(Supplementary Table 1) Iceberg-rafted debris (IBRD) mass accumulation rates (MAR) of IODP site 318-U1361

The Pliocene and Early Pleistocene, between 5.3 and 0.8 million years ago, span a transition from a global climate state that was 2-3 °C warmer than present with limited ice sheets in the Northern Hemisphere to one that was characterized by continental-scale glaciations at both poles. Growth and decay of these ice sheets was paced by variations in the Earth's orbit around the Sun. However, the nature of the influence of orbital forcing on the ice sheets is unclear, particularly in light of the absence of a strong 20,000-year precession signal in geologic records of global ice volume and sea level. Here we present a record of the rate of accumulation of iceberg-rafted debris offshore from the East Antarctic ice sheet, adjacent to the Wilkes Subglacial Basin, between 4.3 and 2.2 million years ago. We infer that maximum iceberg debris accumulation is associated with the enhanced calving of icebergs during ice-sheet margin retreat. In the warmer part of the record, between 4.3 and 3.5 million years ago, spectral analyses show a dominant periodicity of about 40,000 years. Subsequently, the powers of the 100,000-year and 20,000-year signals strengthen. We suggest that, as the Southern Ocean cooled between 3.5 and 2.5 million years ago, the development of a perennial sea-ice field limited the oceanic forcing of the ice sheet. After this threshold was crossed, substantial retreat of the East Antarctic ice sheet occurred only during austral summer insolation maxima, as controlled by the precession cycle.

SARAH POULTON KALLEY (1825-1907): Professora, Missionária e Poetisa

Sarah Poulton Kalley é conhecida, em quase todos os segmentos do protestantismo do Brasil, devido à organização e compilação d e Salmos e Hinos, o mais antigo hinário protestante editado no vernáculo em nosso país. Seus hinos, ainda em uso em muitas igrejas, marcaram por mais de um século a teologia do protestantismo no Brasil. Apesar desta notoriedade, sua influência na gênese do protestantismo brasileiro nunca foi objeto de estudo. Assim, o objetivo desta pesquisa é resgatar e visibilizar áreas e estratégias de atuação que conferem a esta mulher um perfil de atuação relativamente autônomo. Contudo, centrada no estudo da trajetória intelectual e biográfica de um sujeito histórico, a investigação se defronta com um universo de personagens anônimos, envoltos numa complexa teia de relações, através das quais o protestantismo se insere no Brasil em um contexto especifico: huguenotes, puritanos, luddistas, famílias não-conformistas inglesas, líderes políticos e eclesiásticos, exilados madeirenses, brasileiros, portugueses, imigrantes alemães e, principalmente, a mulher protestante brasileira. A busca por informações sobre este universo relegado ao anonimato pela historiografia do protestantismo no Brasil, reve lou alguns documentos inéditos, inclusive um livro escrito por Sarah Poulton Kalley, em 1866: o A Alegria da Casa. Muito além do papel de esposa de um missionário e médico, Sarah Poulton Kalley emerge de uma rede de relações e práticas como professora, missionária e poetisa. Nestes três campos de atuação e através do desenvolvimento de múltiplos contatos e relacionamentos, procurava transformar e influenciar atitudes e crenças de seus interlocutores. Junto com a nova fé divulgava uma cosmovisão própria da cultura anglo-saxã, protestante e puritana, adaptando-a seletivamente ao universo cultural e social de seus interlocutores.(AU)

SARAH POULTON KALLEY (1825-1907): Professora, Missionária e Poetisa

Sarah Poulton Kalley é conhecida, em quase todos os segmentos do protestantismo do Brasil, devido à organização e compilação d e Salmos e Hinos, o mais antigo hinário protestante editado no vernáculo em nosso país. Seus hinos, ainda em uso em muitas igrejas, marcaram por mais de um século a teologia do protestantismo no Brasil. Apesar desta notoriedade, sua influência na gênese do protestantismo brasileiro nunca foi objeto de estudo. Assim, o objetivo desta pesquisa é resgatar e visibilizar áreas e estratégias de atuação que conferem a esta mulher um perfil de atuação relativamente autônomo. Contudo, centrada no estudo da trajetória intelectual e biográfica de um sujeito histórico, a investigação se defronta com um universo de personagens anônimos, envoltos numa complexa teia de relações, através das quais o protestantismo se insere no Brasil em um contexto especifico: huguenotes, puritanos, luddistas, famílias não-conformistas inglesas, líderes políticos e eclesiásticos, exilados madeirenses, brasileiros, portugueses, imigrantes alemães e, principalmente, a mulher protestante brasileira. A busca por informações sobre este universo relegado ao anonimato pela historiografia do protestantismo no Brasil, reve lou alguns documentos inéditos, inclusive um livro escrito por Sarah Poulton Kalley, em 1866: o A Alegria da Casa. Muito além do papel de esposa de um missionário e médico, Sarah Poulton Kalley emerge de uma rede de relações e práticas como professora, missionária e poetisa. Nestes três campos de atuação e através do desenvolvimento de múltiplos contatos e relacionamentos, procurava transformar e influenciar atitudes e crenças de seus interlocutores. Junto com a nova fé divulgava uma cosmovisão própria da cultura anglo-saxã, protestante e puritana, adaptando-a seletivamente ao universo cultural e social de seus interlocutores.(AU)

HLA alleles determine human T-lymphotropic virus-I (HTLV-I) proviral load and the risk of HTLV-I-associated myelopathy

The risk of disease associated with persistent virus infections such as HIV-I, hepatitis B and C, and human T-lymphotropic virus-I (HTLV-I) is strongly determined by the virus load. However, it is not known whether a persistent class I HLA-restricted antiviral cytotoxic T lymphocyte (CTL) response reduces viral load and is therefore beneficial or causes tissue damage and contributes to disease pathogenesis. HTLV-I-associated myelopathy (HAM/TSP) patients have a high virus load compared with asymptomatic HTLV-I carriers. We hypothesized that HLA alleles control HTLV-I provirus load and thus influence susceptibility to HAM/TSP. Here we show that, after infection with HTLV-I, the class I allele HLA-A*02 halves the odds of HAM/TSP (P < 0.0001), preventing 28% of potential cases of HAM/TSP. Furthermore, HLA-A*02+ healthy HTLV-I carriers have a proviral load one-third that (P = 0.014) of HLA-A*02− HTLV-I carriers. An association of HLA-DRB1*0101 with disease susceptibility also was identified, which doubled the odds of HAM/TSP in the absence of the protective effect of HLA-A*02. These data have implications for other persistent virus infections in which virus load is associated with prognosis and imply that an efficient antiviral CTL response can reduce virus load and so prevent disease in persistent virus infections.

KDIGO-based acute kidney injury criteria operate differently in hospitals and the community—findings from a large population cohort

ACKNOWLEDGEMENTS We acknowledge the data management support of Grampian Data Safe Haven (DaSH) and the associated financial support of NHS Research Scotland, through NHS Grampian investment in the Grampian DaSH. S.S. is supported by a Clinical Research Training Fellowship from the Wellcome Trust (Ref 102729/Z/13/Z). We also acknowledge the support from The Farr Institute of Health Informatics Research. The Farr Institute is supported by a 10-funder consortium: Arthritis Research UK, the British Heart Foundation, Cancer Research UK, the Economic and Social Research Council, the Engineering and Physical Sciences Research Council, the Medical Research Council, the National Institute of Health Research, the National Institute for Social Care and Health Research (Welsh Assembly Government), the Chief Scientist Office (Scottish Government Health Directorates) and the Wellcome Trust (MRC Grant Nos: Scotland MR/K007017/1).

Estimating the effect of nitrogen fertilizer on the greenhouse gas balance of soils in Wales under current and future climate

This work was supported by a Grant from the Welsh Government (Glastir Monitoring and Evaluation Project—GMEP).

Protein phosphatase 2C dephosphorylates and inactivates cystic fibrosis transmembrane conductance regulator

cAMP-dependent phosphorylation activates the cystic fibrosis transmembrane conductance regulator (CFTR) in epithelia. However, the protein phosphatase (PP) that dephosphorylates and inactivates CFTR in airway and intestinal epithelia, two major sites of disease, is not certain. We found that in airway and colonic epithelia, neither okadaic acid nor FK506 prevented inactivation of CFTR when cAMP was removed. These results suggested that a phosphatase distinct from PP1, PP2A, and PP2B was responsible. Because PP2C is insensitive to these inhibitors, we tested the hypothesis that it regulates CFTR. We found that PP2Cα is expressed in airway and T84 intestinal epithelia. To test its activity on CFTR, we generated recombinant human PP2Cα and found that it dephosphorylated CFTR and an R domain peptide in vitro. Moreover, in cell-free patches of membrane, addition of PP2Cα inactivated CFTR Cl− channels; reactivation required readdition of kinase. Finally, coexpression of PP2Cα with CFTR in epithelia reduced the Cl− current and increased the rate of channel inactivation. These results suggest that PP2C may be the okadaic acid-insensitive phosphatase that regulates CFTR in human airway and T84 colonic epithelia. It has been suggested that phosphatase inhibitors could be of therapeutic value in cystic fibrosis; our data suggest that PP2C may be an important phosphatase to target.

Vascular endothelial growth factor C induces angiogenesis in vivo

Vascular endothelial growth factor C (VEGF-C) recently has been described to be a relatively specific growth factor for the lymphatic vascular system. Here we report that ectopic application of recombinant VEGF-C also has potent angiogenic effects in vivo. VEGF-C is sufficiently potent to stimulate neovascularization from limbal vessels in the mouse cornea. Similar to VEGF, the angiogenic response of corneas induced by VEGF-C is intensive, with a high density of new capillaries. However, the outgrowth of microvessels stimulated by VEGF-C was significantly longer than that induced by VEGF. In the developing embryo, VEGF-C was able to induce branch sprouts from the established blood vessels. VEGF-C also induced an elongated, spindle-like cell shape change and actin reorganization in both VEGF receptor (VEGFR)-2 and VEGFR-3-overexpressing endothelial cells, but not in VEGFR-1-expressing cells. Further, both VEGFR-2 and VEGFR-3 could mediate proliferative and chemotactic responses in endothelial cells on VEGF-C stimulation. Thus, VEGF-C may regulate physiological angiogenesis and participate in the development and progression of angiogenic diseases in addition to lymphangiogenesis.