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1.
Health Res Policy Syst ; 12: 64, 2014 Nov 27.
Article in English | MEDLINE | ID: mdl-25427859

ABSTRACT

BACKGROUND: The relationship between research funding across therapeutic areas and the burden of disease in Norway has not been investigated. Further, few studies have looked at the association between national research investments and the global disease burden. The aim of the present study was to analyze the correlation between a significant part of Norwegian investment in health research and the burden of disease across therapeutic areas, using both Norwegian and global burden of disease estimates. METHODS: We used research investment records for 2012 from the Research Council of Norway, and the investment records distributed through liaison committees between regional health authorities and universities. Both were classified by the Health Research Classification System (HRCS). Furthermore, we used the years of life lost and Disability Adjusted Life Years (DALYs) for Norway and globally from the Global Burden of Disease 2010 project. We created a matrix to match the expenditures by HRCS with the values from the Global Burden of Disease project. RESULTS: Disease-specific research funding increased with the Norwegian burden of disease measured as years of life lost (correlation coefficient = 0.73). Similar findings were done when the Norwegian disease burden was measured as DALYs (correlation coefficient = 0.62). The correlation between research funding and the global disease burden was low both when years of life lost (correlation coefficient = 0.11) and DALYs (correlation coefficient = 0.12) were used. Generally, when the disease burden was relatively high in Norway compared with the rest of the world, research investments were also high. CONCLUSIONS: Across therapeutic areas, the Norwegian research investments appeared aligned with the Norwegian disease burden. The correlation between the Norwegian research investments and the global disease burden was much lower.


Subject(s)
Health Services Research/economics , Health Services Research/organization & administration , Resource Allocation/economics , Cost of Illness , Disabled Persons , Global Health/economics , Humans , Norway/epidemiology , Quality-Adjusted Life Years , Statistics as Topic
2.
Traffic ; 13(11): 1547-63, 2012 Nov.
Article in English | MEDLINE | ID: mdl-22816767

ABSTRACT

Phosphatidylinositol 3-phosphate (PtdIns3P) orchestrates endosomal cargo transport, fusion and motility by recruiting FYVE or PX domain-containing effector proteins to endosomal membranes. In an attempt to discover novel PtdIns3P effectors involved in the termination of growth factor receptor signalling, we performed an siRNA screen for epidermal growth factor (EGF) degradation, targeting FYVE and PX domain proteins in the human proteome. This screen identified several potential regulators of EGF degradation, including HRS (used as positive control), PX kinase, MTMR4 and Phafin2/PLEKHF2. As Phafin2 has not previously been shown to be required for EGF receptor (EGFR) degradation, we performed further functional studies on this protein. Loss of Phafin2 was found to decrease early endosome size, whereas overexpression of Phafin2 resulted in enlarged endosomes. Moreover, both the EGFR and the fluid-phase marker dextran were retained in abnormally small endosomes in Phafin2-depleted cells. In yeast two-hybrid analysis we identified Phafin2 as a novel interactor of the endosomal-tethering protein EEA1, and Phafin2 colocalized strongly with EEA1 in microdomains of the endosome membrane. Our results suggest that Phafin2 controls receptor trafficking and fluid-phase transport through early endosomes by facilitating endosome fusion in concert with EEA1.


Subject(s)
Endosomes/metabolism , ErbB Receptors/metabolism , Vesicular Transport Proteins/metabolism , Amino Acid Motifs , Endocytosis , Endosomes/ultrastructure , Epidermal Growth Factor/metabolism , HeLa Cells , High-Throughput Screening Assays , Humans , Intracellular Signaling Peptides and Proteins/chemistry , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Nerve Tissue Proteins/chemistry , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Organelle Size , Protein Interaction Domains and Motifs , Protein Serine-Threonine Kinases/chemistry , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Protein Tyrosine Phosphatases, Non-Receptor/chemistry , Protein Tyrosine Phosphatases, Non-Receptor/genetics , Protein Tyrosine Phosphatases, Non-Receptor/metabolism , Proteolysis , Proteome/chemistry , Proteome/metabolism , RNA, Small Interfering , Two-Hybrid System Techniques , Up-Regulation , Vesicular Transport Proteins/chemistry , Vesicular Transport Proteins/genetics
3.
Biol Cell ; 102(5): 293-318, 2010 Mar 12.
Article in English | MEDLINE | ID: mdl-20222872

ABSTRACT

Components of the ESCRT (endosomal sorting complex required for transport) machinery mediate endosomal sorting of ubiquitinated membrane proteins. They are key regulators of biological processes important for cell growth and survival, such as growth-factor-mediated signalling and cytokinesis. In addition, enveloped viruses, such as HIV-1, hijack and utilize the ESCRTs for budding during virus release and infection. Obviously, the ESCRT-facilitated pathways require tight regulation, which is partly mediated by a group of interacting proteins, for which our knowledge is growing. In this review we discuss the different ESCRT-modulating proteins and how they influence ESCRT-dependent processes, for example, by acting as positive or negative regulators or by providing temporal and spatial control. A number of the interactors influence the classical ESCRT-mediated process of endosomal cargo sorting, for example, by modulating the interaction between ubiquitinated cargo and the ESCRTs. Certain accessory proteins have been implicated in regulating the activity or steady-state expression levels of the ESCRT components, whereas other interactors control the cellular localization of the ESCRTs, for example, by inducing shuttling between cytosol and nucleus or endosomes. In conclusion, the discovery of novel interactors has and will extend our knowledge of the biological roles of ESCRTs.


Subject(s)
Endosomal Sorting Complexes Required for Transport/metabolism , Endosomes/metabolism , Gene Expression Regulation , Biological Transport/physiology , Cytokinesis/physiology , Endosomal Sorting Complexes Required for Transport/genetics , Fungal Proteins/metabolism , Humans , Membrane Proteins/metabolism , Protein Subunits/metabolism , Signal Transduction/physiology , Transcription, Genetic , Ubiquitin/metabolism , Vesicular Transport Proteins/metabolism , Viruses/metabolism
4.
Exp Cell Res ; 315(17): 3014-27, 2009 Oct 15.
Article in English | MEDLINE | ID: mdl-19619532

ABSTRACT

Clinical features characterizing Angelman syndrome, previously shown to be caused by disruption of UBE3A, were recently also described in neurologically disabled patients with mutations in SLC9A6, which encodes the Na(+)/H(+) exchanger NHE6. In the present work we have focused on NHE6Delta255-256, the protein product of a specific 6-bp patient deletion in SLC9A6. To resolve the molecular mechanism causing the cellular dysfunction associated with this mutant, we have characterized its intracellular behaviour in comparison to wild type NHE6. Our study demonstrates that NHE6Delta255-256 is much less stable than the wild type protein. Whereas wild type NHE6 is transported to the plasma membrane and early endosomes and remains stable, NHE6Delta255-256 is degraded via two independent pathways mediated by proteasomes and lysosomes, respectively. Depletion of NHE6 had no detectable effect on endosomal pH, but co-depletion of NHE6 and the closely related NHE9 caused enhanced acidification of early endosomes. Our results suggest that NHE6 participates in regulation of endosomal pH and provides a cellular basis for understanding the loss of NHE6 function leading to a neurological phenotype resembling Angelman syndrome.


Subject(s)
Angelman Syndrome/genetics , Nervous System Diseases/genetics , Sodium-Hydrogen Exchangers/genetics , Chromosomes, Human, Pair 15 , DNA Primers , Endosomes/physiology , Female , HeLa Cells/cytology , HeLa Cells/physiology , Humans , Intellectual Disability/genetics , Male , Microscopy, Confocal , Mutation , Nervous System Diseases/metabolism , Polymerase Chain Reaction , Sequence Deletion , Sodium-Hydrogen Exchangers/metabolism
5.
J Cell Biol ; 180(6): 1205-18, 2008 Mar 24.
Article in English | MEDLINE | ID: mdl-18362181

ABSTRACT

Down-regulation of activated and ubiquitinated growth factor (GF) receptors by endocytosis and subsequent lysosomal degradation ensures attenuation of GF signaling. The ubiquitin-binding adaptor protein Eps15 (epidermal growth factor receptor [EGFR] pathway substrate 15) functions in endocytosis of such receptors. Here, we identify an Eps15 isoform, Eps15b, and demonstrate its expression in human cells and conservation across vertebrate species. Although both Eps15 and Eps15b interact with the endosomal sorting protein Hrs (hepatocyte growth factor-regulated tyrosine kinase substrate) in vitro, we find that Hrs specifically binds Eps15b in vivo (whereas adaptor protein 2 preferentially interacts with Eps15). Although Eps15 mainly localizes to clathrin-coated pits at the plasma membrane, Eps15b localizes to Hrs-positive microdomains on endosomes. Eps15b overexpression, similarly to Hrs overexpression, inhibits ligand-mediated degradation of EGFR, whereas Eps15 is without effect. Similarly, depletion of Eps15b but not Eps15 delays degradation and promotes recycling of EGFR. These results indicate that Eps15b is an endosomally localized isoform of Eps15 that is present in the Hrs complex via direct Hrs interaction and important for the sorting function of this complex.


Subject(s)
Calcium-Binding Proteins/metabolism , Endocytosis/physiology , Endosomes/metabolism , ErbB Receptors/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Phosphoproteins/metabolism , Adaptor Proteins, Signal Transducing , Animals , Calcium-Binding Proteins/genetics , Cell Membrane/metabolism , Clathrin/metabolism , Down-Regulation/physiology , Endosomal Sorting Complexes Required for Transport , HeLa Cells , Humans , Intracellular Signaling Peptides and Proteins/genetics , Phosphoproteins/genetics , Protein Binding/physiology , Protein Isoforms/genetics , Protein Isoforms/metabolism , Protein Transport/physiology , Signal Transduction/physiology
6.
Am J Hum Genet ; 82(4): 1003-10, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18342287

ABSTRACT

Linkage analysis and DNA sequencing in a family exhibiting an X-linked mental retardation (XLMR) syndrome, characterized by microcephaly, epilepsy, ataxia, and absent speech and resembling Angelman syndrome, identified a deletion in the SLC9A6 gene encoding the Na(+)/H(+) exchanger NHE6. Subsequently, other mutations were found in a male with mental retardation (MR) who had been investigated for Angelman syndrome and in two XLMR families with epilepsy and ataxia, including the family designated as having Christianson syndrome. Therefore, mutations in SLC9A6 cause X-linked mental retardation. Additionally, males with findings suggestive of unexplained Angelman syndrome should be considered as potential candidates for SLC9A6 mutations.


Subject(s)
Ataxia/genetics , Epilepsy/genetics , Membrane Proteins/genetics , Mental Retardation, X-Linked/genetics , Microcephaly/genetics , Mutation , Sodium-Hydrogen Exchangers/genetics , Adult , Angelman Syndrome/diagnosis , Angelman Syndrome/genetics , Ataxia/diagnosis , Child , Child, Preschool , DNA Mutational Analysis , Electroencephalography , Epilepsy/diagnosis , Humans , Magnetic Resonance Imaging , Male , Mental Retardation, X-Linked/diagnosis , Microcephaly/diagnosis , Pedigree , Phenotype , Syndrome
7.
Plant Cell Physiol ; 48(3): 471-83, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17284469

ABSTRACT

Members of the plant-specific gibberellic acid-stimulated Arabidopsis (GASA) gene family play roles in hormone response, defense and development. We have identified six new Arabidopsis GASA genes, bringing the total number of family members to 14. Here we show that these genes all encode small polypeptides that share the common structural features of an N-terminal putative signal sequence, a highly divergent intermediate region and a conserved 60 amino acid C-terminal domain containing 12 conserved cysteine residues. Analysis of promoter::GUS (beta-glucuronidase) transgenic plants representing six different GASA loci reveals that the promoters are activated in a variety of stage- and tissue-specific patterns during development, indicating that the GASA genes are involved in diverse processes. Characterization of GASA4 shows that the promoter is active in the shoot apex region, developing flowers and developing embryos. Phenotypic analyses of GASA4 loss-of-function and gain-of-function lines indicate that GASA4 regulates floral meristem identity and also positively affects both seed size and total seed yield.


Subject(s)
Arabidopsis Proteins/genetics , Arabidopsis/growth & development , Arabidopsis/genetics , Amino Acid Sequence , Arabidopsis/metabolism , Arabidopsis Proteins/chemistry , Arabidopsis Proteins/metabolism , Conserved Sequence , Flowers/growth & development , Gene Expression Regulation, Developmental , Gene Expression Regulation, Plant , Genes, Plant , Glucuronidase/genetics , Glucuronidase/metabolism , Histocytochemistry , Molecular Sequence Data , Multigene Family , Phenotype , Plants, Genetically Modified , Promoter Regions, Genetic , Protein Structure, Tertiary , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Seeds/growth & development , Sequence Homology, Amino Acid
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