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  • 1
    Publication Date: 2016-04-13
    Description: Background Despite a concerted policy effort in Europe, social inequalities in health are a persistent problem. Developing a standardised measure of socioeconomic level across Europe will improve the understanding of the underlying mechanisms and causes of inequalities. This will facilitate developing, implementing and assessing new and more effective policies, and will improve the comparability and reproducibility of health inequality studies among countries. This paper presents the extension of the European Deprivation Index (EDI), a standardised measure first developed in France, to four other European countries—Italy, Portugal, Spain and England, using available 2001 and 1999 national census data. Methods and results The method previously tested and validated to construct the French EDI was used: first, an individual indicator for relative deprivation was constructed, defined by the minimal number of unmet fundamental needs associated with both objective (income) poverty and subjective poverty. Second, variables available at both individual (European survey) and aggregate (census) levels were identified. Third, an ecological deprivation index was constructed by selecting the set of weighted variables from the second step that best correlated with the individual deprivation indicator. Conclusions For each country, the EDI is a weighted combination of aggregated variables from the national census that are most highly correlated with a country-specific individual deprivation indicator. This tool will improve both the historical and international comparability of studies, our understanding of the mechanisms underlying social inequalities in health and implementation of intervention to tackle social inequalities in health.
    Keywords: Open access, Health service research, Sociology
    Print ISSN: 0143-005X
    Electronic ISSN: 1470-2738
    Topics: Medicine
    Published by BMJ Publishing Group
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  • 2
    Publication Date: 2016-10-15
    Description: SPX domains control phosphate homeostasis in eukaryotes. Ten genes in yeast encode SPX-containing proteins, among which YDR089W is the only one of unknown function. Here, we show that YDR089W encodes a novel subunit of the vacuole transporter chaperone (VTC) complex that produces inorganic polyphosphate (polyP). The polyP synthesis transfers inorganic phosphate (Pi) from the cytosol into the acidocalcisome- and lysosome-related vacuoles of yeast, where it can be released again. It was therefore proposed for buffer changes in cytosolic Pi concentration (Thomas, M. R., and O'Shea, E. K. (2005) Proc. Natl. Acad. Sci. U.S.A. 102, 9565–9570). Vtc5 physically interacts with the VTC complex and accelerates the accumulation of polyP synthesized by it. Deletion of VTC5 reduces polyP accumulation in vivo and in vitro. Its overexpression hyperactivates polyP production and triggers the phosphate starvation response via the PHO pathway. Because this Vtc5-induced starvation response can be reverted by shutting down polyP synthesis genetically or pharmacologically, we propose that polyP synthesis rather than Vtc5 itself is a regulator of the PHO pathway. Our observations suggest that polyP synthesis not only serves to establish a buffer for transient drops in cytosolic Pi levels but that it can actively decrease or increase the steady state of cytosolic Pi.
    Print ISSN: 0021-9258
    Electronic ISSN: 1083-351X
    Topics: Biology , Chemistry and Pharmacology
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  • 3
    Publication Date: 2013-12-21
    Description: The RNA polymerase II (RNApII) C-terminal domain (CTD)-interacting domain (CID) proteins are involved in two distinct RNApII termination pathways and recognize different phosphorylated forms of CTD. To investigate the role of differential CTD-CID interactions in the choice of termination pathway, we altered the CTD-binding specificity of Nrd1 by domain swapping. Nrd1 with the CID from Rtt103 (Nrd1(CIDRtt103)) causes read-through transcription at many genes, but can also trigger termination where multiple Nrd1/Nab3-binding sites and the Ser(P)-2 CTD co-exist. Therefore, CTD-CID interactions target specific termination complexes to help choose an RNApII termination pathway. Interactions of Nrd1 with both CTD and nascent transcripts contribute to efficient termination by the Nrd1 complex. Surprisingly, replacing the Nrd1 CID with that from Rtt103 reduces binding to Rrp6/Trf4, and RNA transcripts terminated by Nrd1(CIDRtt103) are predominantly processed by core exosome. Thus, the Nrd1 CID couples Ser(P)-5 CTD not only to termination, but also to RNA processing by the nuclear exosome.
    Print ISSN: 0021-9258
    Electronic ISSN: 1083-351X
    Topics: Biology , Chemistry and Pharmacology
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  • 4
    Publication Date: 2015-05-16
    Description: Membrane fusion is induced by SNARE complexes that are anchored in both fusion partners. SNAREs zipper up from the N to C terminus bringing the two membranes into close apposition. Their transmembrane domains (TMDs) might be mere anchoring devices, deforming bilayers by mechanical force. Structural studies suggested that TMDs might also perturb lipid structure by undergoing conformational transitions or by zipping up into the bilayer. Here, we tested this latter hypothesis, which predicts that the activity of SNAREs should depend on the primary sequence of their TMDs. We replaced the TMDs of all vacuolar SNAREs (Nyv1, Vam3, and Vti1) by a lipid anchor, by a TMD from a protein unrelated to the membrane fusion machinery, or by artificial leucine-valine sequences. Individual exchange of the native SNARE TMDs against an unrelated transmembrane anchor or an artificial leucine-valine sequence yielded normal fusion activities. Fusion activity was also preserved upon pairwise exchange of the TMDs against unrelated peptides, which eliminates the possibility for specific TMD-TMD interactions. Thus, a specific primary sequence or zippering beyond the SNARE domains is not a prerequisite for fusion. Lipid-anchored Vti1 was fully active, and lipid-anchored Nyv1 permitted the reaction to proceed up to hemifusion, and lipid-anchored Vam3 interfered already before hemifusion. The unequal contribution of proteinaceous TMDs on Vam3 and Nyv1 suggests that Q- and R-SNAREs might make different contributions to the hemifusion intermediate and the opening of the fusion pore. Furthermore, our data support the view that SNARE TMDs serve as nonspecific membrane anchors in vacuole fusion.
    Print ISSN: 0021-9258
    Electronic ISSN: 1083-351X
    Topics: Biology , Chemistry and Pharmacology
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  • 5
    Publication Date: 2015-10-24
    Description: We have reported previously that a missense mutation in the mitochondrial fission gene Dynamin-related protein 1 (Drp1) underlies the Python mouse model of monogenic dilated cardiomyopathy. The aim of this study was to investigate the consequences of the C452F mutation on Drp1 protein function and to define the cellular sequelae leading to heart failure in the Python monogenic dilated cardiomyopathy model. We found that the C452F mutation increased Drp1 GTPase activity. The mutation also conferred resistance to oligomer disassembly by guanine nucleotides and high ionic strength solutions. In a mouse embryonic fibroblast model, Drp1 C452F cells exhibited abnormal mitochondrial morphology and defective mitophagy. Mitochondria in C452F mouse embryonic fibroblasts were depolarized and had reduced calcium uptake with impaired ATP production by oxidative phosphorylation. In the Python heart, we found a corresponding progressive decline in oxidative phosphorylation with age and activation of sterile inflammation. As a corollary, enhancing autophagy by exposure to a prolonged low-protein diet improved cardiac function in Python mice. In conclusion, failure of Drp1 disassembly impairs mitophagy, leading to a downstream cascade of mitochondrial depolarization, aberrant calcium handling, impaired ATP synthesis, and activation of sterile myocardial inflammation, resulting in heart failure.
    Print ISSN: 0021-9258
    Electronic ISSN: 1083-351X
    Topics: Biology , Chemistry and Pharmacology
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