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Mercury is a significant volcanic volatile species from effusive and explosive activity1. Understanding its emission to the atmosphere from volcanic activity, aids our understanding of the global mercury cycle and its environmental impacts. Sedimentary and ice core records can be archives of these mercury enrichments2,3.The Laki 1783-84 AD fissure eruption in Iceland was significant due to its voluminous outpouring of basaltic lava, copious sulphur emissions and widespread environmental effects locally and across the Northern Hemisphere4,5. Extreme weather events were recorded in Europe and North America, owing to a veil of sulphur dioxide that remained at the tropopause for over a year5. Due to the phreatomagmatic and thus explosive nature of Laki, a significant eruption plume was produced4. As such, cryptotephra shards have been located at distal locations from Iceland including ice cores in Svalbard and Greenland6,7 and in an Irish woodland peat at Brackloon Wood, Co. Mayo8. There is evidence to suggest significant heavy metal emission to the atmosphere during the Laki eruption, however these records are currently restricted to Greenland ice cores9. Previous heavy metal findings linked to Laki do not include mercury, despite its significance as a volcanic volatile, and a potentially environmentally damaging heavy metal. Therefore, to expand our knowledge of the Laki 1783-84 AD eruption plume, its associated emissions, and environmental consequences we returned to the woodland peat site in Brackloon Wood, Co. Mayo, Ireland.Analysis of a 50 cm peat core using an AMA 254 mercury analyser was combined with a novel technique to find tephra using BSE (back scattered electron) imaging and geochemical discrimination using SEM-EDX (scanning electron microscopy-energy dispersive x-ray). The Laki tephra is successfully located using this method and coincides with a visible enrichment in mercury relative to background concentrations and organic matter. An age-depth model developed using the tephra layer and two radiocarbon dates indicate a strong likelihood that such enrichments are a product of volcanic emission. Such a finding can expand our understanding of heavy metal deposition during Laki 1783-84 AD away from the poles and to our knowledge, demonstrates the first direct exploration of mercury enrichment in distal peat for this eruption. As a secondary test of volcanic volatile enrichment, trace element analysis of the same bulk peat will be conducted to explore enrichments in other volcanic volatiles such as sulphur, cadmium, lead, copper and zinc. 1. Pyle, D. M. & Mather, T. A. Atmos. Environ. 37, 5115–5124 (2003).2. Schuster, P. F. et al.,. Environ. Sci. Technol. 36, 2303–2310 (2002).3. Roos-Barraclough, F. et al.,. Earth Planet. Sci. Lett. 202, 435–451 (2002).4. Thordarson, T. & Self, S. Bull. Volcanol. 55, 233–263 (1993).5. Thordarson, T. & Self, S., J. Geophys. Res 108, 4011 (2003).6. Kekonen, T. et al., Polar Res. 24, 33–40 (2005).7. Wei, L. et al., Geophys. Res. Lett. 35, L16501 (2008).8. Reilly, E. & Mitchell, F. J., Holocene 25, 241–252 (2015).9. Hong, S. et al., Earth Planet. Sci. Lett. 144, 605–610 (1996).

PDF file, 162K, AR mRNA levels are unaffected upon treatment with VPC-3022 and VPC-3033. Total RNA was extracted after treatment of LNCaP and MDV3100-resistant cells with VPC-3022 and VPC-3033 for 24 hours at the indicated concentrations in the presence of 0.1 nM R1881. Quantitative RT-PCR analysis of AR expression was performed and normalized to 18S rRNA levels. Error bars indicate standard deviation.

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PDF file, 2136K, (A) Effect of VPC-3022 on AR activity in HeLa-AR cells in the presence of cyclohexamide. HeLa-AR cells were treated with serially-diluted concentrations of VPC-3022 (0 - 100 ?M) with or without 10 ?M of cyclohexamide for 8 hours, and then lysed with passive lysis buffer. (B) AR degradation caused by VPC-3031 and VPC-3041 in HeLa-AR cells. HeLa-AR cells were treated by VPC-3031 and VPC-3041 at different concentrations in the presence of 0.1 nM R1881.

PDF file, 1976K, (A) Inhibition of in vitro polymerization of tubulin at 37 {degree sign}C by various concentrations of VPC-3033; turbidity was recorded at 360 nM.The steady-state tubulin assembly level in the absence of inhibitor was set at 100%. (B) IC50 values were determined by sigmoidal fitting of the plot of the steady state levels of tubulin assembly (taken after 45 min) aginst drug concentration and represent the concentration for 50% inhibition of the maximum tubulin polymerization level.

PDF file, 3480K, The binding pose of DHT (A) and VPC-3022 with AR by molecular docking (B) and binding pose of VPC-3022 with AR after 10 ns molecular dynamics (C); RMSD values of the protein backbone, protein-ligand, ligand in the 10 ns molecular dynamics for AR-DHT (D) and AR-VPC-3022 (E).

The human androgen receptor plays a major role in the development and progression of prostate cancer and represents a well-established drug target. All clinically approved androgen receptor antagonists possess similar chemical structures and exhibit the same mode of action on the androgen receptor. Although initially effective, resistance to these androgen receptor antagonists usually develops and the cancer quickly progresses to castration-resistant and metastatic states. Yet even in these late-stage patients, the androgen receptor is critical for the progression of the disease. Thus, there is a continuing need for novel chemical classes of androgen receptor antagonists that could help overcome the problem of resistance. In this study, we implemented and used the synergetic combination of virtual and experimental screening to discover a number of new 10-benzylidene-10H-anthracen-9-ones that not only effectively inhibit androgen receptor transcriptional activity, but also induce almost complete degradation of the androgen receptor. Of these 10-benzylidene-10H-anthracen-9-one analogues, a lead compound (VPC-3033) was identified that showed strong androgen displacement potency, effectively inhibited androgen receptor transcriptional activity, and possesses a profound ability to cause degradation of androgen receptor. Notably, VPC-3033 exhibited significant activity against prostate cancer cells that have already developed resistance to the second-generation antiandrogen enzalutamide (formerly known as MDV3100). VPC-3033 also showed strong antiandrogen receptor activity in the LNCaP in vivo xenograft model. These results provide a foundation for the development of a new class of androgen receptor antagonists that can help address the problem of antiandrogen resistance in prostate cancer. Mol Cancer Ther; 12(11); 2425–35. ©2013 AACR.

PDF file, 109K, Inhibition of VPC-3022 against wild-type AR in HeLa-AR cells. HeLa-AR cells transfected with ARR3tk-luciferase reporter were treated with VPC-3022 for 24 hours in various concentrations in the presence of 0.1 nM R1881. Error bars indicate standard deviation.

The persistence of Archaean cratons for >2.5Ga was aided by thick, mechanically strong, and cool lithospheric mantle keels up to 250km deep. It is widely accepted that the cratonic mantle, dominated by depleted harzburgite, lherzolite and dunite, was formed by extensive melt extraction from originally fertile mantle peridotite. Models seeking to explain the formation of deep cratonic mantle in the garnet and diamond stability fields, initially sought to answer how such rocks could form in-situ at high temperatures and pressures and envisaged large-scale thermochemical plume upwellings. More recently, mineralogical and geochemical observations, namely the high Cr content of garnet and low whole rock HREE concentrations in cratonic harzburgites, have led to the conclusion that the deep cratonic mantle couldn’t have originally melted in the garnet stability field. Mechanical stacking of shallowly depleted oceanic lithosphere was therefore proposed to have thickened the depleted lithosphere cratonic roots. In this process, the spinel facies minerals are envisaged to transform into the garnet stability field.Here we present the first results of combined thermodynamic and geochemical modelling at temperatures high enough to reconcile the very refractory residues. We found that the requirement for initially shallow melting is no longer supported. Deep (150-250km), ultra-hot (>1800°C), incremental melting can produce the mineralogical and geochemical signatures of depleted cratonic harzburgites. The modelling also implies a link between areas of extreme depletion in the deep lithospheric mantle and the genesis of Earth’s hottest lavas (Al-enriched komatiite) by re-melting depleted harzburgite. Diamond inclusion minerals have a well-documented skew to the most refractory compositions found in cratonic peridotite. We propose that these ultra-depleted, highly reducing regions of the lithospheric root possess the highest diamond formation and preservation potential.

Chloroquine (CQ), a lysosomotropic agent, is commonly used to inhibit lysosomal degradation and macroautophagy/autophagy. Here we investigated the cell-extrinsic effects of CQ on secretion. We showed that lysosomal and autophagy inhibition by CQ altered the secretome, and induced the release of Atg8 orthologs and autophagy receptors. Atg8-family proteins, in particular, were secreted inside small extracellular vesicles (sEVs) in a lipidation-dependent manner. CQ treatment enhanced the release of Atg8-family proteins inside sEVs. Using full-length ATG16L1 and an ATG16L1 mutant that enables Atg8-family protein lipidation on double but not on single membranes, we demonstrated that LC3B is released in two distinct sEV populations: one enriched with SDCBP/Syntenin-1, CD63, and endosomal lipidated LC3B, and another that contains LC3B but is not enriched with SDCBP/Syntenin-1 or CD63, and which our data supports as originating from a double-membrane source. Our findings underscore the context-dependency of sEV heterogeneity and composition, and illustrate the integration of autophagy and sEV composition in response to lysosomal inhibition. Abbreviations: ACTB: actin beta; ANOVA: analysis of variance; ATG4B: autophagy related 4B cysteine peptidase; Atg8: autophagy related 8; ATG16L1: autophagy related 16 like 1; ATP5F1A/ATP5a: ATP synthase F1 subunit alpha; CALCOCO2: calcium binding and coiled-coil domain 2; CASP3: caspase 3; CASP7: caspase 7; CQ: chloroquine; CD9: CD9 molecule; CD63: CD63 molecule; DAPI: 4’,6-diamidino-2-phenylindole; DQ-BSA: dye quenched-bovine serum albumin; ER: endoplasmic reticulum; ERN1/IRE1a: endoplasmic reticulum to nucleus signaling 1; EV: extracellular vesicles; FBS: fetal bovine serum; FDR: false discovery rate; GABARAP: GABA type A receptor-associated protein; GABARAPL2: GABA type A receptor associated protein like 2; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; GO: gene ontology; HCQ: hydroxychloroquine; HSP90AA1: heat shock protein 90 alpha family class A member 1; IP: immunoprecipitation; KO: knockout; LAMP2: lysosomal associated membrane protein 2; LIR: LC3-interacting region; LMNA: lamin A/C; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MS: mass spectrometry; NBR1: NBR1 autophagy cargo receptor; NCOA4: nuclear receptor coactivator 4; NTA: nanoparticle tracking analysis; PE: phosphatidylethanolamine; PECA: probe-level expression change averaging; SDCBP/syntenin-1: syndecan binding protein; SD: standard deviation; SE: secreted; sEV: small extracellular vesicles; SQSTM1/p62: sequestosome 1; TAX1BP1: Tax1 binding protein 1; TEM: transmission electron microscopy; TMT: tandem-mass tag; TSG101: tumor susceptibility 101; ULK1: unc-51 like autophagy activating kinase 1; WC: whole cell