A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.3448Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H

Reversible cardiopathy after accidental overdose of mitoxantrone

Mitoxantrone is an anthraquinone structurally related to the anthracycline drugs doxorubicin and daunorubicin. In animal tumor models, it was equally cytotoxic as but less cardiotoxic than the parent compounds. We here describe the clinical course of a 9-year old girl who inadvertently received 100 mg/m2 of mitoxantrone as a bolus injection. Hemoperfusion carried out twice with the-objective of increasing the drug clearance was totally inefficient. Severe but transient myelotoxicity was induced. Sequential echocardiograms demonstrated a reversible decrease of the shortening fraction of the left ventricle

Ocean alkalinity enhancement through enhanced silicate weathering in coastal areas: a long-term mesocosm study

Enhanced silicate weathering (ESW) in coastal environments is a promising method for ocean alkalinity enhancement. The idea behind ESW is to generate alkalinity by application of silicate minerals in coastal areas, where waves, currents and bioturbation can speed up the weathering rate. Due to its potentially large CO2 sequestration capacity and relatively high technological readiness, allowing rapid upscaling, coastal ESW currently receives substantial interest from researchers and policymakers. However, the vast majority of studies on ESW have been conducted in idealised laboratory conditions, while research on the method in natural environments is lacking. As a result, the CO2 sequestration efficiency and environmental risks when applying ESW in the field remain largely unknown. Here we present results from the first and longest-running mesocosm experiment investigating ESW and associated CO2 uptake in coastal marine sediments. Using tanks containing one square meter of natural seafloor each, we have studied biogeochemical cycling in sediment treated with the fast-weathering silicate mineral olivine. Lugworms (Arenicola marina) were added to some tanks to investigate the effect of bioturbation on the olivine dissolution rate, as well as the impact of olivine addition on biota. In the mesocosms, we quantified the sedimentary release of alkalinity and other weathering end-products (trace metals and dissolved silicate). Five years into the experiment, olivine dissolution is obvious from an elevated sedimentary alkalinity release and decreased average olivine grain size. The elevated alkalinity release has further led to higher CO2 sequestrations in tanks with olivine. Based on the results from this unique mesocosm setup, we will discuss the large-scale effect of ESW on biogeochemical cycling in coastal ecosystems

Chapter 2 - Philology’s roommate: hermeneutics, antiquity, and the seminar

This chapter starts from the extraordinary historical circumstance that Schleiermacher and Schlegel, a theologian and classical scholar and philosopher, who both had a huge influence on the development of their disciplines and the institution of the university, shared lodgings as students. It explores their relationship, and the importance of it for their subsequent careers, and expands from this to consider how the seminary, as dominant theological educational institution, was overtaken in the university by the seminar – to explore how both educational forums show similar negotiations of the dynamic between personal, affective relationships and methodological rigour. It thus raises questions about how the public and the private, emotion and objectivity became values of scholarship between philology and theology in the universit

Chapter 2 - Philology’s roommate: hermeneutics, antiquity, and the seminar

This chapter starts from the extraordinary historical circumstance that Schleiermacher and Schlegel, a theologian and classical scholar and philosopher, who both had a huge influence on the development of their disciplines and the institution of the university, shared lodgings as students. It explores their relationship, and the importance of it for their subsequent careers, and expands from this to consider how the seminary, as dominant theological educational institution, was overtaken in the university by the seminar – to explore how both educational forums show similar negotiations of the dynamic between personal, affective relationships and methodological rigour. It thus raises questions about how the public and the private, emotion and objectivity became values of scholarship between philology and theology in the universit