Suchergebnisse

This is the final version of the article. Available from the publisher via the DOI in this record. ; Although mitochondrial dysfunction is a consistent feature of Alzheimer's disease in the brain and blood, the molecular mechanisms behind these phenomena are unknown. Here we have replicated our previous findings demonstrating reduced expression of nuclear-encoded oxidative phosphorylation (OXPHOS) subunits and subunits required for the translation of mitochondrial-encoded OXPHOS genes in blood from people with Alzheimer's disease and mild cognitive impairment. Interestingly this was accompanied by increased expression of some mitochondrial-encoded OXPHOS genes, namely those residing closest to the transcription start site of the polycistronic heavy chain mitochondrial transcript (MT-ND1, MT-ND2, MT-ATP6, MT-CO1, MT-CO2, MT-C03) and MT-ND6 transcribed from the light chain. Further we show that mitochondrial DNA copy number was unchanged suggesting no change in steady-state numbers of mitochondria. We suggest that an imbalance in nuclear and mitochondrial genome-encoded OXPHOS transcripts may drive a negative feedback loop reducing mitochondrial translation and compromising OXPHOS efficiency, which is likely to generate damaging reactive oxygen species. ; This work represents independent research part funded by the InnoMed (Innovative Medicines in Europe) an Integrated Project funded by the European Union of the Sixth Framework program priority FP6-2004-LIFESCIHEALTH-5, Alzheimer's Research UK, The John and Lucille van Geest Foundation, the Rosetrees Trust, the National Institute for Health Research (NIHR) Biomedical Research Centre and Dementia Unit at South London and Maudsley NHS Foundation Trust and King's College London and the National Institute for Health Research University College London Hospitals Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. A. H. receives support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement no115372, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007e2013) and EFPIA companies in kind contribution. R. D. is supported by awards to establish the Farr Institute of Health Informatics Research at UCL Partners, from the Medical Research Council, Arthritis Research UK, British Heart Foundation, Cancer Research UK, Chief Scientist Office, Economic and Social Research Council, Engineering and Physical Sciences Research Council, National Institute for Health Research, National Institute for Social Care and Health Research, and Wellcome Trust (grant MR/K006584/1)

Frontmatter -- CHAPTER FOUR Myth and Folktale -- CONTRIBUTORS -- ACKNOWLEDGMENTS -- Chapter 1 GLOBALIZATION AND GOVERNANCE -- PART 1 Globalization and Changing Locations of Governance -- Chapter 2 THE LEVERAGE OF ECONOMIC THEORIES Explaining Governance in an Internationalized Industry -- Chapter 3 POLITICAL INTEGRATION AND DISINTEGRATION IN THE GLOBAL ECONOMY -- Chapter 4 GLOBALIZATION AND FISCAL DECENTRALIZATION -- Chapter 5 GLOBALIZATION AND DEMANDS FOR REGIONAL AUTONOMY IN EUROPE -- Chapter 6 MONETARY GOVERNANCE IN A WORLD OF REGIONAL CURRENCIES -- Chapter 7 GOVERNING GLOBAL FINANCIAL MARKETS International Responses to the Hedge-Fund Problem -- Chapter 8 PUBLIC AND PRIVATE GOVERNANCE IN SETTING INTERNATIONAL STANDARDS -- Chapter 9 GLOBALIZATION AND INDUSTRY SELF-REGULATION -- PART 2 Convergence in National Governance -- Chapter 10 INTERNATIONAL CAPITAL MOBILITY AND NATIONAL POLICY DIVERGENCE -- Chapter 11 GLOBALIZATION AND POLICY DIFFUSION Explaining Three Decades of Liberalization -- Chapter 12 CORPORATE GOVERNANCE Global Markets, National Politics -- Chapter 13 GLOBALIZATION, INSTITUTIONS, AND CONVERGENCE Fiscal Adjustment in Europe -- PART 3 Democratic Deficits and the Problem of Accountability -- Chapter 14 DEMOCRACY, ACCOUNTABILITY, AND RIGHTS IN SUPRANATIONAL GOVERNANCE -- Chapter 15 REDEFINING ACCOUNTABILITY FOR GLOBAL GOVERNANCE -- GLOBALIZATION AND CHANGING PATTERNS OF POLITICAL AUTHORITY -- REFERENCES -- INDEX

Published ; Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't ; BACKGROUND: The study aimed to validate previously discovered plasma biomarkers associated with AD, using a design based on imaging measures as surrogate for disease severity and assess their prognostic value in predicting conversion to dementia. METHODS: Three multicenter cohorts of cognitively healthy elderly, mild cognitive impairment (MCI), and AD participants with standardized clinical assessments and structural neuroimaging measures were used. Twenty-six candidate proteins were quantified in 1148 subjects using multiplex (xMAP) assays. RESULTS: Sixteen proteins correlated with disease severity and cognitive decline. Strongest associations were in the MCI group with a panel of 10 proteins predicting progression to AD (accuracy 87%, sensitivity 85%, and specificity 88%). CONCLUSIONS: We have identified 10 plasma proteins strongly associated with disease severity and disease progression. Such markers may be useful for patient selection for clinical trials and assessment of patients with predisease subjective memory complaints. ; Medical Research Council (MRC) ; Alzheimer's Research UK ; The National Institute for Health Research (NIHR) Biomedical Research Centre ; Biomedical Research Unit for Dementia ; AddNeuroMed through the EU FP6 program ; Innovative Medicines Initiative Joint Undertaking under an EMIF grant ; European Union's Seventh Framework Programme (FP7/2007-2013)

Two leaders engaged in international co-operation must each build trust by credibly signalling that they will not exploit the other by defecting at the implementation stage. Previous research does not reveal the difficulty and cost of such international reassurance. The role that costly adjustments by markets play in international reassurance is analysed, showing that fully efficient information revelation can be achieved when market actors under intense competitive pressures undergo sufficiently costly adjustments in expectation of international co-operation. 'Nice' leaders can reveal their true preferences simply by saying they intend to co-operate, because 'mean' leaders are unwilling to mislead market actors into undergoing futile costly adjustments. However, market imperfections prevent full information revelation unless market actors prefer international co-operation to the status quo. (British Journal of Political Science / FUB)