analogues at Site U1308), from detrital layers within interglacial stages manifested by multiple detrital layer proxies (including Ca/Sr) but usually not associated with IRD, that may be attributed to a distinct depositional process, namely drainage and debris-flow events funneled down the nearby NAMOC (North Atlantic Mid-Ocean Channel).

  16. Supporting Adolescent Orphan Girls to Stay in School as HIV Risk Prevention: Evidence From a Randomized Controlled Trial in Zimbabwe

    PubMed Central

    Cho, Hyunsan; Rusakaniko, Simbarashe; Iritani, Bonita; Mapfumo, John; Halpern, Carolyn

    2011-01-01

    Objectives. Using a randomized controlled trial in rural eastern Zimbabwe, we tested whether comprehensive support to keep orphan adolescent girls in school could reduce HIV risk. Methods. All orphan girls in grade 6 in 25 primary schools were invited to participate in the study in fall 2007 (n = 329). Primary schools were randomized to condition. All primary schools received a universal daily feeding program; intervention participants received fees, uniforms, and a school-based helper to monitor attendance and resolve problems. We conducted annual surveys and collected additional information on school dropout, marriage, and pregnancy rates. We analyzed data using generalized estimating equations over 3 time points, controlling for school and age at baseline. Results. The intervention reduced school dropout by 82% and marriage by 63% after 2 years. Compared with control participants, the intervention group reported greater school bonding, better future expectations, more equitable gender attitudes, and more concerns about the consequences of sex. Conclusions. We found promising evidence that comprehensive school support may reduce HIV risk for orphan girls. Further study, including assessment of dose response, cost benefit, and HIV and herpes simplex virus 2 biomarker measurement, is warranted. PMID:21493943

  17. Ugandan HIV/AIDS orphans in charge of their households speak out: a study of their health-related worries.

    PubMed

    Satzinger, F; Kipp, W; Rubaale, T

    2012-01-01

    The number of children orphaned due to HIV/AIDS in sub-Saharan Africa was estimated in 2007 by UNAIDS at upwards of 12 million. In Uganda alone, 800,000 of the estimated 1.6 million orphans are said to be orphaned due to this cause. These children suffer life-long consequences from the loss of their parents. This study explores the situation of children living in child-headed households in Uganda's western Kabarole district. Through qualitative research, including in-depth interviews with 20 child heads of households, the health concerns of these children are documented. The interview data were analysed using qualitative research techniques. The study reveals that the psychological and physical effects of orphanhood are magnified for those living in child-headed households. In particular, it highlights the fears of theft and abuse which are a constant source of anxiety for these children. It reports that illness episodes among younger siblings are also particularly worrisome for child heads of households. The article concludes with recommendations for addressing this urgent problem in sub-Saharan Africa. PMID:19844818

  18. Do children orphaned by AIDS experience distress over time? A latent growth curve analysis of depressive symptoms.

    PubMed

    Chi, Peilian; Li, Xiaoming; Barnett, Douglas; Zhao, Junfeng; Zhao, Guoxiang

    2014-01-01

    This longitudinal study aimed to examine the enduring effects of parental HIV/AIDS on children's psychological well-being in Asia. A sample of 1625 children aged from 6 to 18 years old were assessed annually for their depressive symptoms over three years. Latent growth curve modeling (LGCM) was used to examine the trajectories of depressive symptoms among AIDS orphans and vulnerable children in comparison with children from HIV-free families. AIDS orphans demonstrated the highest initial level of depressive symptoms among the three groups. On average, children's depressive symptoms' scores can be expected to realize an approximate 25% decrease for AIDS orphans, 19% decrease for vulnerable children, and 15% decrease for comparison children over a three-year period. Individual differences within the groups showed that children with higher initial level of depressive symptoms can be expected to decrease slower over time. Multiple group LGCM showed that the three groups of children demonstrated significantly different trajectories of depressive symptoms. Among the key demographic factors, only age exerted an effect on the trajectory of depressive symptoms of vulnerable children, indicating that the younger children showed higher level of initial depressive symptoms and lower rate of decrease than the older children. The current study enriched our knowledge on the longitudinal effect of parental HIV/AIDS on children's emotional distress. Future psychological support might take the children's developmental stages and cultural appropriateness into consideration and deliver service for the most vulnerable group of children affected by HIV/AIDS. PMID:24090100

  19. Growing up without parents: socialisation and gender relations in orphaned-child-headed households in rural Zimbabwe.

    PubMed

    Francis-Chizororo, Monica

    2010-01-01

    The most distressing consequences of the HIV/AIDS pandemic's impact on children has been the development of child-headed households (CHHs). Child 'only' households challenge notions of the ideal home, family, and 'normal' childhood, as well as undermining international attempts to institute children's rights. The development of these households raises practical questions about how the children will cope without parental guidance during their childhood and how this experience will affect their adulthood. Drawing on ethnographic research with five child heads and their siblings, this article explores how orphaned children living in 'child only' households organise themselves in terms of household domestic and paid work roles, explores the socialisation of children by children and the negotiation of teenage girls' movement. Further, it examines whether the orphaned children are in some way attempting to 'mimic' previously existing family/household gender relations after parental death. The study showed that all members in the CHHs irrespective of age and gender are an integral part of household labour including food production. Although there is masculinisation of domestic chores in boys 'only' households, roles are distributed by age. On the other hand, households with a gender mix tended to follow traditional gender norms. Conflict often arose when boys controlled teenage girls' movement and sexuality. There is a need for further research on CHHs to better understand orphans' experiences, and to inform policy interventions. PMID:20879189

  20. 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

  1. 'Read me to resilience': Exploring the use of cultural stories to boost the positive adjustment of children orphaned by AIDS.

    PubMed

    Wood, Lesley; Theron, Linda; Mayaba, Nokhanyo

    2012-10-01

    The study explored whether and how culturally sensitive stories can encourage resilience in young children orphaned by AIDS. The purpose of the investigation was allied to the paradigm of positive psychology, which focuses on the promotion of potential strengths to buffer children against adversity, as well as on social ecological understandings of resilience, which emphasise that social ecologies have a duty to facilitate children's positive adjustment to adversity. A pre-post-intervention evaluation was used to gather qualitative data on orphaned children's resilience to AIDS-related adversity by employing participatory visual methods. The intervention, called Read-me-to-Resilience (Rm2R), consisted of telling 22 culturally sensitive stories to the children. We compared the pre- and post-intervention data for each participant before thematically analysing the total findings. Our analysis indicates that the children's resilience had been bolstered in the period between the pre-test and post-test. We conclude that culturally relevant stories could be used by South African caregivers, service providers, and educators as an accessible, inexpensive and ready-made tool to directly empower children who have been orphaned by AIDS. PMID:25860098

  2. Activation of the orphan nuclear receptor steroidogenic factor 1 by oxysterols

    PubMed Central

    Lala, Deepak S.; Syka, Peter M.; Lazarchik, Steven B.; Mangelsdorf, David J.; Parker, Keith L.; Heyman, Richard A.

    1997-01-01

    Steroidogenic factor 1 (SF-1), an orphan member of the intracellular receptor superfamily, plays an essential role in the development and function of multiple endocrine organs. It is expressed in all steroidogenic tissues where it regulates the P450 steroidogenic genes to generate physiologically active steroids. Although many of the functions of SF-1 in vivo have been defined, an unresolved question is whether a ligand modulates its transcriptional activity. Here, we show that 25-, 26-, or 27-hydroxycholesterol, known suppressors of cholesterol biosynthesis, enhance SF-1-dependent transcriptional activity. This activation is dependent upon the SF-1 activation function domain, and, is specific for SF-1 as several other receptors do not respond to these molecules. The oxysterols activate at concentrations comparable to those previously shown to inhibit cholesterol biosynthesis, and, can be derived from cholesterol by P450c27, an enzyme expressed within steroidogenic tissues. Recent studies have shown that the nuclear receptor LXR also is activated by oxysterols. We demonstrate that different oxysterols differ in their rank order potency for these two receptors, with 25-hydroxycholesterol preferentially activating SF-1 and 22(R)-hydroxycholesterol preferentially activating LXR. These results suggest that specific oxysterols may mediate transcriptional activation via different intracellular receptors. Finally, ligand-dependent transactivation of SF-1 by oxysterols may play an important role in enhancing steroidogenesis in vivo. PMID:9144161

  3. Agent of whirling disease meets orphan worm: phylogenomic analyses firmly place Myxozoa in Cnidaria.

    PubMed

    Nesnidal, Maximilian P; Helmkampf, Martin; Bruchhaus, Iris; El-Matbouli, Mansour; Hausdorf, Bernhard

    2013-01-01

    Myxozoa are microscopic obligate endoparasites with complex live cycles. Representatives are Myxobolus cerebralis, the causative agent of whirling disease in salmonids, and the enigmatic "orphan worm" Buddenbrockia plumatellae parasitizing in Bryozoa. Originally, Myxozoa were classified as protists, but later several metazoan characteristics were reported. However, their phylogenetic relationships remained doubtful. Some molecular phylogenetic analyses placed them as sister group to or even within Bilateria, whereas the possession of polar capsules that are similar to nematocysts of Cnidaria and of minicollagen genes suggest a close relationship between Myxozoa and Cnidaria. EST data of Buddenbrockia also indicated a cnidarian origin of Myxozoa, but were not sufficient to reject a closer relationship to bilaterians. Phylogenomic analyses of new genomic sequences of Myxobolus cerebralis firmly place Myxozoa as sister group to Medusozoa within Cnidaria. Based on the new dataset, the alternative hypothesis that Myxozoa form a clade with Bilateria can be rejected using topology tests. Sensitivity analyses indicate that this result is not affected by long branch attraction artifacts or compositional bias. PMID:23382916

  4. Subfertility with Defective Folliculogenesis in Female Mice Lacking Testicular Orphan Nuclear Receptor 4

    PubMed Central

    Chen, Lu-Min; Wang, Ruey-Sheng; Lee, Yi-Fen; Liu, Ning-Chun; Chang, Yu-Jia; Wu, Cheng-Chia; Xie, Shaozhen; Hung, Yao-Ching; Chang, Chawnshang

    2008-01-01

    Testicular orphan nuclear receptor 4 (TR4) plays essential roles for normal spermatogenesis in male mice. However, its roles in female fertility and ovarian function remain largely unknown. Here we found female mice lacking TR4 (TR4−/−) displayed subfertility and irregular estrous cycles. TR4−/− female mice ovaries were smaller with fewer or no preovulatory follicles and corpora lutea. After superovulation, TR4−/− female mice produced fewer oocytes, preovulatory follicles, and corpora lutea. In addition, more intensive granulosa apoptosis was found in TR4−/− ovaries. Functional analyses suggest that subfertility in TR4−/− female mice can be due to an ovarian defect with impaired folliculogenesis rather than a deficiency in pituitary gonadotropins. Molecular mechanism dissection of defective folliculogenesis found TR4 might induce LH receptor (LHR) gene expression via direct binding to its 5′ promoter. The consequence of reduced LHR expression in TR4−/− female mice might then result in reduced gonadal sex hormones via reduced expression of enzymes involved in steroidogenesis. Together, our results showed TR4 might play essential roles in normal folliculogenesis by influencing LHR signals. Modulation of TR4 expression and/or activation via its upstream signals or unidentified ligand(s) might allow us to develop small molecule(s) to control folliculogenesis. PMID:18174360

  5. The "Super Chimpanzee": The Ecological Dimensions of Rehabilitation of Orphan Chimpanzees in Guinea, West Africa.

    PubMed

    Ongman, Lissa; Colin, Christelle; Raballand, Estelle; Humle, Tatyana

    2013-01-01

    To date few studies, especially among non-human primates, have evaluated or monitored rehabilitation effectiveness and identified key species-specific behavioral indicators for release success. This four-months study aimed to identify behavioral indicators of rehabilitation success among ten infant and juvenile orphaned chimpanzees cared for in peer groups at the Centre for Conservation of Chimpanzees (CCC), Guinea, West Africa. Behavioral data focused on foraging skills and activity budget. During bush-outings, rehabilitants spent on average nearly a quarter of their activity budget foraging, resting or traveling, respectively. Neither age, sex, the level of abnormal behaviors demonstrated upon arrival nor human contact during bush-outings predicted individual dietary knowledge. However, individuals who spent more time arboreal demonstrated a greater dietary breadth than conspecifics who dwelled more terrestrially. Although our data failed to demonstrate a role of conspecific observation in dietary acquisition, we propose that the mingling of individuals from different geographical origins may act as a catalyst for acquiring new dietary knowledge, promoted by ecological opportunities offered during bush-outings. This "Super Chimpanzee" theory opens up new questions about cultural transmission and socially-biased learning among our closest living relatives and provides a novel outlook on rehabilitation in chimpanzees. PMID:26487312

  6. 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

  7. 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

  8. Developmental expression of orphan G protein-coupled receptor 50 in the mouse brain.

    PubMed

    Grünewald, Ellen; Tew, Kenneth D; Porteous, David J; Thomson, Pippa A

    2012-06-20

    Mental disorders have a complex etiology resulting from interactions between multiple genetic risk factors and stressful life events. Orphan G protein-coupled receptor 50 (GPR50) has been identified as a genetic risk factor for bipolar disorder and major depression in women, and there is additional genetic and functional evidence linking GPR50 to neurite outgrowth, lipid metabolism, and adaptive thermogenesis and torpor. However, in the absence of a ligand, a specific function has not been identified. Adult GPR50 expression has previously been reported in brain regions controlling the HPA axis, but its developmental expression is unknown. In this study, we performed extensive expression analysis of GPR50 and three protein interactors using rt-PCR and immunohistochemistry in the developing and adult mouse brain. Gpr50 is expressed at embryonic day 13 (E13), peaks at E18, and is predominantly expressed by neurons. Additionally we identified novel regions of Gpr50 expression, including brain stem nuclei involved in neurotransmitter signaling: the locus coeruleus, substantia nigra, and raphe nuclei, as well as nuclei involved in metabolic homeostasis. Gpr50 colocalizes with yeast-two-hybrid interactors Nogo-A, Abca2, and Cdh8 in the hypothalamus, amygdala, cortex, and selected brain stem nuclei at E18 and in the adult. With this study, we identify a link between GPR50 and neurotransmitter signaling and strengthen a likely role in stress response and energy homeostasis. PMID:22860215

  9. The paediatric rheumatologist and orphan disease – a story without happy ending

    PubMed Central

    Roszkiewicz, Justyna; Biernacka-Zielińska, Małgorzata

    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

  10. Hypoxia induces PDK4 gene expression through induction of the orphan nuclear receptor ERRγ.

    PubMed

    Lee, Ja Hee; Kim, Eun-Jin; Kim, Don-Kyu; Lee, Ji-Min; Park, Seung Bum; Lee, In-Kyu; Harris, Robert A; Lee, Mi-Ock; Choi, Hueng-Sik

    2012-01-01

    Multiple cellular signaling pathways that control metabolism and survival are activated when cell are incubated under hypoxic conditions. Activation of the hypoxia inducible factor (HIF)-1 promotes expression of genes that increase the capacity to cope with the stress imposed by a reduced oxygen environment. Here we show that the orphan nuclear receptor estrogen related receptor γ (ERRγ) plays a critical role in hypoxia-mediated activation of pyruvate dehydrogenase kinase 4 (PDK4) gene expression. ERRγ mRNA and protein levels were increased by hypoxia or desferrioxamine (DFO) treatment in hepatoma cell lines. Co-expression of HIF-1α and β increased ERRγ promoter activity as well as mRNA expression, while knockdown of endogenous HIF-1α reduced the hypoxia-mediated induction of ERRγ. In addition, hypoxia also increased the promoter activity and mRNA level of PDK4 in HepG2 cells. Adenovirus mediated-overexpression of ERRγ specifically increased PDK4 gene expression, while ablation of endogenous ERRγ significantly decreased hypoxia-mediated induction of PDK4 gene expression. Finally, GSK5182, an inverse agonist of ERRγ, strongly inhibited the hypoxia-mediated induction of PDK4 protein and promoter activity. Regulation of the transcriptional activity of ERRγ may provide a therapeutic approach for the regulation of PDK4 gene expression under hypoxia. PMID:23050013

  11. Orphan nuclear receptor estrogen-related receptor γ (ERRγ) is key regulator of hepatic gluconeogenesis.

    PubMed

    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

    2012-06-22

    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

  12. Hypoxia Induces PDK4 Gene Expression through Induction of the Orphan Nuclear Receptor ERRγ

    PubMed Central

    Lee, Ji-Min; Park, Seung Bum; Lee, In-Kyu; Harris, Robert A.; Lee, Mi-Ock; Choi, Hueng-Sik

    2012-01-01

    Multiple cellular signaling pathways that control metabolism and survival are activated when cell are incubated under hypoxic conditions. Activation of the hypoxia inducible factor (HIF)-1 promotes expression of genes that increase the capacity to cope with the stress imposed by a reduced oxygen environment. Here we show that the orphan nuclear receptor estrogen related receptor γ (ERRγ) plays a critical role in hypoxia–mediated activation of pyruvate dehydrogenase kinase 4 (PDK4) gene expression. ERRγ mRNA and protein levels were increased by hypoxia or desferrioxamine (DFO) treatment in hepatoma cell lines. Co-expression of HIF-1α and β increased ERRγ promoter activity as well as mRNA expression, while knockdown of endogenous HIF-1α reduced the hypoxia-mediated induction of ERRγ. In addition, hypoxia also increased the promoter activity and mRNA level of PDK4 in HepG2 cells. Adenovirus mediated-overexpression of ERRγ specifically increased PDK4 gene expression, while ablation of endogenous ERRγ significantly decreased hypoxia-mediated induction of PDK4 gene expression. Finally, GSK5182, an inverse agonist of ERRγ, strongly inhibited the hypoxia-mediated induction of PDK4 protein and promoter activity. Regulation of the transcriptional activity of ERRγ may provide a therapeutic approach for the regulation of PDK4 gene expression under hypoxia. PMID:23050013

  13. Orphan nuclear receptor TR3 acts in autophagic cell death via mitochondrial signaling pathway.

    PubMed

    Wang, Wei-jia; Wang, Yuan; Chen, Hang-zi; Xing, Yong-zhen; Li, Feng-wei; Zhang, Qian; Zhou, Bo; Zhang, Hong-kui; Zhang, Jie; Bian, Xue-li; Li, Li; Liu, Yuan; Zhao, Bi-xing; Chen, Yan; Wu, Rong; Li, An-zhong; Yao, Lu-ming; Chen, Ping; Zhang, Yi; Tian, Xu-yang; Beermann, Friedrich; Wu, Mian; Han, Jiahuai; Huang, Pei-qiang; Lin, Tianwei; Wu, Qiao

    2014-02-01

    Autophagy is linked to cell death, yet the associated mechanisms are largely undercharacterized. We discovered that melanoma, which is generally resistant to drug-induced apoptosis, can undergo autophagic cell death with the participation of orphan nuclear receptor TR3. A sequence of molecular events leading to cellular demise is launched by a specific chemical compound, 1-(3,4,5-trihydroxyphenyl)nonan-1-one, newly acquired from screening a library of TR3-targeting compounds. The autophagic cascade comprises TR3 translocation to mitochondria through interaction with the mitochondrial outer membrane protein Nix, crossing into the mitochondrial inner membrane through Tom40 and Tom70 channel proteins, dissipation of mitochondrial membrane potential by the permeability transition pore complex ANT1-VDAC1 and induction of autophagy. This process leads to excessive mitochondria clearance and irreversible cell death. It implicates a new approach to melanoma therapy through activation of a mitochondrial signaling pathway that integrates a nuclear receptor with autophagy for cell death. PMID:24316735

  14. Orphan nuclear receptor nurr1 as a potential novel marker for progression in human prostate cancer.

    PubMed

    Wang, Jian; Yang, Jing; Zou, Ying; Huang, Guo-Liang; He, Zhi-Wei

    2013-01-01

    A number of studies have indicated that Nurr1, which belongs to a novel class of orphan nuclear receptors (the NR4A family), is important for carcinogenesis. Here we investigated expression of Nurr1 protein in benign and malignant human prostate tissues and association with clinicopathologic features using immunohistochemical techniques. Moreover, we also investigated the ability of Nurr1 to influence proliferation, migration, invasion and apoptosis of human prostate cancer cells using small interfering RNA silencing. Immunohistochemical analysis revealed that the expression of Nurr1 protein was higher in prostate cancer tissues than in benign prostate tissue (P < 0.001), levels being positively correlated with tumor T classification (P = 0.003), N classification (P = 0.017), M classification (P = 0.011) and the Gleason score (P = 0.020) of prostate cancer patients. In vitro, silencing of endogenous Nurr1 attenuated cell proliferation, migration and invasion, and induced apoptosis of prostate cancer cells. These results suggest that Nurr1 may be used as an indicator for prostate cancer progression and be useful for novel potential therapeutic strategies. PMID:23679312

  15. Why orphan drug coverage reimbursement decision-making needs patient and public involvement.

    PubMed

    Douglas, Conor M W; Wilcox, Elizabeth; Burgess, Michael; Lynd, Larry D

    2015-05-01

    Recently there has been an increase in the active involvement of publics and patients in healthcare and research, which is extending their roles beyond the passive recipients of medicines. However, there has been noticeably less work engaging them into decision-making for healthcare rationing exercises, priority setting, health technology assessment, and coverage decision-making. This is particularly evident in reimbursement decision-making for 'orphan drugs' or drugs for rare diseases. Medicinal products for rare disease offer particular challenges in coverage decision-making because they often lack the 'evidence of efficacy' profiles of common drugs that have been trialed on larger populations. Furthermore, many of these drugs are priced in the high range, and with limited health care budgets the prospective opportunity costs of funding them means that those resources cannot be allocated elsewhere. Here we outline why decision-making for drugs for rare diseases could benefit from increased levels of publics and patients involvement, suggest some possible forms that involvement could take, and advocate for empirical experimentation in this area to evaluate the effects of such involvement. Focus is given to the Canadian context in which we are based; however, potentialities and challenges relating to involvement in this area are likely to be similar elsewhere. PMID:25641123

  16. The QQS orphan gene of Arabidopsis modulates carbon and nitrogen allocation in soybean

    PubMed Central

    Li, Ling; Wurtele, Eve Syrkin

    2015-01-01

    The genome of each species contains as high as 8% of genes that are uniquely present in that species. Little is known about the functional significance of these so-called species specific or orphan genes. The Arabidopsis thaliana gene Qua-Quine Starch (QQS) is species specific. Here, we show that altering QQS expression in Arabidopsis affects carbon partitioning to both starch and protein. We hypothesized QQS may be conserved in a feature other than primary sequence, and as such could function to impact composition in another species. To test the potential of QQS in affecting composition in an ectopic species, we introduced QQS into soybean. Soybean T1 lines expressing QQS have up to 80% decreased leaf starch and up to 60% increased leaf protein; T4 generation seeds from field-grown plants contain up to 13% less oil, while protein is increased by up to 18%. These data broaden the concept of QQS as a modulator of carbon and nitrogen allocation, and demonstrate that this species-specific gene can affect the seed composition of an agronomic species thought to have diverged from Arabidopsis 100 million years ago. PMID:25146936

  17. 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

  18. The orphan nuclear receptor small heterodimer partner mediates male infertility induced by diethylstilbestrol in mice

    PubMed Central

    Volle, David H.; Decourteix, Mélanie; Garo, Erwan; McNeilly, Judy; Fenichel, Patrick; Auwerx, Johan; McNeilly, Alan S.; Schoonjans, Kristina; Benahmed, Mohamed

    2009-01-01

    Studies in rodents have shown that male sexual function can be disrupted by fetal or neonatal administration of compounds that alter endocrine homeostasis, such as the synthetic nonsteroidal estrogen diethylstilbestrol (DES). Although the molecular basis for this effect remains unknown, estrogen receptors likely play a critical role in mediating DES-induced infertility. Recently, we showed that the orphan nuclear receptor small heterodimer partner (Nr0b2), which is both a target gene and a transcriptional repressor of estrogen receptors, controls testicular function by regulating germ cell entry into meiosis and testosterone synthesis. We therefore hypothesized that some of the harmful effects of DES on testes could be mediated through Nr0b2. Here, we present data demonstrating that Nr0b2 deficiency protected mice against the negative effects of DES on testis development and function. During postnatal development, Nr0b2-null mice were resistant to DES-mediated inhibition of germ cell differentiation, which may be the result of interference by Nr0b2 with retinoid signals that control meiosis. Adult Nr0b2-null male mice were also protected against the effects of DES; however, we suggest that this phenomenon was due to the removal of the repressive effects of Nr0b2 on steroidogenesis. Together, these data demonstrate that Nr0b2 plays a critical role in the pathophysiological changes induced by DES in the mouse testis. PMID:19884658

  19. Lessons from writing sessions: a school-based randomized trial with adolescent orphans in Rwanda

    PubMed Central

    Unterhitzenberger, Johanna; Rosner, Rita

    2014-01-01

    Background Treatments for adolescents affected by long-term loss in low- and middle-income countries are lacking. As school-based interventions are cost-efficient and easy to disseminate, an evaluation of this treatment setting for adolescents is worthwhile. Objective Examining the effect of a school-based unstructured emotional writing intervention (sensu Pennebaker, group 1) about the loss of a parent to reduce adaptation problems to loss, compared to writing about a hobby (group 2), and non-writing (group 3). Method We randomly assigned 14–18-year-old Rwandan orphans to one of the three conditions (n=23 per condition). Before and after the intervention, subjects completed the Prolonged Grief Questionnaire for Adolescents and the Mini International Neuropsychiatric Interview for Children and Adolescents, Part A, on depression as self-report measures of long-term effects of early parental loss. Results Repeated measures analyses of variance showed no differential effect for any of the three conditions but revealed a significant effect of time at posttest regarding grief severity. Reduction of grief symptoms was significantly higher in subjects with elevated grief. Depressive symptoms showed no significant change from pre- to posttest in the emotional writing condition, whereas they significantly decreased in the control condition. Conclusions Results imply that unstructured, brief emotional writing might not be indicated in adolescents affected by early parental loss who show severe and long-term distress; a more structured approach seems recommendable. PMID:25537814

  20. Principles for consistent value assessment and sustainable funding of orphan drugs in Europe.

    PubMed

    Gutierrez, Laura; Patris, Julien; Hutchings, Adam; Cowell, Warren

    2015-01-01

    The European Orphan Medicinal Products (OMP) Regulation has successfully encouraged research to develop treatments for rare diseases resulting in the authorisation of new OMPs in Europe. While decisions on OMP designation and marketing authorisation are made at the European Union level, reimbursement decisions are made at the national level. OMP value and affordability are high priority issues for policymakers and decisions regarding their pricing and funding are highly complex. There is currently no European consensus on how OMP value should be assessed and inequalities of access to OMPs have previously been observed. Against this background, policy makers in many countries are considering reforms to improve access to OMPs. This paper proposes ten principles to be considered when undertaking such reforms, from the perspective of an OMP manufacturer. We recommend the continued prioritisation of rare diseases by policymakers, an increased alignment between payer and regulatory frameworks, pricing centred on OMP value, and mechanisms to ensure long-term financial sustainability allowing a continuous and virtuous development of OMPs. Our recommendations support the development of more consistent frameworks and encourage collaboration between all stakeholders, including research-based industry, payers, clinicians, and patients. PMID:25935555

  1. The QQS orphan gene of Arabidopsis modulates carbon and nitrogen allocation in soybean.

    PubMed

    Li, Ling; Wurtele, Eve Syrkin

    2015-02-01

    The genome of each species contains as high as 8% of genes that are uniquely present in that species. Little is known about the functional significance of these so-called species specific or orphan genes. The Arabidopsis thaliana gene Qua-Quine Starch (QQS) is species specific. Here, we show that altering QQS expression in Arabidopsis affects carbon partitioning to both starch and protein. We hypothesized QQS may be conserved in a feature other than primary sequence, and as such could function to impact composition in another species. To test the potential of QQS in affecting composition in an ectopic species, we introduced QQS into soybean. Soybean T1 lines expressing QQS have up to 80% decreased leaf starch and up to 60% increased leaf protein; T4 generation seeds from field-grown plants contain up to 13% less oil, while protein is increased by up to 18%. These data broaden the concept of QQS as a modulator of carbon and nitrogen allocation, and demonstrate that this species-specific gene can affect the seed composition of an agronomic species thought to have diverged from Arabidopsis 100 million years ago. PMID:25146936

  2. 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

  3. 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

  4. Legal Briefing: Adult Orphans and the Unbefriended: Making Medical Decisions for Unrepresented Patients without Surrogates.

    PubMed

    Pope, Thaddeus Mason

    2015-01-01

    This issue's "Legal Briefing" column covers recent legal developments involving medical decision making for incapacitated patients who have no available legally authorized surrogate decision maker. These individuals are frequently referred to either as "adult orphans" or as "unbefriended," "isolated," or "unrepresented" patients. The challenges involved in obtaining consent for medical treatment on behalf of these individuals have been the subject of major policy reports. Indeed, caring for the unbefriended has even been described as the "single greatest category of problems" encountered in bioethics consultation. In 2012, JCE published a comprehensive review of the available mechanisms by which to make medical decisions for the unbefriended. The purpose of this "Legal Briefing" is to update the 2012 study. Accordingly, this "Legal Briefing" collects and describes significant legal developments from only the past three years. My basic assessment has not changed. "Existing mechanisms to address the issue of decision making for the unbefriended are scant and not uniform." Most facilities are "muddling through on an ad hoc basis." But the situation is not wholly negative. There have been a number of promising new initiatives. I group these developments into the following seven categories: 1. Increased Attention and Discussion 2. Prevention through Better Advance Care Planning 3. Prevention through Expanded Default Surrogate Lists 4. Statutorily Authorized Intramural Mechanisms 5. California Litigation Challenging the Team Approach 6. Public Guardianship 7. Improving Existing Guardianship Processes. PMID:26132070

  5. The ABCC6 Transporter as a Paradigm for Networking from an Orphan Disease to Complex Disorders.

    PubMed

    De Vilder, Eva Y G; Hosen, Mohammad Jakir; Vanakker, Olivier M

    2015-01-01

    The knowledge on the genetic etiology of complex disorders largely results from the study of rare monogenic disorders. Often these common and rare diseases show phenotypic overlap, though monogenic diseases generally have a more extreme symptomatology. ABCC6, the gene responsible for pseudoxanthoma elasticum, an autosomal recessive ectopic mineralization disorder, can be considered a paradigm gene with relevance that reaches far beyond this enigmatic orphan disease. Indeed, common traits such as chronic kidney disease or cardiovascular disorders have been linked to the ABCC6 gene. While during the last decade the awareness of the wide ramifications of ABCC6 has increased significantly, the gene itself and the transmembrane transporter it encodes have not unveiled all of the mysteries that surround them. To gain more insights, multiple approaches are being used including next-generation sequencing, computational methods, and various "omics" technologies. Much effort is made to place the vast amount of data that is gathered in an integrated system-biological network; the involvement of ABCC6 in common disorders provides a good view on the wide implications and potential of such a network. In this review, we summarize the network approaches used to study ABCC6 and the role of this gene in several complex diseases. PMID:26356190

  6. 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

  7. Agent of Whirling Disease Meets Orphan Worm: Phylogenomic Analyses Firmly Place Myxozoa in Cnidaria

    PubMed Central

    Nesnidal, Maximilian P.; Helmkampf, Martin; Bruchhaus, Iris; El-Matbouli, Mansour; Hausdorf, Bernhard

    2013-01-01

    Myxozoa are microscopic obligate endoparasites with complex live cycles. Representatives are Myxobolus cerebralis, the causative agent of whirling disease in salmonids, and the enigmatic “orphan worm” Buddenbrockia plumatellae parasitizing in Bryozoa. Originally, Myxozoa were classified as protists, but later several metazoan characteristics were reported. However, their phylogenetic relationships remained doubtful. Some molecular phylogenetic analyses placed them as sister group to or even within Bilateria, whereas the possession of polar capsules that are similar to nematocysts of Cnidaria and of minicollagen genes suggest a close relationship between Myxozoa and Cnidaria. EST data of Buddenbrockia also indicated a cnidarian origin of Myxozoa, but were not sufficient to reject a closer relationship to bilaterians. Phylogenomic analyses of new genomic sequences of Myxobolus cerebralis firmly place Myxozoa as sister group to Medusozoa within Cnidaria. Based on the new dataset, the alternative hypothesis that Myxozoa form a clade with Bilateria can be rejected using topology tests. Sensitivity analyses indicate that this result is not affected by long branch attraction artifacts or compositional bias. PMID:23382916

  8. The ABCC6 Transporter as a Paradigm for Networking from an Orphan Disease to Complex Disorders

    PubMed Central

    De Vilder, Eva Y. G.; Hosen, Mohammad Jakir; Vanakker, Olivier M.

    2015-01-01

    The knowledge on the genetic etiology of complex disorders largely results from the study of rare monogenic disorders. Often these common and rare diseases show phenotypic overlap, though monogenic diseases generally have a more extreme symptomatology. ABCC6, the gene responsible for pseudoxanthoma elasticum, an autosomal recessive ectopic mineralization disorder, can be considered a paradigm gene with relevance that reaches far beyond this enigmatic orphan disease. Indeed, common traits such as chronic kidney disease or cardiovascular disorders have been linked to the ABCC6 gene. While during the last decade the awareness of the wide ramifications of ABCC6 has increased significantly, the gene itself and the transmembrane transporter it encodes have not unveiled all of the mysteries that surround them. To gain more insights, multiple approaches are being used including next-generation sequencing, computational methods, and various “omics” technologies. Much effort is made to place the vast amount of data that is gathered in an integrated system-biological network; the involvement of ABCC6 in common disorders provides a good view on the wide implications and potential of such a network. In this review, we summarize the network approaches used to study ABCC6 and the role of this gene in several complex diseases. PMID:26356190

  9. 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

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

    PubMed

    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

    2015-09-29

    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

  11. Potentially traumatic experiences and sexual health among orphaned and separated adolescents in five low- and middle-income countries

    PubMed Central

    Gray, Christine L.; Whetten, Kathryn; Messer, Lynne C.; Whetten, Rachel A.; Ostermann, Jan; O'Donnell, Karen; Thielman, Nathan M.; Pence, Brian W.

    2016-01-01

    ABSTRACT Orphans and separated children (OSC) are a vulnerable population whose numbers are increasing, particularly in sub-Saharan Africa and Asia. Over 153 million children worldwide have lost one or both parents, including 17 million orphaned by AIDS, and millions more have been separated from their parents. As younger orphans enter adolescence, their sexual health and HIV-related risk behaviors become key considerations for their overall health. Importantly, their high prevalence of exposure to potentially traumatic events (PTEs) may put OSC at additional risk for adverse sexual health outcomes. The Positive Outcomes for Orphans study followed OSC randomly sampled from institution-based care and from family-based care, as well as a convenience sample of non-OSC, at six sites in five low-and middle-income countries. This analysis focused on the 90-month follow-up, during which adolescents 16 and older were assessed for sexual health, including age at sexual debut, past-year sex, past-year condom use, and perceptions of condom use. We specifically examined the relationship between PTEs and sexual health outcomes. Of the 1258 OSC and 138 non-OSC assessed, 11% reported ever having sex. Approximately 6% of participants reported recent sex and 5% reported having recent unprotected sex. However, 70% of those who had recent sex reported that they did not use a condom every time, and perceptions of condom use tended to be unfavorable for protection against sexual risk behavior. Nearly all (90%) of participants reported experiencing at least one lifetime PTE. For those who experienced “any” PTE, we found increased prevalence of recent sex (PR = 1.39 [0.47, 4.07]) and of recent unprotected sex (PR = 3.47 [0.60, 19.91]). This study highlights the need for caregivers, program managers, and policymakers to promote condom use for sexually active OSC and identify interventions for trauma support services. Orphans living in family-based care may also be particularly

  12. Why so many unknown genes? Partitioning orphans from a representative transcriptome of the lone star tick Amblyomma americanum

    PubMed Central

    2013-01-01

    Background Genomic resources within the phylum Arthropoda are largely limited to the true insects but are beginning to include unexplored subphyla, such as the Crustacea and Chelicerata. Investigations of these understudied taxa uncover high frequencies of orphan genes, which lack detectable sequence homology to genes in pre-existing databases. The ticks (Acari: Chelicerata) are one such understudied taxon for which genomic resources are urgently needed. Ticks are obligate blood-feeders that vector major diseases of humans, domesticated animals, and wildlife. In analyzing a transcriptome of the lone star tick Amblyomma americanum, one of the most abundant disease vectors in the United States, we find a high representation of unannotated sequences. We apply a general framework for quantifying the origin and true representation of unannotated sequences in a dataset and for evaluating the biological significance of orphan genes. Results Expressed sequence tags (ESTs) were derived from different life stages and populations of A. americanum and combined with ESTs available from GenBank to produce 14,310 ESTs, over twice the number previously available. The vast majority (71%) has no sequence homology to proteins archived in UniProtKB. We show that poor sequence or assembly quality is not a major contributor to this high representation by orphan genes. Moreover, most unannotated sequences are functional: a microarray experiment demonstrates that 59% of functional ESTs are unannotated. Lastly, we attempt to further annotate our EST dataset using genomic datasets from other members of the Acari, including Ixodes scapularis, four other tick species and the mite Tetranychus urticae. We find low homology with these species, consistent with significant divergence within this subclass. Conclusions We conclude that the abundance of orphan genes in A. americanum likely results from 1) taxonomic isolation stemming from divergence within the tick lineage and limited genomic

  13. Adverse childhood experiences, psychosocial well-being and cognitive development among orphans and abandoned children in five low income countries

    PubMed Central

    2014-01-01

    Background Development policymakers and child-care service providers are committed to improving the educational opportunities of the 153 million orphans worldwide. Nevertheless, the relationship between orphanhood and education outcomes is not well understood. Varying factors associated with differential educational attainment leave policymakers uncertain where to intervene. This study examines the relationship between psychosocial well-being and cognitive development in a cohort of orphans and abandoned children (OAC) relative to non-OAC in five low and middle income countries (LMICs) to understand better what factors are associated with success in learning for these children. Methods Positive Outcomes for Orphans (POFO) is a longitudinal study, following a cohort of single and double OAC in institutional and community-based settings in five LMICs in Southeast Asia and sub-Saharan Africa: Cambodia, Ethiopia, India, Kenya, and Tanzania. Employing two-stage random sampling survey methodology to identify representative samples of OAC in six sites, the POFO study aimed to better understand factors associated with child well-being. Using cross-sectional and child-level fixed effects regression analyses on 1,480 community based OAC and a comparison sample of non-OAC, this manuscript examines associations between emotional difficulties, cognitive development, and a variety of possible co-factors, including potentially traumatic events. Results The most salient finding is that increases in emotional difficulties are associated with lags in cognitive development for two separate measures of learning within and across multiple study sites. Exposure to potentially traumatic events, male gender, and lower socio-economic status are associated with more reported emotional difficultiesin some sites. Being female and having an illiterate caregiver is associated with lower performance on cognitive development tests in some sites, while greater wealth is associated with higher

  14. Potentially traumatic experiences and sexual health among orphaned and separated adolescents in five low- and middle-income countries.

    PubMed

    Gray, Christine L; Whetten, Kathryn; Messer, Lynne C; Whetten, Rachel A; Ostermann, Jan; O'Donnell, Karen; Thielman, Nathan M; Pence, Brian W

    2016-07-01

    Orphans and separated children (OSC) are a vulnerable population whose numbers are increasing, particularly in sub-Saharan Africa and Asia. Over 153 million children worldwide have lost one or both parents, including 17 million orphaned by AIDS, and millions more have been separated from their parents. As younger orphans enter adolescence, their sexual health and HIV-related risk behaviors become key considerations for their overall health. Importantly, their high prevalence of exposure to potentially traumatic events (PTEs) may put OSC at additional risk for adverse sexual health outcomes. The Positive Outcomes for Orphans study followed OSC randomly sampled from institution-based care and from family-based care, as well as a convenience sample of non-OSC, at six sites in five low-and middle-income countries. This analysis focused on the 90-month follow-up, during which adolescents 16 and older were assessed for sexual health, including age at sexual debut, past-year sex, past-year condom use, and perceptions of condom use. We specifically examined the relationship between PTEs and sexual health outcomes. Of the 1258 OSC and 138 non-OSC assessed, 11% reported ever having sex. Approximately 6% of participants reported recent sex and 5% reported having recent unprotected sex. However, 70% of those who had recent sex reported that they did not use a condom every time, and perceptions of condom use tended to be unfavorable for protection against sexual risk behavior. Nearly all (90%) of participants reported experiencing at least one lifetime PTE. For those who experienced "any" PTE, we found increased prevalence of recent sex (PR = 1.39 [0.47, 4.07]) and of recent unprotected sex (PR = 3.47 [0.60, 19.91]). This study highlights the need for caregivers, program managers, and policymakers to promote condom use for sexually active OSC and identify interventions for trauma support services. Orphans living in family-based care may also be particularly vulnerable

  15. Low-Density Lipoprotein Receptor-Related Protein 6 (LRP6) Is a Novel Nutritional Therapeutic Target for Hyperlipidemia, Non-Alcoholic Fatty Liver Disease, and Atherosclerosis

    PubMed Central

    Go, Gwang-woong

    2015-01-01

    Low-density lipoprotein receptor-related protein 6 (LRP6) is a member of the low-density lipoprotein receptor family and has a unique structure, which facilitates its multiple functions as a co-receptor for Wnt/β-catenin signaling and as a ligand receptor for endocytosis. The role LRP6 plays in metabolic regulation, specifically in the nutrient-sensing pathway, has recently garnered considerable interest. Patients carrying an LRP6 mutation exhibit elevated levels of LDL cholesterol, triglycerides, and fasting glucose, which cooperatively constitute the risk factors of metabolic syndrome and atherosclerosis. Since the discovery of this mutation, the general role of LRP6 in lipid homeostasis, glucose metabolism, and atherosclerosis has been thoroughly researched. These studies have demonstrated that LRP6 plays a role in LDL receptor-mediated LDL uptake. In addition, when the LRP6 mutant impaired Wnt-LRP6 signaling, hyperlipidemia, non-alcoholic fatty liver disease, and atherosclerosis developed. LRP6 regulates lipid homeostasis and body fat mass via the nutrient-sensing mechanistic target of the rapamycin (mTOR) pathway. Furthermore, the mutant LRP6 triggers atherosclerosis by activating platelet-derived growth factor (PDGF)-dependent vascular smooth muscle cell differentiation. This review highlights the exceptional opportunities to study the pathophysiologic contributions of LRP6 to metabolic syndrome and cardiovascular diseases, which implicate LRP6 as a latent regulator of lipid metabolism and a novel therapeutic target for nutritional intervention. PMID:26046396

  16. Low-density lipoprotein receptor-related protein-1 : a serial clearance homeostatic mechanism controlling Alzheimer's amyloid β-peptide elimination from the brain

    PubMed Central

    Zlokovic, Berislav V.; Deane, Rashid; Sagare, Abhay P.; Bell, Robert D.; Winkler, Ethan A.

    2010-01-01

    Low-density lipoprotein receptor-related protein-1 (LRP1), a member of the LDL receptor family, has major roles in the cellular transport of cholesterol, endocytosis of forty structurally diverse ligands, transcytosis of ligands across the blood-brain barrier, and transmembrane and nuclear signaling. Recent evidence indicates that LRP1 regulates brain and systemic clearance of Alzheimer's disease (AD) amyloid β-peptide (Aβ). According to the two hit vascular hypothesis for AD, vascular damage precedes cerebrovascular and brain Aβ accumulation (hit 1) which then further amplifies neurovascular dysfunction (hit 2) preceding neurodegeneration. In this study, we discuss the roles of LRP1 during the hit 1 and hit 2 stage of AD pathogenesis and describe a three-level serial LRP1-dependent homeostatic control of Aβ clearance including (i) cell-surface LRP1 at the BBB and cerebrovascular cells mediating brain-to-blood Aβ clearance (ii) circulating LRP1 providing a key endogenous peripheral ‘sink’ activity for plasma Aβ which prevents free Aβ access to the brain, and (iii) LRP1 in the liver mediating systemic Aβ clearance. Pitfalls in experimental Aβ brain clearance measurements with the concurrent use of peptides/proteins such as receptor-associated protein and aprotinin are also discussed. We suggest that LRP1 has a critical role in AD pathogenesis and is an important therapeutic target in AD. PMID:20854368

  17. Low Density Lipoprotein-Receptor Related Protein 1 Is Differentially Expressed by Neuronal and Glial Populations in the Developing and Mature Mouse Central Nervous System

    PubMed Central

    Auderset, Loic; Cullen, Carlie L.; Young, Kaylene M.

    2016-01-01

    The low density lipoprotein-receptor related protein 1 (LRP1) is a large endocytic cell surface receptor that is known to interact with a variety of ligands, intracellular adaptor proteins and other cell surface receptors to regulate cellular behaviours ranging from proliferation to cell fate specification, migration, axon guidance, and lipid metabolism. A number of studies have demonstrated that LRP1 is expressed in the brain, yet it is unclear which central nervous system cell types express LRP1 during development and in adulthood. Herein we undertake a detailed study of LRP1 expression within the mouse brain and spinal cord, examining a number of developmental stages ranging from embryonic day 13.5 to postnatal day 60. We report that LRP1 expression in the brain peaks during postnatal development. On a cellular level, LRP1 is expressed by radial glia, neuroblasts, microglia, oligodendrocyte progenitor cells (OPCs), astrocytes and neurons, with the exception of parvalbumin+ interneurons in the cortex. Most cell populations exhibit stable expression of LRP1 throughout development; however, the proportion of OPCs that express LRP1 increases significantly from ~69% at E15.5 to ~99% in adulthood. We also report that LRP1 expression is rapidly lost as OPCs differentiate, and is absent from all oligodendrocytes, including newborn oligodendrocytes. While LRP1 function has been primarily examined in mature neurons, these expression data suggest it plays a more critical role in glial cell regulation–where expression levels are much higher. PMID:27280679

  18. Low Density Lipoprotein-Receptor Related Protein 1 Is Differentially Expressed by Neuronal and Glial Populations in the Developing and Mature Mouse Central Nervous System.

    PubMed

    Auderset, Loic; Cullen, Carlie L; Young, Kaylene M

    2016-01-01

    The low density lipoprotein-receptor related protein 1 (LRP1) is a large endocytic cell surface receptor that is known to interact with a variety of ligands, intracellular adaptor proteins and other cell surface receptors to regulate cellular behaviours ranging from proliferation to cell fate specification, migration, axon guidance, and lipid metabolism. A number of studies have demonstrated that LRP1 is expressed in the brain, yet it is unclear which central nervous system cell types express LRP1 during development and in adulthood. Herein we undertake a detailed study of LRP1 expression within the mouse brain and spinal cord, examining a number of developmental stages ranging from embryonic day 13.5 to postnatal day 60. We report that LRP1 expression in the brain peaks during postnatal development. On a cellular level, LRP1 is expressed by radial glia, neuroblasts, microglia, oligodendrocyte progenitor cells (OPCs), astrocytes and neurons, with the exception of parvalbumin+ interneurons in the cortex. Most cell populations exhibit stable expression of LRP1 throughout development; however, the proportion of OPCs that express LRP1 increases significantly from ~69% at E15.5 to ~99% in adulthood. We also report that LRP1 expression is rapidly lost as OPCs differentiate, and is absent from all oligodendrocytes, including newborn oligodendrocytes. While LRP1 function has been primarily examined in mature neurons, these expression data suggest it plays a more critical role in glial cell regulation-where expression levels are much higher. PMID:27280679

  19. Neuronal low-density lipoprotein receptor-related protein 1 (LRP1) enhances the anti-apoptotic effect of intravenous immunoglobulin (IVIg) in ischemic stroke.

    PubMed

    Lok, Ker Zhing; Manzanero, Silvia; Arumugam, Thiruma V

    2016-08-01

    The low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional and multi-ligand endocytic receptor abundantly expressed in neurons. Intravenous immunoglobulin (IVIg) is a purified preparation of plasma-derived human immunoglobulin used for the treatment of several neurological inflammatory disorders, and proposed for the treatment of stroke for its potent neuroprotective effects. LRP1 has been shown to be involved in the transcytosis of IVIg, and IVIg-LRP1 interaction leads to LRP1 tyrosine phosphorylation, which may contribute to the anti-inflammatory effects of IVIg. However, the question remains whether IVIg could induce its neuroprotective effects via LRP1 in neurons under ischemic stroke conditions. In cultured neurons and in a transient ischemic mouse model, ischemia decrease LRP1 levels and phosphorylation, and IVIg blocks these effects. In ischemic neurons, LRP1 antagonism by receptor associated protein (RAP) enhances the activation of pro-death signaling pathways such as nuclear factor-kappa B (NF-κB), mitogen-activated protein kinases (MAPKs), and caspase-3, and IVIg reduces these effects. When applied to ischemic neuronal cultures, RAP induces a dramatic drop in Akt activation, and IVIg reverses this effect, as it does with the decrease in Bcl-2 levels caused by ischemic injury in the presence of RAP. Altogether, these results show evidence of LRP1 expression and activity modulation by IVIg, and support the role of LRP1 as a partner of IVIg in the execution of its neuroprotective effects. PMID:27181517

  20. Extracellular matrix structure and tissue stiffness control postnatal lung development through the lipoprotein receptor-related protein 5/Tie2 signaling system.

    PubMed

    Mammoto, Tadanori; Jiang, Elisabeth; Jiang, Amanda; Mammoto, Akiko

    2013-12-01

    Physical properties of the tissues and remodeling of extracellular matrix (ECM) play an important role in organ development. Recently, we have reported that low-density lipoprotein receptor-related protein (LRP) 5/Tie2 signaling controls postnatal lung development by modulating angiogenesis. Here we show that tissue stiffness modulated by the ECM cross-linking enzyme, lysyl oxidase (LOX), regulates postnatal lung development through LRP5-Tie2 signaling. The expression of LRP5 and Tie2 is up-regulated twofold in lung microvascular endothelial cells when cultured on stiff matrix compared to those cultured on soft matrix in vitro. LOX inhibitor, β-aminopropionitrile, disrupts lung ECM (collagen I, III, and VI, and elastin) structures, softens neonatal mouse lung tissue by 20%, and down-regulates the expression of LRP5 and Tie2 by 20 and 60%, respectively, which leads to the inhibition of postnatal lung development (30% increase in mean linear intercept, 1.5-fold increase in air space area). Importantly, hyperoxia treatment (Postnatal Days 1-10) disrupts ECM structure and stiffens mouse lung tissue by up-regulating LOX activity, thereby increasing LRP5 and Tie2 expression and deregulating alveolar morphogenesis in neonatal mice, which is attenuated by inhibiting LOX activity. These findings suggest that appropriate physical properties of lung tissue are necessary for physiological postnatal lung development, and deregulation of this mechanism contributes to postnatal lung developmental disorders, such as bronchopulmonary dysplasia. PMID:23841513

  1. Low-density lipoprotein receptor-related protein-1 mediates endocytic clearance of tissue inhibitor of metalloproteinases-1 and promotes its cytokine-like activities.

    PubMed

    Thevenard, Jessica; Verzeaux, Laurie; Devy, Jerôme; Etique, Nicolas; Jeanne, Albin; Schneider, Christophe; Hachet, Cathy; Ferracci, Géraldine; David, Marion; Martiny, Laurent; Charpentier, Emmanuelle; Khrestchatisky, Michel; Rivera, Santiago; Dedieu, Stéphane; Emonard, Hervé

    2014-01-01

    Tissue inhibitor of metalloproteinases-1 (TIMP-1) regulates the extracellular matrix turnover by inhibiting the proteolytic activity of matrix metalloproteinases (MMPs). TIMP-1 also displays MMP-independent activities that influence the behavior of various cell types including neuronal plasticity, but the underlying molecular mechanisms remain mostly unknown. The trans-membrane receptor low-density lipoprotein receptor-related protein-1 (LRP-1) consists of a large extracellular chain with distinct ligand-binding domains that interact with numerous ligands including TIMP-2 and TIMP-3 and a short transmembrane chain with intracellular motifs that allow endocytosis and confer signaling properties to LRP-1. We addressed TIMP-1 interaction with recombinant ligand-binding domains of LRP-1 expressed by CHO cells for endocytosis study, or linked onto sensor chips for surface plasmon resonance analysis. Primary cortical neurons bound and internalized endogenous TIMP-1 through a mechanism mediated by LRP-1. This resulted in inhibition of neurite outgrowth and increased growth cone volume. Using a mutated inactive TIMP-1 variant we showed that TIMP-1 effect on neurone morphology was independent of its MMP inhibitory activity. We conclude that TIMP-1 is a new ligand of LRP-1 and we highlight a new example of its MMP-independent, cytokine-like functions. PMID:25075518

  2. Low-Density Lipoprotein Receptor-Related Protein-1 Mediates Endocytic Clearance of Tissue Inhibitor of Metalloproteinases-1 and Promotes Its Cytokine-Like Activities

    PubMed Central

    Devy, Jerôme; Etique, Nicolas; Jeanne, Albin; Schneider, Christophe; Hachet, Cathy; Ferracci, Géraldine; David, Marion; Martiny, Laurent; Charpentier, Emmanuelle; Khrestchatisky, Michel; Rivera, Santiago; Dedieu, Stéphane; Emonard, Hervé

    2014-01-01

    Tissue inhibitor of metalloproteinases-1 (TIMP-1) regulates the extracellular matrix turnover by inhibiting the proteolytic activity of matrix metalloproteinases (MMPs). TIMP-1 also displays MMP-independent activities that influence the behavior of various cell types including neuronal plasticity, but the underlying molecular mechanisms remain mostly unknown. The trans-membrane receptor low-density lipoprotein receptor-related protein-1 (LRP-1) consists of a large extracellular chain with distinct ligand-binding domains that interact with numerous ligands including TIMP-2 and TIMP-3 and a short transmembrane chain with intracellular motifs that allow endocytosis and confer signaling properties to LRP-1. We addressed TIMP-1 interaction with recombinant ligand-binding domains of LRP-1 expressed by CHO cells for endocytosis study, or linked onto sensor chips for surface plasmon resonance analysis. Primary cortical neurons bound and internalized endogenous TIMP-1 through a mechanism mediated by LRP-1. This resulted in inhibition of neurite outgrowth and increased growth cone volume. Using a mutated inactive TIMP-1 variant we showed that TIMP-1 effect on neurone morphology was independent of its MMP inhibitory activity. We conclude that TIMP-1 is a new ligand of LRP-1 and we highlight a new example of its MMP-independent, cytokine-like functions. PMID:25075518

  3. Acceleration of Lung Regeneration by Platelet-Rich Plasma Extract through the Low-Density Lipoprotein Receptor-Related Protein 5-Tie2 Pathway.

    PubMed

    Mammoto, Tadanori; Chen, Zhao; Jiang, Amanda; Jiang, Elisabeth; Ingber, Donald E; Mammoto, Akiko

    2016-01-01

    Angiogenesis, the growth of new blood vessels, plays a key role in organ development, homeostasis, and regeneration. The cooperation of multiple angiogenic factors, rather than a single factor, is required for physiological angiogenesis. Recently, we have reported that soluble platelet-rich plasma (PRP) extract, which contains abundant angiopoietin-1 and multiple other angiogenic factors, stimulates angiogenesis and maintains vascular integrity in vitro and in vivo. In this report, we have demonstrated that mouse PRP extract increases phosphorylation levels of the Wnt coreceptor low-density lipoprotein receptor-related protein 5 (LRP5) and thereby activates angiogenic factor receptor Tie2 in endothelial cells (ECs) and accelerates EC sprouting and lung epithelial cell budding in vitro. PRP extract also increases phosphorylation levels of Tie2 in the mouse lungs and accelerates compensatory lung growth and recovery of exercise capacity after unilateral pneumonectomy in mice, whereas soluble Tie2 receptor or Lrp5 knockdown attenuates the effects of PRP extract. Because human PRP extract is generated from autologous peripheral blood and can be stored at -80°C, our findings may lead to the development of novel therapeutic interventions for various angiogenesis-related lung diseases and to the improvement of strategies for lung regeneration. PMID:26091161

  4. Blockade of Glucocorticoid-Induced Tumor Necrosis Factor-Receptor-Related Protein Signaling Ameliorates Murine Collagen-Induced Arthritis by Modulating Follicular Helper T Cells.

    PubMed

    Ma, Jie; Feng, Dingqi; Wei, Yancai; Tian, Jie; Tang, Xinyi; Rui, Ke; Lu, Liwei; Xu, Huaxi; Wang, Shengjun

    2016-06-01

    Recent studies have shown that glucocorticoid-induced tumor necrosis factor-receptor-related protein (GITR) and its ligand (GITRL) are critically involved in the pathogenesis of autoimmune arthritis, but the role of GITRL/GITR signaling in modulating CD4(+) follicular helper T (Tfh) cell response during autoimmune arthritis remains largely unclear. We showed that splenic Tfh cells from mice with collagen-induced arthritis expressed higher levels of GITR compared with non-Tfh cells. In vitro, GITRL treatment markedly enhanced the percentage and number of Tfh cells. The administration of GITR fused to fragment crystallizable of IgG protein in mice with collagen-induced arthritis suppressed the Tfh cell response, resulting in ameliorated disease severity, and reduced production of autoantibody and the number of autoantibody-secreting cells in both the spleen and bone marrow. Together, these results indicate that blockade of GITR signaling can ameliorate arthritis progression mainly by modulating the Tfh cell response. PMID:27106763

  5. 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

  6. Family Economic Strengthening and Parenting Stress Among Caregivers of AIDS-Orphaned Children: Results from a Cluster Randomized Clinical Trial in Uganda

    PubMed Central

    Nabunya, Proscovia; Ssewamala, Fred M.; Ilic, Vilma

    2014-01-01

    This study examines the impact of a family economic strengthening intervention on parenting stress among caregivers of AIDS-orphaned children in Uganda. The study uses data from a 4-year (2008-2012) NIMH randomized clinical trial for AIDS-orphaned children known as Suubi-Maka (N=346 dyads). Child-caregiver dyads from 10 comparable primary schools were randomly assigned to either the control group (n=167 dyads) receiving usual care for school-going orphaned children (such as food aid and scholastic materials) or the treatment group (n=179 dyads) receiving a family economic strengthening intervention (focused on a matched savings account), financial planning and management workshops over and above the usual care. Interviews were conducted at baseline, 12 months and 24 months follow-up. This study uses data from baseline and 24 months post-intervention. We use multivariate regression methods, controlling for socioeconomic characteristics. At 24 months, caregivers in the treatment group reported significantly lower levels of parenting stress compared to caregivers in the control group. Findings from this study point to the potential of a family economic strengthening intervention to improve caregiver’s psychosocial wellbeing and that of their families. We conclude that programs and policies aimed at improving the psychosocial wellbeing of families caring for AIDS-orphaned children may consider incorporating economic strengthening components in their programming to help support these kinds of families, caregivers of AIDS-orphaned children especially those residing in developing countries. PMID:25136142

  7. Promoting uptake of child HIV testing: an evaluation of the role of a home visiting program for orphans and vulnerable children in South Africa

    PubMed Central

    Thurman, Tonya R.; Luckett, Brian; Taylor, Tory; Carnay, Melissa

    2016-01-01

    ABSTRACT HIV counseling and testing (HCT) is critical for children in generalized epidemic settings, but significant shortfalls in coverage persist, notably among orphans and others at disproportionate risk of infection. This study investigates the impact of a home visiting program in South Africa on orphaned and vulnerable children’s uptake of HCT. Using propensity score matching, survey data for children receiving home visits from trained community-based care workers were compared to data from children living in similar households that had not yet received home visits (n = 1324). Home visits by community-based care workers increased the odds of a child being tested by 97% (OR = 1.97, 95% CI = 1.34–2.92). The home visitation program had an especially pronounced effect on orphans, more than doubling their odds of being tested (OR = 2.12, 95% CI = 1.00–4.47) compared to orphans living in similar households that did not receive home visits. Orphan status alone had no effect on HCT independent of program exposure, suggesting that the program was uniquely able to increase testing in this subgroup. Results highlight the potential for increasing HCT access among children at high risk through targeted community-based initiatives. PMID:27306743

  8. Promoting uptake of child HIV testing: an evaluation of the role of a home visiting program for orphans and vulnerable children in South Africa.

    PubMed

    Thurman, Tonya R; Luckett, Brian; Taylor, Tory; Carnay, Melissa

    2016-03-01

    HIV counseling and testing (HCT) is critical for children in generalized epidemic settings, but significant shortfalls in coverage persist, notably among orphans and others at disproportionate risk of infection. This study investigates the impact of a home visiting program in South Africa on orphaned and vulnerable children's uptake of HCT. Using propensity score matching, survey data for children receiving home visits from trained community-based care workers were compared to data from children living in similar households that had not yet received home visits (n = 1324). Home visits by community-based care workers increased the odds of a child being tested by 97% (OR = 1.97, 95% CI = 1.34-2.92). The home visitation program had an especially pronounced effect on orphans, more than doubling their odds of being tested (OR = 2.12, 95% CI = 1.00-4.47) compared to orphans living in similar households that did not receive home visits. Orphan status alone had no effect on HCT independent of program exposure, suggesting that the program was uniquely able to increase testing in this subgroup. Results highlight the potential for increasing HCT access among children at high risk through targeted community-based initiatives. PMID:27391993

  9. Family Economic Strengthening and Parenting Stress Among Caregivers of AIDS-Orphaned Children: Results from a Cluster Randomized Clinical Trial in Uganda.

    PubMed

    Nabunya, Proscovia; Ssewamala, Fred M; Ilic, Vilma

    2014-09-01

    This study examines the impact of a family economic strengthening intervention on parenting stress among caregivers of AIDS-orphaned children in Uganda. The study uses data from a 4-year (2008-2012) NIMH randomized clinical trial for AIDS-orphaned children known as Suubi-Maka (N=346 dyads). Child-caregiver dyads from 10 comparable primary schools were randomly assigned to either the control group (n=167 dyads) receiving usual care for school-going orphaned children (such as food aid and scholastic materials) or the treatment group (n=179 dyads) receiving a family economic strengthening intervention (focused on a matched savings account), financial planning and management workshops over and above the usual care. Interviews were conducted at baseline, 12 months and 24 months follow-up. This study uses data from baseline and 24 months post-intervention. We use multivariate regression methods, controlling for socioeconomic characteristics. At 24 months, caregivers in the treatment group reported significantly lower levels of parenting stress compared to caregivers in the control group. Findings from this study point to the potential of a family economic strengthening intervention to improve caregiver's psychosocial wellbeing and that of their families. We conclude that programs and policies aimed at improving the psychosocial wellbeing of families caring for AIDS-orphaned children may consider incorporating economic strengthening components in their programming to help support these kinds of families, caregivers of AIDS-orphaned children especially those residing in developing countries. PMID:25136142

  10. De-Orphaning the Structural Proteome through Reciprocal Comparison of Evolutionarily Important Structural Features

    PubMed Central

    Ward, R. Matthew; Erdin, Serkan; Tran, Tuan A.; Kristensen, David M.; Lisewski, Andreas Martin; Lichtarge, Olivier

    2008-01-01

    Function prediction frequently relies on comparing genes or gene products to search for relevant similarities. Because the number of protein structures with unknown function is mushrooming, however, we asked here whether such comparisons could be improved by focusing narrowly on the key functional features of protein structures, as defined by the Evolutionary Trace (ET). Therefore a series of algorithms was built to (a) extract local motifs (3D templates) from protein structures based on ET ranking of residue importance; (b) to assess their geometric and evolutionary similarity to other structures; and (c) to transfer enzyme annotation whenever a plurality was reached across matches. Whereas a prototype had only been 80% accurate and was not scalable, here a speedy new matching algorithm enabled large-scale searches for reciprocal matches and thus raised annotation specificity to 100% in both positive and negative controls of 49 enzymes and 50 non-enzymes, respectively—in one case even identifying an annotation error—while maintaining sensitivity (∼60%). Critically, this Evolutionary Trace Annotation (ETA) pipeline requires no prior knowledge of functional mechanisms. It could thus be applied in a large-scale retrospective study of 1218 structural genomics enzymes and reached 92% accuracy. Likewise, it was applied to all 2935 unannotated structural genomics proteins and predicted enzymatic functions in 320 cases: 258 on first pass and 62 more on second pass. Controls and initial analyses suggest that these predictions are reliable. Thus the large-scale evolutionary integration of sequence-structure-function data, here through reciprocal identification of local, functionally important structural features, may contribute significantly to de-orphaning the structural proteome. PMID:18461181

  11. Orphan G protein-coupled receptor GPR116 regulates pulmonary surfactant pool size.

    PubMed

    Bridges, James P; Ludwig, Marie-Gabrielle; Mueller, Matthias; Kinzel, Bernd; Sato, Atsuyasu; Xu, Yan; Whitsett, Jeffrey A; Ikegami, Machiko

    2013-09-01

    Pulmonary surfactant levels within the alveoli are tightly regulated to maintain lung volumes and promote efficient gas exchange across the air/blood barrier. Quantitative and qualitative abnormalities in surfactant are associated with severe lung diseases in children and adults. Although the cellular and molecular mechanisms that control surfactant metabolism have been studied intensively, the critical molecular pathways that sense and regulate endogenous surfactant levels within the alveolus have not been identified and constitute a fundamental knowledge gap in the field. In this study, we demonstrate that expression of an orphan G protein-coupled receptor, GPR116, in the murine lung is developmentally regulated, reaching maximal levels 1 day after birth, and is highly expressed on the apical surface of alveolar type I and type II epithelial cells. To define the physiological role of GPR116 in vivo, mice with a targeted mutation of the Gpr116 locus, Gpr116(Δexon17), were generated. Gpr116(Δexon17) mice developed a profound accumulation of alveolar surfactant phospholipids at 4 weeks of age (12-fold) that was further increased at 20 weeks of age (30-fold). Surfactant accumulation in Gpr116(Δexon17) mice was associated with increased saturated phosphatidylcholine synthesis at 4 weeks and the presence of enlarged, lipid-laden macrophages, neutrophilia, and alveolar destruction at 20 weeks. mRNA microarray analyses indicated that P2RY2, a purinergic receptor known to mediate surfactant secretion, was induced in Gpr116(Δexon17) type II cells. Collectively, these data support the concept that GPR116 functions as a molecular sensor of alveolar surfactant lipid pool sizes by regulating surfactant secretion. PMID:23590306

  12. Histone acetylation regulates orphan nuclear receptor NR4A1 expression in hypercholesterolaemia.

    PubMed

    Xie, Xina; Song, Xuhong; Yuan, Song; Cai, Haitao; Chen, Yequn; Chang, Xiaolan; Liang, Bin; Huang, Dongyang

    2015-12-01

    Hypercholesterolaemia and inflammation are correlated with atherogenesis. Orphan nuclear receptor NR4A1, as a key regulator of inflammation, is closely associated with lipid levels in vivo. However, the mechanism by which lipids regulate NR4A1 expression remains unknown. We aimed to elucidate the underlying mechanism of NR4A1 expression in monocytes during hypercholesterolaemia, and reveal the potential role of NR4A1 in hypercholesterolaemia-induced circulating inflammation. Circulating leucocytes were collected from blood samples of 139 patients with hypercholesterolaemia and 139 sex- and age-matched healthy subjects. We found that there was a low-grade inflammatory state and higher expression of NR4A1 in patients. Both total cholesterol and low-density lipoprotein cholesterol levels in plasma were positively correlated with NR4A1 mRNA level. ChIP revealed that acetylation of histone H3 was enriched in the NR4A1 promoter region in patients. Human mononuclear cell lines THP-1 and U937 were treated with cholesterol. Supporting our clinical observations, cholesterol enhanced p300 acetyltransferase and decreased HDAC7 (histone deacetylase 7) recruitment to the NR4A1 promoter region, resulting in histone H3 hyperacetylation and further contributing to NR4A1 up-regulation in monocytes. Moreover, cytosporone B, an NR4A1 agonist, completely reversed cholesterol-induced IL-6 (interleukin 6) and MCP-1 (monocyte chemoattractant protein 1) expression to below basal levels, and knockdown of NR4A1 expression by siRNA not only mimicked, but also exaggerated the effects of cholesterol on inflammatory biomarker up-regulation. Thus we conclude that histone acetylation contributes to the regulation of NR4A1 expression in hypercholesterolaemia, and that NR4A1 expression reduces hypercholesterolaemia-induced inflammation. PMID:26396259

  13. 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.

  14. Orphans in the Human Cytochrome P450 Superfamily: Approaches to Discovering Functions and Relevance in Pharmacology

    PubMed Central

    Cheng, Qian

    2011-01-01

    As a result of technical advances in recombinant DNA technology and nucleotide sequencing, entire genome sequences have become available in the past decade and offer potential in understanding diseases. However, a central problem in the biochemical sciences is that the functions of only a fraction of the genes/proteins are known, and this is also an issue in pharmacology. This review is focused on issues related to the functions of cytochrome P450 (P450) enzymes. P450 functions can be categorized in several groups: 1) Some P450s have critical roles in the metabolism of endogenous substrates (e.g., sterols and fat-soluble vitamins). 2) Some P450s are not generally critical to normal physiology but function in relatively nonselective protection from the many xenobiotic chemicals to which mammals (including humans) are exposed in their diets [as well as more anthropomorphic chemicals (e.g., drugs, pesticides)]. 3) Some P450s have not been extensively studied and are termed “orphans” here. With regard to elucidation of any physiological functions of the orphan P450s, the major subject of this review, it is clear that simple trial-and-error approaches with individual substrate candidates will not be very productive in addressing questions about function. A series of liquid chromatography/mass spectrometry/informatics approaches are discussed, along with some successes with both human and bacterial P450s. Current information on what are still considered “orphan” P450s is presented. The potential for application of some of these approaches to other enzyme systems is also discussed. PMID:21737533

  15. Saving lives for a lifetime: supporting orphans and vulnerable children impacted by HIV/AIDS.

    PubMed

    Nyberg, Beverly J; Yates, Dee Dee; Lovich, Ronnie; Coulibaly-Traore, Djeneba; Sherr, Lorraine; Thurman, Tonya Renee; Sampson, Anita; Howard, Brian

    2012-08-15

    President's Emergency Plan for AIDS Relief (PEPFAR's) response to the millions of children impacted by HIV/AIDS was to designate 10% of its budget to securing their futures, making it the leading supporter of programs reaching orphan and vulnerable children (OVC) programs globally. This article describes the evolution of PEPFAR's OVC response based on programmatic lessons learned and an evergrowing understanding of the impacts of HIV/AIDS. In launching this international emergency effort and transitioning it toward sustainable local systems, PEPFAR helped establish both the technical content and the central importance of care and support for OVC as a necessary complement to biomedical efforts to end the HIV/AIDS epidemic. Critical services are reaching millions of HIV-affected children and families through vast networks of community-based responders and strengthened national systems of care. But rapid program scale-up has at times resulted in inconsistent responses, failure to match resources to properly assessed needs, and a dearth of rigorous program evaluations. Key investments should continue to be directed toward more sustainable and effective responses. These include greater attention to children's most significant developmental stages, a focus on building the resilience of families and communities, a proper balance of government and civil society investments, and more rigorous evaluation and research to ensure evidence-based programming. Even as HIV prevalence declines and medical treatment improves and expands, the impacts of HIV/AIDS on children, families, communities, economies, and societies will continue to accumulate for generations. Protecting the full potential of children-and thus of societies-requires sustained and strategic global investments aligned with experience and science. PMID:22797734

  16. 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

  17. [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

  18. 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

  19. ANTIOXIDANT ENZYME ACTIVITY AMONG ORPHANS INFECTED WITH INTESTINAL PARASITES IN PATHUM THANI PROVINCE, THAILAND.

    PubMed

    Mahittikorn, Aongart; Prasertbun, Rapeepan; Mori, Hirotake; Popruk, Supaluk

    2014-11-01

    Intestinal parasitic infections can negatively impact growth and nutrition in children. The infections can induce oxidative stress, resulting in a variety of illnesses. We measured antioxidant enzyme levels in orphan children infected with intestinal parasites to investigate the influence of nutritional status on antioxidant enzymes. This cross sectional study was conducted at an orphanage in Thailand. Stool samples were obtained from each subject and examined for intestinal parasites. Anthropometric measurements, complete blood count and biochemical parameters, including serum superoxide dismutase (SOD) and glutathione peroxidase (GPx) levels, were obtained from studied subjects. One hundred twenty-eight children were included in the study. Intestinal parasites were found on microscopic examination of the stools in 36.7% (47/128); 18% (23/128) had a mixed parasite infection. Intestinal protozoa were found in 34.4% of subjects and intestinal helminthes were found in 2.3%. The median GPx level in children infected with intestinal parasites (2.3 ng/ml) was significantly lower than in non-infected children (7.7 ng/ml) (p < 0.05). However, there was no significant difference in SOD levels between the two groups. When comparing GPx levels in children with 1) pathogenic parasites, 2) non-pathogenic parasites and 3) no intestinal parasite infection, GPx levels differed significantly among three groups (2.2 ng/ml, 2.4 ng/ml and 7.7 ng/ml, respectively) (p < 0.05). When separating children by BMI and type of infection, the median SOD level in underweight children infected with pathogenic parasites (107.2 ng/ml) was significantly higher than in underweight children infected with non-pathogenic parasites (68.6 ng/ml) and without intestinal parasite infections (72.2 ng/ml). The present study identified two key findings: low GPx levels in children with intestinal parasitic infections, and the potential impact of malnutrition on some antioxidants. PMID:26466411

  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. PMID:26968209

  1. 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

  2. Fatty acid profiles, growth, and immune responses of neonatal lambs fed milk replacer and supplemented with fish oil or safflower oil

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Diets supplemented with long-chain, n-3 (e.g., marine fish oil) polyunsaturated fatty acids (PUFA) have improved the health and performance of neonatal and growing animals. This study was conducted with lambs that were orphaned at approximately 1 day of age to determine whether supplementing milk re...

  3. Structure of thinned continental crust across the Orphan Basin from a dense wide-angle seismic profile and gravity data

    NASA Astrophysics Data System (ADS)

    Lau, K. W. Helen; Watremez, Louise; Louden, Keith E.; Nedimovíć, Mladen R.

    2015-09-01

    We present a 500-km long, 2-D P-wave velocity model across the Orphan Basin, offshore NE Newfoundland, Canada, from Flemish Cap to the Bonavista Platform, formed using refraction and wide-angle reflection data from 89 ocean-bottom seismometers. This layered model builds on a recent traveltime tomography result using additional constraints from coincident multichannel seismic reflection and gravity data plus borehole logs from three wells. The model shows (i) post-rift Tertiary (velocities ˜1.7-3.5 km s-1) and (ii) both post-rift and syn-rift, Cretaceous and Jurassic sediments (˜4-5 km s-1), deposited within an eastern and a western sub-basin that are separated by a major basement block. The existence of Jurassic sediments indicates a pre-Cretaceous rifting phase in the eastern sub-basin, and possibly in the western sub-basin. However, there is no evidence that Triassic sediments are widespread across the Orphan Basin. Two upper crustal sublayers and one lower crustal layer are defined by differences in velocities (5.4-6.1, 6.1-6.5 and 6.3-7.1 km s-1, respectively) and vertical velocity gradients (mean = 0.14, 0.10 and 0.05 s-1, respectively). Crustal thinning is asymmetric across the Orphan Basin. Within the eastern sub-basin, continental crust beneath Flemish Cap (˜32 km thick; β ˜ 1.1) thins westward into a 35-km-wide zone of hyperextended crust (<10 km thick; β > 3.4) beneath an 11-km-deep sedimentary basin. Within the western sub-basin, the Bonavista Platform crust (˜32 km thick) thins eastward into a 116-km-wide zone of hyperextended crust. Two zones of thicker crust (β = 2-3.5) exist within the central section, with muted topography within the eastern part and large basement highs in the western part, separated by the eastward dipping White Sail Fault (WSF). The zone to the east of the WSF displays higher velocities in the lower crust than to the west. This can only be explained by a lateral ductile flow across the zone boundary. By combining the two

  4. Family-based care and psychological problems of AIDS orphans: does it matter who was the care-giver?

    PubMed

    Zhao, Guoxiang; Zhao, Qun; Li, Xiaoming; Fang, Xiaoyi; Zhao, Junfeng; Zhang, Liying

    2010-05-01

    The purpose of this study is to compare psychological symptoms among double AIDS orphans (i.e. children who lost both of their parents to HIV/AIDS) who were in the care of different family-based caregivers (i.e. surviving parent, grandparents, other relatives, and non-relatives) before they were replaced in orphanages. The participants include 176 double AIDS orphans from four AIDS orphanages in rural China. Prior to being replaced in AIDS orphanages, these children had received family-based care by different caregivers, which included surviving parent (38%), grandparents (22%), other relatives (19%), and non-relatives (22%). The psychological measures include traumatic symptoms, depression, and loneliness. Both bivariate and multivariate analyses suggested that children who were previously cared for by non-relatives scored significantly higher in traumatic symptoms, depression, and loneliness scales than children who were previously cared for by their surviving parent, grandparents, and other relatives. Children in the care of grandparents reported the best scores on all psychological measures among children in the care of non-parent relatives. Multivariate analysis, controlling for children's gender, age, length in orphanages, number of household replacements, and total duration of replacement, revealed that the type of caregivers was significantly associated with psychological problems. Results in the current study suggest that children under the care of their grandparents reported the best psychological outcomes when their parents were unable to care for them because of AIDS. Appropriate psychological support and counseling services are needed for AIDS orphans who were either currently or previously under non-relative family-based care in China. PMID:20480436

  5. Community-based family-style group homes for children orphaned by AIDS in rural China: an ethnographic investigation

    PubMed Central

    Hong, Yan; Chi, Peilian; Li, Xiaoming; Zhao, Guoxiang; Zhao, Junfeng; Stanton, Bonita; Li, Li

    2015-01-01

    As the number of children orphaned by AIDS (Acquired Immunodeficiency Syndrome) has reached 17.3 million, most living in resource-poor settings, interest has grown in identifying and evaluating appropriate care arrangements for them. In this study, we describe the community-based family-style group homes (‘group homes’) in rural China. Guided by an ecological framework of children’s wellbeing, we conducted a series of ethnographic observations, in-depth interviews and group discussions in the rural areas of Henan Province, which has been severely impacted by the AIDS endemic through commercial blood collection. Based on our observations and discussions, group homes appear to provide stable and safe living environments for children orphaned by AIDS. Adequate financial support from non-government organizations (NGOs) as well as the central and provincial governments has ensured a low child–caregiver ratio and attention to the basic needs of the children at group homes. The foster parents were selected from the local community and appear to have adequate qualifications and dedication. They receive a monthly stipend, periodical evaluation and parenting consultation from supporting NGOs. The foster parents and children in the group homes have formed strong bonds. Both children and foster parents reported positively on health and education. Characteristics of community-based group homes can be replicated in other care arrangements for AIDS orphans in resource-poor settings for the optimal health outcomes of those vulnerable children. We also call for capacity building for caregivers and communities to provide sustainable and supportive living environment for these children. PMID:25124083

  6. Discordance of HIV and HSV-2 Biomarkers and Self-reported Sexual Behavior among Orphan Adolescents in Western Kenya

    PubMed Central

    Cho, Hyunsan; Luseno, Winnie; Halpern, Carolyn; Zhang, Lei; Mbai, Isabella; Milimo, Benson; Hallfors, Denise

    2015-01-01

    Background This paper examines the discordance between biological data of HIV and HSV-2 infections and self-reported questionnaire responses among orphan adolescents in Western Kenya. Methods In 2011 a total of 837 orphan adolescents from 26 primary schools were enrolled in an HIV prevention trial. At baseline, blood samples were drawn for HIV and HSV-2 infection biomarker testing, and participants completed an audio computer-assisted self-interviewing (ACASI) survey. Results Comparing biological data with self-reported responses indicated that 70% of HIV positive (7 out of 10) and 64% of HSV-2 positive (18 out of 28 positive) participants reported never having had sex. Among ever-married adolescents 65% (57 out of 88) reported never having had sex. Overall, 10% of study participants appeared to have inconsistently reported their sexual behavior. Logistic regression analyses indicated that lower educational level and exam scores were significant predictors of inconsistent reporting. Conclusions Our study demonstrates the discordance between infections measured by biomarkers and self-reports of having had sex among orphan adolescents in Kenya. In order to detect program effects accurately in prevention research, it is necessary to collect both baseline and endline biological data. Furthermore, it is recommended to triangulate multiple data sources about adolescent participants’ self-reported information about marriage and pregnancies from school records and parent/guardians to verify the information. Researchers should recognize potential threats to validity in data and design surveys to consider cognitive factors and/or cultural context to obtain more accurate and reliable information from adolescents regarding HIV/STI risk behaviors. PMID:25378660

  7. Could a plasma in quasi-thermal equilibrium be associated to the "orphan" TeV flares?

    NASA Astrophysics Data System (ADS)

    Fraija, N.

    2015-12-01

    TeV γ-ray detections in flaring states without activity in X-rays from blazars have attracted much attention due to the irregularity of these "orphan" flares. Although the synchrotron self-Compton model has been very successful in explaining the spectral energy distribution and spectral variability of these sources, it has not been able to describe these atypical flaring events. On the other hand, an electron-positron pair plasma at the base of the AGN jet was proposed as the mechanism of bulk acceleration of relativistic outflows. This plasma in quasi-thermal equilibrium called Wein fireball emits radiation at MeV-peak energies serving as target of accelerated protons. In this work we describe the "orphan" TeV flares presented in blazars 1ES 1959+650 and Mrk 421 assuming geometrical considerations in the jet and evoking the interactions of Fermi-accelerated protons and MeV-peak target photons coming from the Wein fireball. After describing successfully these "orphan" TeV flares, we correlate the TeV γ-ray, neutrino and UHECR fluxes through pγ interactions and calculate the number of high-energy neutrinos and UHECRs expected in IceCube/AMANDA and TA experiment, respectively. In addition, thermal MeV neutrinos produced mainly through electron-positron annihilation at the Wein fireball will be able to propagate through it. By considering two- (solar, atmospheric and accelerator parameters) and three-neutrino mixing, we study the resonant oscillations and estimate the neutrino flavor ratios as well as the number of thermal neutrinos expected on Earth.

  8. Community-based family-style group homes for children orphaned by AIDS in rural China: an ethnographic investigation.

    PubMed

    Hong, Yan; Chi, Peilian; Li, Xiaoming; Zhao, Guoxiang; Zhao, Junfeng; Stanton, Bonita; Li, Li

    2015-09-01

    As the number of children orphaned by AIDS (Acquired Immunodeficiency Syndrome) has reached 17.3 million, most living in resource-poor settings, interest has grown in identifying and evaluating appropriate care arrangements for them. In this study, we describe the community-based family-style group homes ('group homes') in rural China. Guided by an ecological framework of children's wellbeing, we conducted a series of ethnographic observations, in-depth interviews and group discussions in the rural areas of Henan Province, which has been severely impacted by the AIDS endemic through commercial blood collection. Based on our observations and discussions, group homes appear to provide stable and safe living environments for children orphaned by AIDS. Adequate financial support from non-government organizations (NGOs) as well as the central and provincial governments has ensured a low child-caregiver ratio and attention to the basic needs of the children at group homes. The foster parents were selected from the local community and appear to have adequate qualifications and dedication. They receive a monthly stipend, periodical evaluation and parenting consultation from supporting NGOs. The foster parents and children in the group homes have formed strong bonds. Both children and foster parents reported positively on health and education. Characteristics of community-based group homes can be replicated in other care arrangements for AIDS orphans in resource-poor settings for the optimal health outcomes of those vulnerable children. We also call for capacity building for caregivers and communities to provide sustainable and supportive living environment for these children. PMID:25124083

  9. The “Super Chimpanzee”: The Ecological Dimensions of Rehabilitation of Orphan Chimpanzees in Guinea, West Africa

    PubMed Central

    Ongman, Lissa; Colin, Christelle; Raballand, Estelle; Humle, Tatyana

    2013-01-01

    Simple Summary This study examines relevant behavioral indicators of rehabilitation success of orphaned chimpanzees, victims of the bushmeat and pet trade, and contributes to identifying future release candidates. Results highlight the importance of bush-outings in the development of species-specific behaviors. Neither trauma upon arrival nor contact with human caretakers predicted dietary knowledge among rehabilitants at the Chimpanzee Conservation Centre where the study took place. The studied orphans demonstrated a relatively broad dietary knowledge. We attributed this result to the combined effect of the multiregional origins of residents and the learning opportunities available during bush-outings, which we termed the “Super Chimpanzee” theory. Abstract To date few studies, especially among non-human primates, have evaluated or monitored rehabilitation effectiveness and identified key species-specific behavioral indicators for release success. This four-months study aimed to identify behavioral indicators of rehabilitation success among ten infant and juvenile orphaned chimpanzees cared for in peer groups at the Centre for Conservation of Chimpanzees (CCC), Guinea, West Africa. Behavioral data focused on foraging skills and activity budget. During bush-outings, rehabilitants spent on average nearly a quarter of their activity budget foraging, resting or traveling, respectively. Neither age, sex, the level of abnormal behaviors demonstrated upon arrival nor human contact during bush-outings predicted individual dietary knowledge. However, individuals who spent more time arboreal demonstrated a greater dietary breadth than conspecifics who dwelled more terrestrially. Although our data failed to demonstrate a role of conspecific observation in dietary acquisition, we propose that the mingling of individuals from different geographical origins may act as a catalyst for acquiring new dietary knowledge, promoted by ecological opportunities offered during bush

  10. Genome-Wide Analysis of Binding Sites and Direct Target Genes of the Orphan Nuclear Receptor NR2F1/COUP-TFI

    PubMed Central

    Montemayor, Celina; Montemayor, Oscar A.; Ridgeway, Alex; Lin, Feng; Wheeler, David A.; Pletcher, Scott D.; Pereira, Fred A.

    2010-01-01

    Background Identification of bona fide direct nuclear receptor gene targets has been challenging but essential for understanding regulation of organismal physiological processes. Results We describe a methodology to identify transcription factor binding sites and target genes in vivo by intersecting microarray data, computational binding site queries, and evolutionary conservation. We provide detailed experimental validation of each step and, as a proof of principle, utilize the methodology to identify novel direct targets of the orphan nuclear receptor NR2F1 (COUP-TFI). The first step involved validation of microarray gene expression profiles obtained from wild-type and COUP-TFI−/− inner ear tissues. Secondly, we developed a bioinformatic tool to search for COUP-TFI DNA binding sites in genomes, using a classification-type Hidden Markov Model trained with 49 published COUP-TF response elements. We next obtained a ranked list of candidate in vivo direct COUP-TFI targets by integrating the microarray and bioinformatics analyses according to the degree of binding site evolutionary conservation and microarray statistical significance. Lastly, as proof-of-concept, 5 specific genes were validated for direct regulation. For example, the fatty acid binding protein 7 (Fabp7) gene is a direct COUP-TFI target in vivo because: i) we identified 2 conserved COUP-TFI binding sites in the Fabp7 promoter; ii) Fapb7 transcript and protein levels are significantly reduced in COUP-TFI−/− tissues and in MEFs; iii) chromatin immunoprecipitation demonstrates that COUP-TFI is recruited to the Fabp7 promoter in vitro and in vivo and iv) it is associated with active chromatin having increased H3K9 acetylation and enrichment for CBP and SRC-1 binding in the newborn brain. Conclusion We have developed and validated a methodology to identify in vivo direct nuclear receptor target genes. This bioinformatics tool can be modified to scan for response elements of transcription factors

  11. Adipose-Derived Mesenchymal Stem Cells Ameliorate Ulcerative Colitis Through miR-1236 Negatively Regulating the Expression of Retinoid-Related Orphan Receptor Gamma.

    PubMed

    Zhang, Ying; Jin, Yu; Lin, Yan; Lin, Lian-jie; Cao, Yong; Wang, Dong-xu; Zheng, Chang-qing

    2015-10-01

    Mesenchymal stem cells (MSCs) were reported to accelerate the curing of ulcerative colitis (UC). Altered expression of microRNAs (miRNAs) has recently revealed association with UC. However, the effect of adipose-derived MSCs (ASCs) on UC and the mechanism of how miRNAs regulate UC remain unclear. We investigated the effect of ASCs on 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced UC in rat colon tissues. qRT-PCR and immunofluorescence analyses were performed to monitor the expression of miR-1236 and its target molecule, retinoid-related orphan receptor γ (RORγ). Regulation of the expression of RORγ by miR-1236 was assessed using luciferase reporter construct assays and miR-1236 mimic transfection. The relationship between miR-1236 and RORγ was further investigated in HT29 cells induced by TNF-α. ASCs highly ameliorated UC and decreased the inflammation markers in rats with TNBS-induced UC. In addition, ASCs upregulated the expression of miR-1236 and decreased the expression of RORγ in the TNBS-induced rat model of UC. The luciferase reporter assay and bioinformatic analysis demonstrated that the expression of RORγ was directly targeted and regulated by miR-1236. Specifically, the expression of RORγ was suppressed by miR-1236 mimic and enhanced by miR-1236 inhibitor. Furthermore, we demonstrated that exogenous miR-1236 mimic could inhibit the expression of RORγ in HT29 cell induced by TNF-α. ASCs effectively alleviated UC in rats with the expression of miR-1236 alteration, and miR-1236 may play important roles in UC by downregulating the expression of RORγ. PMID:26237452

  12. Pregnancy-associated osteoporosis with a heterozygous deactivating LDL receptor-related protein 5 (LRP5) mutation and a homozygous methylenetetrahydrofolate reductase (MTHFR) polymorphism.

    PubMed

    Cook, Fiona J; Mumm, Steven; Whyte, Michael P; Wenkert, Deborah

    2014-04-01

    Pregnancy-associated osteoporosis (PAO) is a rare, idiopathic disorder that usually presents with vertebral compression fractures (VCFs) within 6 months of a first pregnancy and delivery. Spontaneous improvement is typical. There is no known genetic basis for PAO. A 26-year-old primagravida with a neonatal history of unilateral blindness attributable to hyperplastic primary vitreous sustained postpartum VCFs consistent with PAO. Her low bone mineral density (BMD) seemed to respond to vitamin D and calcium therapy, with no fractures after her next successful pregnancy. Investigation of subsequent fetal losses revealed homozygosity for the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism associated both with fetal loss and with osteoporosis (OP). Because her neonatal unilateral blindness and OP were suggestive of loss-of-function mutation(s) in the gene that encodes LDL receptor-related protein 5 (LRP5), LRP5 exon and splice site sequencing was also performed. This revealed a unique heterozygous 12-bp deletion in exon 21 (c.4454_4465del, p.1485_1488del SSSS) in the patient, her mother and sons, but not her father or brother. Her mother had a normal BMD, no history of fractures, PAO, ophthalmopathy, or fetal loss. Her two sons had no ophthalmopathy and no skeletal issues. Her osteoporotic father (with a family history of blindness) and brother had low BMDs first documented at ages ∼40 and 32 years, respectively. Serum biochemical and bone turnover studies were unremarkable in all subjects. We postulate that our patient's heterozygous LRP5 mutation together with her homozygous MTHFR polymorphism likely predisposed her to low peak BMD. However, OP did not cosegregate in her family with the LRP5 mutation, the homozygous MTHFR polymorphism, or even the combination of the two, implicating additional genetic or nongenetic factors in her PAO. Nevertheless, exploration for potential genetic contributions to PAO may explain part of the pathogenesis of this

  13. The low density lipoprotein receptor-related protein/alpha2-macroglobulin receptor regulates cell surface plasminogen activator activity on human trophoblast cells.

    PubMed

    Zhang, J C; Sakthivel, R; Kniss, D; Graham, C H; Strickland, D K; McCrae, K R

    1998-11-27

    The low density lipoprotein receptor-related protein/alpha2-macroglobulin receptor (LRP/alpha2MR) mediates the internalization of numerous ligands, including prourokinase (pro-UK) and complexes between two-chain urokinase (tc-u-PA) and plasminogen activator inhibitor type-1 (PAI-1). It has been suggested that through its ability to internalize these ligands, LRP/alpha2MR may regulate the expression of plasminogen activator activity on cell surfaces; this hypothesis, however, has not been experimentally confirmed. To address this issue, we assessed the ability of LRP/alpha2MR to regulate plasminogen activator activity on human trophoblast cells, which express both LRP/alpha2MR and the urokinase receptor (uPAR). Trophoblasts internalized and degraded exogenous 125I-pro-UK (primarily following its conversion to tc-u-PA and incorporation into tc-u-PA.PAI complexes) in an LRP/alpha2MR-dependent manner, which was inhibited by the LRP/alpha2MR receptor-associated protein. Receptor-associated protein also caused a approximately 50% reduction in cell surface plasminogen activator activity and delayed the regeneration of unoccupied uPAR by cells on which uPAR were initially saturated with pro-UK. Identical effects were caused by anti-LRP/alpha2MR antibodies. These results demonstrate that LRP/alpha2MR promotes the expression of cell surface plasminogen activator activity on trophoblasts by facilitating the clearance of tc-u-PA.PAI complexes and regeneration of unoccupied cell surface uPAR. PMID:9822706

  14. The role of the low-density lipoprotein receptor-related protein (LRP1) in Alzheimer's A beta generation: development of a cell-based model system.

    PubMed

    Goto, Joy J; Tanzi, Rudolph E

    2002-01-01

    The clearance and degradation of extracellular A beta is critical for regulating beta-amyloid deposition, a major hallmark of brains of patients with A beta in Alzheimer's Disease. The low-density lipoprotein receptor-related protein, LRP1, is a large endocytic receptor that significantly contributes to the balance between degradation and production of A beta. An extracellular portion of the LRP, known as the cluster II region can bind to the secreted form of APP (sAPP-KPI). We show here that a GST fusion protein containing the cluster II region of LRP can be used as a 'mini-receptor' that specifically binds to sAPP-KPI from conditioned cultured medium. The binding between the GST-LRP-cluster II fusion protein and sAPP-KPI can be inhibited with the strong binding ligand of LRP1, called receptor-associated protein (RAP). Furthermore, a cell-based in vitro assay system has been developed to monitor the production of total A beta and A beta(1-42) in the presence and absence of RAP in Chinese hamster ovary (CHO) cell lines both deficient in LRP and expressing LRP. A 3-day treatment of the L2 (CHO cells deficient in LRP and overexpressing APP751) and L3 (CHO cells expressing LRP and overexpressing APP751) cell lines with RAP showed a decrease in total A beta and, interestingly, also a decrease in the ratio of A beta42/A beta(total). This cell-based model system and LRP-cluster II mini-receptor will be very useful for screening novel compounds that can reduce A beta accumulation by inhibiting binding of APP-KPI to LRP1. PMID:12212791

  15. LDL receptor-related protein-1 regulates NFκB and microRNA-155 in macrophages to control the inflammatory response.

    PubMed

    Mantuano, Elisabetta; Brifault, Coralie; Lam, Michael S; Azmoon, Pardis; Gilder, Andrew S; Gonias, Steven L

    2016-02-01

    LDL receptor-related protein-1 (LRP1) is an endocytic and cell-signaling receptor. In mice in which LRP1 is deleted in myeloid cells, the response to lipopolysaccharide (LPS) was greatly exacerbated. LRP1 deletion in macrophages in vitro, under the control of tamoxifen-activated Cre-ER(T) fusion protein, robustly increased expression of proinflammatory cytokines and chemokines. In LRP1-expressing macrophages, proinflammatory mediator expression was regulated by LRP1 ligands in a ligand-specific manner. The LRP1 agonists, α2-macroglobulin and tissue-type plasminogen activator, attenuated expression of inflammatory mediators, even in the presence of LPS. The antagonists, receptor-associated protein (RAP) and lactoferrin (LF), and LRP1-specific antibody had the entirely opposite effect, promoting inflammatory mediator expression and mimicking LRP1 deletion. NFκB was rapidly activated in response to RAP and LF and responsible for the initial increase in expression of proinflammatory mediators. RAP and LF also significantly increased expression of microRNA-155 (miR-155) after a lag phase of about 4 h. miR-155 expression reflected, at least in part, activation of secondary cell-signaling pathways downstream of TNFα. Although miR-155 was not involved in the initial induction of cytokine expression in response to LRP1 antagonists, miR-155 was essential for sustaining the proinflammatory response. We conclude that LRP1, NFκB, and miR-155 function as members of a previously unidentified system that has the potential to inhibit or sustain inflammation, depending on the continuum of LRP1 ligands present in the macrophage microenvironment. PMID:26787872

  16. Flow Cytofluorimetric Analysis of Anti-LRP4 (LDL Receptor-Related Protein 4) Autoantibodies in Italian Patients with Myasthenia Gravis

    PubMed Central

    Marino, Mariapaola; Scuderi, Flavia; Samengo, Daniela; Saltelli, Giorgia; Maiuri, Maria Teresa; Shen, Chengyong; Mei, Lin; Sabatelli, Mario; Pani, Giovambattista; Antonini, Giovanni; Evoli, Amelia; Bartoccioni, Emanuela

    2015-01-01

    Background Myasthenia gravis (MG) is an autoimmune disease in which 90% of patients have autoantibodies against the muscle nicotinic acetylcholine receptor (AChR), while autoantibodies to muscle-specific tyrosine kinase (MuSK) have been detected in half (5%) of the remaining 10%. Recently, the low-density lipoprotein receptor-related protein 4 (LRP4), identified as the agrin receptor, has been recognized as a third autoimmune target in a significant portion of the double sero-negative (dSN) myasthenic individuals, with variable frequency depending on different methods and origin countries of the tested population. There is also convincing experimental evidence that anti-LRP4 autoantibodies may cause MG. Methods The aim of this study was to test the presence and diagnostic significance of anti-LRP4 autoantibodies in an Italian population of 101 myasthenic patients (55 dSN, 23 AChR positive and 23 MuSK positive), 45 healthy blood donors and 40 patients with other neurological diseases as controls. All sera were analyzed by a cell-based antigen assay employing LRP4-transfected HEK293T cells, along with a flow cytofluorimetric detection system. Results We found a 14.5% (8/55) frequency of positivity in the dSN-MG group and a 13% frequency of co-occurrence (3/23) in both AChR and MuSK positive patients; moreover, we report a younger female prevalence with a mild form of disease in LRP4-positive dSN-MG individuals. Conclusion Our data confirm LRP4 as a new autoimmune target, supporting the value of including anti-LRP4 antibodies in further studies on Myasthenia gravis. PMID:26284792

  17. Regulation of macrophage alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein by lipopolysaccharide and interferon-gamma.

    PubMed Central

    LaMarre, J; Wolf, B B; Kittler, E L; Quesenberry, P J; Gonias, S L

    1993-01-01

    alpha 2-Macroglobulin receptor/low density lipoprotein receptor-related protein (alpha 2M-R/LRP) is a broad specificity receptor that may function in lipoprotein metabolism, proteinase regulation, and growth factor regulation. In this study, we demonstrated that alpha 2M-R/LRP expression in macrophages can be markedly decreased by LPS and by IFN-gamma. Regulation of alpha 2M-R/LRP in RAW 264.7 cells was demonstrated at the mRNA, antigen, and receptor-function levels. In receptor-function studies, the decrease in alpha 2M-R/LRP expression was detected as a 90% decrease in the Bmax or maximum receptor binding capacity for activated alpha 2M after treatment with LPS or IFN-gamma. Western blot analysis of whole cell lysates demonstrated significant loss of alpha 2M-R/LRP heavy-chain. Northern blot analysis of poly(A)+ RNA revealed a marked decrease in alpha 2M-R/LRP mRNA after treatment with LPS (79% decrease) or IFN-gamma (70% decrease). Other cytokines, including tumor necrosis factor-alpha, transforming growth factor-beta-1, and interleukin-6 did not regulate alpha 2M-R/LRP. The ability of LPS and IFN-gamma to regulate alpha 2M-R/LRP was confirmed in experiments with primary cultures of murine bone marrow macrophages. These studies demonstrate that macrophage alpha 2M-R/LRP is subject to significant downregulation by physiologically significant cytokines and signaling macromolecules. Images PMID:7680664

  18. Low-density lipoprotein receptor-related protein 1 is a novel modulator of radial glia stem cell proliferation, survival, and differentiation.

    PubMed

    Safina, Dina; Schlitt, Frederik; Romeo, Ramona; Pflanzner, Thorsten; Pietrzik, Claus U; Narayanaswami, Vasanthy; Edenhofer, Frank; Faissner, Andreas

    2016-08-01

    The LDL family of receptors and its member low-density lipoprotein receptor-related protein 1 (LRP1) have classically been associated with a modulation of lipoprotein metabolism. Current studies, however, indicate diverse functions for this receptor in various aspects of cellular activities, including cell proliferation, migration, differentiation, and survival. LRP1 is essential for normal neuronal function in the adult CNS, whereas the role of LRP1 in development remained unclear. Previously, we have observed an upregulation of LewisX (LeX) glycosylated LRP1 in the stem cells of the developing cortex and demonstrated its importance for oligodendrocyte differentiation. In the current study, we show that LeX-glycosylated LRP1 is also expressed in the stem cell compartment of the developing spinal cord and has broader functions in the developing CNS. We have investigated the basic properties of LRP1 conditional knockout on the neural stem/progenitor cells (NSPCs) from the cortex and the spinal cord, created by means of Cre-loxp-mediated recombination in vitro. The functional status of LRP1-deficient cells has been studied using proliferation, differentiation, and apoptosis assays. LRP1 deficient NSPCs from both CNS regions demonstrated altered differentiation profiles. Their differentiation capacity toward oligodendrocyte progenitor cells (OPCs), mature oligodendrocytes and neurons was reduced. In contrast, astrocyte differentiation was promoted. Moreover, LRP1 deletion had a negative effect on NSPCs proliferation and survival. Our observations suggest that LRP1 facilitates NSPCs differentiation via interaction with apolipoprotein E (ApoE). Upon ApoE4 stimulation wild type NSPCs generated more oligodendrocytes, but LRP1 knockout cells showed no response. The effect of ApoE seems to be independent of cholesterol uptake, but is rather mediated by downstream MAPK and Akt activation. GLIA 2016 GLIA 2016;64:1363-1380. PMID:27258849

  19. Impact of Concanavalin-A-Mediated Cytoskeleton Disruption on Low-Density Lipoprotein Receptor-Related Protein-1 Internalization and Cell Surface Expression in Glioblastomas

    PubMed Central

    Nanni, Samuel Burke; Pratt, Jonathan; Beauchemin, David; Haidara, Khadidja; Annabi, Borhane

    2016-01-01

    The low-density lipoprotein receptor-related protein 1 (LRP-1) is a multiligand endocytic receptor, which plays a pivotal role in controlling cytoskeleton dynamics during cancer cell migration. Its rapid endocytosis further allows efficient clearance of extracellular ligands. Concanavalin-A (ConA) is a lectin used to trigger in vitro physiological cellular processes, including cytokines secretion, nitric oxide production, and T-lymphocytes activation. Given that ConA exerts part of its effects through cytoskeleton remodeling, we questioned whether it affected LRP-1 expression, intracellular trafficking, and cell surface function in grade IV U87 glioblastoma cells. Using flow cytometry and confocal microscopy, we found that loss of the cell surface 600-kDa mature form of LRP-1 occurs upon ConA treatment. Consequently, internalization of the physiological α2-macroglobulin and the synthetic angiopep-2 ligands of LRP-1 was also decreased. Silencing of known mediators of ConA, such as the membrane type-1 matrix metalloproteinase, and the Toll-like receptors (TLR)-2 and TLR-6 was unable to rescue ConA-mediated LRP-1 expression decrease, implying that the loss of LRP-1 was independent of cell surface relayed signaling. The ConA-mediated reduction in LRP-1 expression was emulated by the actin cytoskeleton-disrupting agent cytochalasin-D, but not by the microtubule inhibitor nocodazole, and required both lysosomal- and ubiquitin-proteasome system-mediated degradation. Our study implies that actin cytoskeleton integrity is required for proper LRP-1 cell surface functions and that impaired trafficking leads to specialized compartmentation and degradation. Our data also strengthen the biomarker role of cell surface LRP-1 functions in the vectorized transport of therapeutic angiopep bioconjugates into brain cancer cells. PMID:27226736

  20. Models of care for orphaned and separated children and upholding children’s rights: cross-sectional evidence from western Kenya

    PubMed Central

    2014-01-01

    Background Sub-Saharan Africa is home to approximately 55 million orphaned children. The growing orphan crisis has overwhelmed many communities and has weakened the ability of extended families to meet traditional care-taking expectations. Other models of care and support have emerged in sub-Saharan Africa to address the growing orphan crisis, yet there is a lack of information on these models available in the literature. We applied a human rights framework using the United Nations Convention on the Rights of the Child to understand what extent children’s basic human rights were being upheld in institutional vs. community- or family-based care settings in Uasin Gishu County, Kenya. Methods The Orphaned and Separated Children’s Assessments Related to their Health and Well-Being Project is a 5-year cohort of orphaned children and adolescents aged ≤18 year. This descriptive analysis was restricted to baseline data. Chi-Square test was used to test for associations between categorical /dichotomous variables. Fisher’s exact test was also used if some cells had expected value of less than 5. Results Included in this analysis are data from 300 households, 19 Charitable Children’s Institutions (CCIs) and 7 community-based organizations. In total, 2871 children were enrolled and had baseline assessments done: 1390 in CCI’s and 1481 living in households in the community. We identified and described four broad models of care for orphaned and separated children, including: institutional care (sub-classified as ‘Pure CCI’ for those only providing residential care, ‘CCI-Plus’ for those providing both residential care and community-based supports to orphaned children , and ‘CCI-Shelter’ which are rescue, detention, or other short-term residential support), family-based care, community-based care and self-care. Children in institutional care (95%) were significantly (p < 0.0001) more likely to have their basic material needs met in comparison to those

  1. Importance of milk replacer intake and composition in rearing orphan foals

    PubMed Central

    Cymbaluk, Nadia F.; Smart, Marion E.; Bristol, Frank M.; Pouteaux, Victor A.

    1993-01-01

    Effects of milk replacer composition and intake on the growth of orphan foals were evaluated. Twenty foals were assigned to four treatments: 1) mare-nursed, 2) commercial foal milk replacer at recommended intakes (standard), 3) commercial foal milk replacer at high intakes (high), and 4) acidified replacer at recommended intakes (acidified). Foals fed milk replacer diets were weaned at 12-24 hours postpartum and fed milk replacer for 50 days. Mare-nursed foals were weaned between 52 and 56 days of age. Foals fed replacer diets gained 12% to 28% less weight than mare-nursed foals up to two weeks of age. However, by four months of age, weights of replacer-fed foals were similar to those of mare-nursed foals and 32 other mare-nursed foals at the farm weaned between three and four months postparium. Foals drank 10 to 12 L/100 kg body weight (BW) in fluid replacer daily over the trial period. During the first week, high intake foals consumed 26% more replacer (p<0.05) than foals fed acidified or standard diets. This higher intake resulted in diarrhea earlier (6-11 days vs 11-22 days) and for a longer time (6.3 days vs 2.5-3.6 days) than in foals fed recommended amounts. Mare-nursed foals developed “foal heat scours” in the second week postpartum. After the first week, foals fed high replacer diet voluntarily consumed the same volume of fluid replacer as foals fed the standard intake. Foals ate less than 1 kg grain mix/100 kg BW daily to one month of age, then increased intake to 1.5-2 kg/ 100 kg BW to weaning. Water intake was 20-40% of daily fluid intake and was correlated (r = 0.85) to dry matter intake. Foals in the high intake group ate less (p<0.05) solid feed and drank less water than foals fed the standard and acidified diets. The foal's stomach capacity appears to limit meal size and thus replacer intake. If recommended feeding intervals are used, replacer intakes by foals are less than 15% BW daily. High volume intakes appeared to prolong diarrhea. Normal

  2. Safety and Security of Radioactive Sealed and Disused/Orphan Sources in Ukraine - German Contribution - 13359

    SciTech Connect

    Brasser, Thomas; Hertes, Uwe; Meyer, Thorsten; Uhlenbruck, Hermann; Shevtsov, Alexey

    2013-07-01

    transports of radioactive sources within the city of Kiev. In future, the new established hot cell at IZOTOP's transport and storage facility will be useful for identification and characterization of orphan/disused radioactive sources. The projects implemented are performed in accordance with international recommendations (e. g. IAEA) and national normative documents and will make a crucial contribution towards an improved safety and security management of radioactive sources in Ukraine. (authors)

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

    PubMed

    Lammi, Johanna; Rajalin, Ann-Marie; Huppunen, Johanna; Aarnisalo, Piia

    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. PMID:17543277

  4. A discrete choice experiment investigating preferences for funding drugs used to treat orphan diseases: an exploratory study.

    PubMed

    Mentzakis, Emmanouil; Stefanowska, Patricia; Hurley, Jeremiah

    2011-07-01

    Policy debate about funding criteria for drugs used to treat rare, orphan diseases is gaining prominence. This study presents evidence from a discrete choice experiment using a convenience sample of university students to investigate individual preferences regarding public funding for drugs used to treat rare diseases and common diseases. This pilot study finds that: other things equal, the respondents do not prefer to have the government spend more for drugs used to treat rare diseases; that respondents are not willing to pay more per life year gained for a rare disease than a common disease; and that respondents weigh relevant attributes of the coverage decisions (e.g. costs, disease severity and treatment effectiveness) similarly for both rare and common diseases. The results confirm the importance of severity and treatment effectiveness in preferences for public funding. Although this is the first study of its kind, the results send a cautionary message regarding the special treatment of orphan drugs in coverage decision-making. PMID:21205401

  5. miR-30e reciprocally regulates the differentiation of adipocytes and osteoblasts by directly targeting low-density lipoprotein receptor-related protein 6.

    PubMed

    Wang, J; Guan, X; Guo, F; Zhou, J; Chang, A; Sun, B; Cai, Y; Ma, Z; Dai, C; Li, X; Wang, B

    2013-01-01

    Reciprocal relationship usually exists between osteoblastogenesis and adipogenesis, with factors stimulating one of these processes at the same time inhibiting the other. In the present study, miR-30e was found to be involved in the reciprocal regulation of osteoblast and adipocyte differentiation. Our data indicated that miR-30e was induced in primarily cultured mouse bone marrow stromal cell, mesenchymal cell line C3H10T1/2 and preadipocyte 3T3-L1 after adipogenic treatment. Conversely, it was reduced in mouse stromal line ST2 and preosteoblast MC3T3-E1 after osteogenic treatment. Enforced expression of miR-30e in 3T3-L1 significantly suppressed the growth of the cells and induced the preadipocytes to differentiate into mature adipocytes, along with increased expression of adipocyte-specific transcription factors peroxisome proliferator-activated receptor-γ (PPARγ), CCAAT/enhancer binding protein-α (C/EBPα) and C/EBPβ, and the marker gene aP2. In contrast, inhibition of the endogenous miR-30e enhanced the cell growth and repressed preadipocytes to differentiate. Conversely, supplementing miR-30e activity blocked, whereas knocking down miR-30e enforced the preosteoblast MC3T3-E1 to fully differentiate. Furthermore, miR-30e overexpression stimulated adipocyte formation and inhibited osteoblast differentiation from marrow stromal cells. Low-density lipoprotein receptor-related protein 6 (LRP6), one of the critical coreceptor for Wnts, was shown to be a direct target of miR-30e by using the luciferase assay. Knockdown of LRP6 in 3T3-L1 cells downregulated β-catenin/T-cell factor (TCF) transcriptional activity and dramatically potentiated the differentiation of the cells into mature adipocytes. Taken together, the present work suggests that the expression of miR-30e is indispensable for maintaining the balance of adipocytes and osteoblasts by targeting the canonical Wnt/β-catenin signaling. PMID:24113179

  6. Identification of Thiotetronic Acid Antibiotic Biosynthetic Pathways by Target-directed Genome Mining.

    PubMed

    Tang, Xiaoyu; Li, Jie; Millán-Aguiñaga, Natalie; Zhang, Jia Jia; O'Neill, Ellis C; Ugalde, Juan A; Jensen, Paul R; Mantovani, Simone M; Moore, Bradley S

    2015-12-18

    Recent genome sequencing efforts have led to the rapid accumulation of uncharacterized or "orphaned" secondary metabolic biosynthesis gene clusters (BGCs) in public databases. This increase in DNA-sequenced big data has given rise to significant challenges in the applied field of natural product genome mining, including (i) how to prioritize the characterization of orphan BGCs and (ii) how to rapidly connect genes to biosynthesized small molecules. Here, we show that by correlating putative antibiotic resistance genes that encode target-modified proteins with orphan BGCs, we predict the biological function of pathway specific small molecules before they have been revealed in a process we call target-directed genome mining. By querying the pan-genome of 86 Salinispora bacterial genomes for duplicated house-keeping genes colocalized with natural product BGCs, we prioritized an orphan polyketide synthase-nonribosomal peptide synthetase hybrid BGC (tlm) with a putative fatty acid synthase resistance gene. We employed a new synthetic double-stranded DNA-mediated cloning strategy based on transformation-associated recombination to efficiently capture tlm and the related ttm BGCs directly from genomic DNA and to heterologously express them in Streptomyces hosts. We show the production of a group of unusual thiotetronic acid natural products, including the well-known fatty acid synthase inhibitor thiolactomycin that was first described over 30 years ago, yet never at the genetic level in regards to biosynthesis and autoresistance. This finding not only validates the target-directed genome mining strategy for the discovery of antibiotic producing gene clusters without a priori knowledge of the molecule synthesized but also paves the way for the investigation of novel enzymology involved in thiotetronic acid natural product biosynthesis. PMID:26458099

  7. "We Have to Do Something for Ourselves": Using Photovoice and Participatory Action Research to Assess the Barriers to Caregiving for Abandoned and Orphaned Children in Sierra Leone

    ERIC Educational Resources Information Center

    Walker, Ashley; Early, Jody

    2010-01-01

    The purpose of this qualitative participatory action research study was multi-fold: first, to identify the ecological factors which impede and promote health and well-being among orphaned and abandoned children in Sierra Leone; second, to facilitate Photovoice, a participatory action research method, among NGO workers to identify barriers to…

  8. TaFROG, a novel plant orphan gene, interacts with SnRK1 and enhances resistance to a mycotoxigenic fungus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    All genomes encode taxonomically restricted ‘orphan’ genes, most of which are of unknown function. We report the functional characterization of the orphan gene TaFROG as a component of the wheat resistance to the globally important Fusarium head blight (FHB) disease. TaFROG is taxonomically restrict...

  9. The orphan histidine protein kinase SgmT is a c-di-GMP receptor and regulates composition of the extracellular matrix together with the orphan DNA binding response regulator DigR in Myxococcus xanthus

    PubMed Central

    Petters, Tobias; Zhang, Xin; Nesper, Jutta; Treuner-Lange, Anke; Gomez-Santos, Nuria; Hoppert, Michael; Jenal, Urs; Søgaard-Andersen, Lotte

    2012-01-01

    In Myxococcus xanthus the extracellular matrix is essential for type IV pili-dependent motility and starvation-induced fruiting body formation. Proteins of two-component systems including the orphan DNA binding response regulator DigR are essential in regulating the composition of the extracellular matrix. We identify the orphan hybrid histidine kinase SgmT as the partner kinase of DigR. In addition to kinase and receiver domains, SgmT consists of an N-terminal GAF domain and a C-terminal GGDEF domain. The GAF domain is the primary sensor domain. The GGDEF domain binds the second messenger bis-(3′-5′)-cyclic-dimeric-GMP (c-di-GMP) and functions as a c-di-GMP receptor to spatially sequester SgmT. We identify the DigR binding site in the promoter of the fibA gene, which encodes an abundant extracellular matrix metalloprotease. Whole-genome expression profiling experiments in combination with the identified DigR binding site allowed the identification of the DigR regulon and suggests that SgmT/DigR regulates the expression of genes for secreted proteins and enzymes involved in secondary metabolite synthesis. We suggest that SgmT/DigR regulates extracellular matrix composition and that SgmT activity is regulated by two sensor domains with ligand binding to the GAF domain resulting in SgmT activation and c-di-GMP binding to the GGDEF domain resulting in spatial sequestration of SgmT. PMID:22394314

  10. 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

  11. Heterologous expression of an orphan NRPS gene cluster from Paenibacillus larvae in Escherichia coli revealed production of sevadicin.

    PubMed

    Tang, Ying; Frewert, Simon; Harmrolfs, Kirsten; Herrmann, Jennifer; Karmann, Lisa; Kazmaier, Uli; Xia, Liqiu; Zhang, Youming; Müller, Rolf

    2015-01-20

    The Gram-positive bacterium Paenibacillus larvae is the causative agent of the fateful honey bee disease American Foulbrood (AFB). Sequence analysis of P. larvae genomic DNA showed the presence of numerous nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) encoding gene clusters, not correlating with secondary metabolite production. As NRPS and PKS derived metabolites are known to exhibit diverse biological activities, their identification is of particular interest for infection and drug research. Here an 11.6kb orphan NRPS gene cluster was directly cloned from the genomic DNA of P. larvae and expressed in Escherichia coli resulting in the production of sevadicin. Isolation of the metabolite was followed by structural characterization, synthesis and bioactivity studies. PMID:25529345

  12. 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.

  13. Workshop Proceedings: Streamlined Development of Safety Assessment Programs Supporting Orphan/Rare Diseases-Are We There Yet?

    PubMed

    Allamneni, Krishna P; Parker, Suezanne; O'Neill, Charles A; Wright, Teresa L; King, Sruthi; Andrews, Laura

    2016-07-01

    A workshop entitled "Streamlined Development of Safety Assessment Programs Supporting Orphan/Rare Diseases-Are We There Yet?" was held at the 36th Annual Meeting of the American College of Toxicology in Summerlin, Nevada. The workshop was sponsored by Shire and Ultragenyx and was designed to present the nonclinical considerations for the development of various products for rare diseases. A panel of experts from industry and government highlighted the nonclinical considerations in developing toxicology programs supporting rare disease therapeutics, challenges in preclinical safety assessment, reviewed the current guidance, and presented the progress that has been made to date. The main learning from the workshop was that nonclinical testing of therapeutics targeting rare disease warrants special considerations, and early collaboration between sponsors and health authorities may help optimize the scope and timing of the supportive studies. Specific examples for nonclinical development programs for enzyme replacement therapy (ERT) were presented. Although the symposium focused on ERTs, the concepts are broadly applicable. PMID:27272885

  14. Impairment of Drosophila Orthologs of the Human Orphan Protein C19orf12 Induces Bang Sensitivity and Neurodegeneration

    PubMed Central

    Iuso, Arcangela; Sibon, Ody C. M.; Gorza, Matteo; Heim, Katharina; Organisti, Cristina; Meitinger, Thomas; Prokisch, Holger

    2014-01-01

    Mutations in the orphan gene C19orf12 were identified as a genetic cause in a subgroup of patients with NBIA, a neurodegenerative disorder characterized by deposits of iron in the basal ganglia. C19orf12 was shown to be localized in mitochondria, however, nothing is known about its activity and no functional link exists to the clinical phenotype of the patients. This situation led us to investigate the effects of C19orf12 down-regulation in the model organism Drosophila melanogaster. Two genes are present in D. melanogaster, which are orthologs of C19orf12, CG3740 and CG11671. Here we provide evidence that transgenic flies with impaired C19orf12 homologs reflect the neurodegenerative phenotype and represent a valid tool to further analyze the pathomechanism in C19orf12-associated NBIA. PMID:24586779

  15. 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.

  16. 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

  17. Nuclear orphan receptor Nor-1 contributes to depressive behavior in the Wistar-Kyoto rat model of depression.

    PubMed

    Schaffer, Daniel J; Tunc-Ozcan, Elif; Shukla, Pradeep K; Volenec, Andreja; Redei, Eva E

    2010-11-29

    The current study explored the effects of prolonged antidepressant treatment on mRNA levels of two nuclear receptors in specific brain regions of an animal model of depression, the Wistar-Kyoto (WKY) rat. Both nuclear receptors have been implicated in the development or treatment of depression. The expression of nuclear orphan receptor-1 (Nor-1), a member of the NR4A nuclear orphan receptor family, is induced by electroconvulsive shock, an effective treatment for depression. Deficit in the levels or function of the glucocorticoid receptor (GR) found in depressed patients has been causally implicated in depression, as this deficit is normalized by antidepressant treatments. Baseline levels of amygdalar Nor-1 and GR mRNA were higher in the WKYs compared to the comparison control Sprague-Dawley rats (SD). Prolonged treatment with the antidepressant desipramine (DMI) decreased the expression of both transcripts in the WKY strain concomitantly with decreased immobility in the forced swim test (FST) of depressive behavior. Using short hairpin RNA (shRNA) targeted against Nor-1, we investigated the direct contribution of elevated Nor-1 expression in the amygdala of WKY to their exaggerated depressive behavior in the FST. After validating the shRNA targeting of Nor-1 in vitro, Nor-1 shRNA containing vector was infused intracerebroventricularly, using a linear polyethylenimine (PEI)-containing in vivo gene delivery system. Repeated administration of Nor-1 shRNA ameliorated the depressive behavior of WKYs in the FST and decreased amygdalar Nor-1 mRNA levels without affecting GR mRNA levels. These data demonstrate that brain region-specific changes in GR expression in response to DMI are strain dependent and that elevated amygdalar Nor-1 expression can contribute to depressive behavior in the WKY model of depression. PMID:20851110

  18. 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

  19. Effectiveness of a Motivation and Practical Skills Development Methods on the Oral Hygiene of Orphans Children in Kaunas, Lithuania

    PubMed Central

    Narbutaite, Julija

    2015-01-01

    ABSTRACT Objectives The aim of this study was to evaluate the effect of a motivation and practical skills development methods on the oral hygiene of orphans. Material and Methods Sixty eight orphans aged between 7 and 17 years from two orphanages in Kaunas were divided into two groups: practical application group and motivation group. Children were clinically examined by determining their oral hygiene status using Silness-Löe plaque index. Questionnaire was used to estimate the oral hygiene knowledge and practices at baseline and after 3 months. Statistical analysis included: Chi-square test (χ2), Fisher‘s exact test, Student‘s t-test, nonparametric Mann-Whitney test, Spearman’s rho correlation coefficient and Kappa coefficient. Results All children had a plaque on at least one tooth in both groups: motivation 1.14 (SD 0.51), practical application 1.08 (SD 0.4) (P = 0.58). Girls in both groups showed significantly better oral hygiene than boys (P < 0.001). After 3 months educational program oral hygiene status improved in both groups significantly 0.4 (SD 0.35) (P < 0.001). Significantly better oral hygiene was determined in practical application group 0.19 (SD 0.27) in comparison with motivation group 0.55 (SD 0.32) (P < 0.001). By comparing results of first and second questionnaire surveys on use of soft drinks, the statistically significant decline of their use was in both groups (P = 0.004). Conclusions Educational programs are effective in improving oral hygiene, especially when they’re based on practical skills training. PMID:26539284

  20. Improved water and household water purification practices among orphans and vulnerable children in a multi-sectoral empowerment program in Eastern province, Kenya.

    PubMed

    Goodman, Michael; Elliott, Aleisha; Gitari, Stanley; Keiser, Philip H; Raimer-Goodman, Lauren A

    2016-06-01

    Water quality is an important determinant of diarrheal illnesses, especially affecting children in sub-Saharan Africa. Orphans and vulnerable children (OVC) in sub-Saharan Africa are at increased risk of poor quality drinking water, and therefore of diarrheal illness. The present study assesses primary drinking water source and typical household water purification among OVC households involved in a multi-sectoral empowerment program in semi-rural Kenya. Findings show water purification practices, but not water source, significantly increase with more time in the program. Other factors associated with safer water include household income, orphan type, food consumption and security, school completion, psychological resilience, engaging in sexual intercourse with more than one partner in the past 12 months, and previous year's financial status. Incorporating water quality improvements in a community-based empowerment program such as the one described may be one method of improving water quality and decreasing diarrheal illnesses among OVCs in sub-Saharan Africa. PMID:27280615