Ocean acidification increases copper toxicity differentially in two key marine invertebrates with distinct acid-base responses.

Published onlineJournal ArticleOcean acidification (OA) is expected to indirectly impact biota living in contaminated coastal environments by altering the bioavailability and potentially toxicity of many pH-sensitive metals. Here, we show that OA (pH 7.71; pCO2 1480 μatm) significantly increases the toxicity responses to a global coastal contaminant (copper ~0.1 μM) in two keystone benthic species; mussels (Mytilus edulis) and purple sea urchins (Paracentrotus lividus). Mussels showed an extracellular acidosis in response to OA and copper individually which was enhanced during combined exposure. In contrast, urchins maintained extracellular fluid pH under OA by accumulating bicarbonate but exhibited a slight alkalosis in response to copper either alone or with OA. Importantly, copper-induced damage to DNA and lipids was significantly greater under OA compared to control conditions (pH 8.14; pCO2 470 μatm) for both species. However, this increase in DNA-damage was four times lower in urchins than mussels, suggesting that internal acid-base regulation in urchins may substantially moderate the magnitude of this OA-induced copper toxicity effect. Thus, changes in metal toxicity under OA may not purely be driven by metal speciation in seawater and may be far more diverse than either single-stressor or single-species studies indicate. This has important implications for future environmental management strategies.CL was supported by a Natural Environment Research Council (NERC) UK Fellowship: NE/G014728/1. CL, RE and RW were supported by a UK-OARP NERC consortium grant NE/H017496/1. SN was supported by a Cefas-Exeter funded studentship. Thanks to Jan Shears, Darren Rowe and John Dowdle for their excellent technical support. The determination of total copper in the seawater media was undertaken by Dr. A. Fisher of the Analytical Research Facility, SoGEES, Plymouth University under ISO 9001:2008 certification. The authors would like to thank John Spicer for his insightful comments on the manuscript

UNICEF’s contribution to the adoption and implementation of option B+ for preventing mother-to-child transmission of HIV: a policy analysis

Abstract Background Between 2011 and 2013, global and national guidelines for preventing mother-to-child transmission (PMTCT) of HIV shifted to recommend Option B+, the provision of lifelong antiretroviral treatment for all HIV-infected pregnant women. Methods We aimed to analyse how Option B+ reached the policy agenda, and unpack the processes, actors and politics that explain its adoption, with a focus on examining UNICEF’s contribution to these events. Analysis drew on published articles and other documentation, 30 key informants interviews with staff at UNICEF, partner organisations and government officials, and country case studies. Cameroon, India, South Africa and Zimbabwe were each visited for 5–8 days. Interview transcripts were analysed using Dedoose software, reviewed several times and then coded thematically. Results A national policy initiative in Malawi in 2011, in which the country adopted Option B+, rather than existing WHO recommended regimens, irrevocably placed the policy on the global agenda. UNICEF and other organisations recognised the policy’s potential impact and strategically crafted arguments to support it, framing these around operational considerations, cost-effectiveness and values. As ‘policy entrepreneurs’, these organisations vigorously promoted the policy through a variety of channels and means, overcoming concerted opposition. WHO, on the basis of scanty evidence, released a series of documents towards the policy’s endorsement, paving the way for its widespread adoption. National-level policy transformation was rapid and definitive, distinct from previous incremental policy processes. Many organisations, including UNICEF, facilitated these changes in country, acting individually, or in concert. Conclusions The adoption of the Option B+ policy marked a departure from established processes for PMTCT policy formulation which had been led by WHO with the support of technical experts, and in which recommendations were developed following shifts in evidence. Rather, changes were spurred by a country-level initiative, and a set of strategically framed arguments that resonated with funders and country-level actors. This bottom-up approach, supported by normative agencies, was transformative. For UNICEF, alignment between the organisation’s country focus and the policy’s underpinning values, enabled it to work with partners and accelerate widespread policy change

Structure of the Epigenetic Oncogene MMSET and Inhibition by <i>N</i>‑Alkyl Sinefungin Derivatives

The members of the NSD subfamily of lysine methyl transferases are compelling oncology targets due to the recent characterization of gain-of-function mutations and translocations in several hematological cancers. To date, these proteins have proven intractable to small molecule inhibition. Here, we present initial efforts to identify inhibitors of MMSET (aka NSD2 or WHSC1) using solution phase and crystal structural methods. On the basis of 2D NMR experiments comparing NSD1 and MMSET structural mobility, we designed an MMSET construct with five point mutations in the N-terminal helix of its SET domain for crystallization experiments and elucidated the structure of the mutant MMSET SET domain at 2.1 Å resolution. Both NSD1 and MMSET crystal systems proved resistant to soaking or cocrystallography with inhibitors. However, use of the close homologue SETD2 as a structural surrogate supported the design and characterization of <i>N</i>-alkyl sinefungin derivatives, which showed low micromolar inhibition against both SETD2 and MMSET