Vein-type graphite deposits in Sri Lanka: the ultimate fate of granulite fluids

The world-best vein graphite deposits in Sri-Lanka occur scattered through the high-grade terrain of the Wanni and Highland Complexes of Sri-Lanka. The Wanni Complex (amphibolite to granulite grade) consists of ~770-1100 Ma metagranitoids, metagabbro, charnockite, enderbitic gneisses, migmatites, clastic metasediments, including garnet-cordierite gneisses, rare to minor calc-silicate rocks as well as late to post-tectonic granites (Kröner et al., 2013). Higher metamorphic grade, reaching in places UHT-conditions (T>1000 °C) characterizes the Highland Complex. Peak metamorphism occurred during the Neoproterozoic Pan-African orogeny (~620-535 Ma), which led to the accretion of terrains in Sri Lanka and played a key role for the amalgamation of the Gondwana supercontinent (Tsunogae and Santosh, 2010). Structurally disposed in extensional fractures post-dating the Pan-African ductile structures (Kehelpannala, 1999), the graphite veins equilibrated at relatively low temperature (500-600 °C). However, the presence of mesoperthites indicate that graphite precipitation may have started at higher temperature. Samples from khondalite host rocks and quartz co-precipitated with graphite from the Bogala and Kahatagana graphite mines in the Wanni Complex were studied. Host-rocks show spectacular decompression reaction aureoles around feldspars and garnet. They contain small CO2 inclusions in garnet cores or quartz in decompression reaction aureoles. Larger, highly transposed brine inclusions are more abundant and are responsible for metasomatic features (feldspar leaching and deposition) observed in the aureoles. Fluid inclusions in vein minerals are dominantly aqueous, rarely mixed H2O+CO2. Fluid inclusions and petrographic data suggest that graphite has been deposited from fluids at decreasing pressure and temperature at relatively reduced redox conditions. Carbon isotope data indicate a dominant mantle source, mixed with small quantities of light C-bearing fluids. It has been proposed that large quantities of mantle-derived CO2 fluid have infiltrated the lower crust during the final stage of Gondwana supercontinent amalgamation (Touret et al., 2016). Formed during strong decompression at the end of a long (up to a few 10 Ma) period of isobaric cooling, the graphite veins in Sri-Lanka (and elsewhere in the former Gondwana) reflects the escape of these granulite fluids to higher crustal levels. In this respect, they are comparable to the quartz-carbonates mega-shear zones found in other granulite terranes (Newton and Manning, 2002). Depending on the redox conditions, former lower crustal fluids (mantle-derived CO2 and/or brines) may either result in mid to upper-crustal quartz-carbonate or graphite veins

State of organic seeds in France

A comprehensive range of investigations carried out between 2010 and 2012 provided information on the state of organic seeds in France. Results fit with the hypothesis that the market is a significant factor influencing the choice of seeds and cultivars (local cultivars, landraces, modern cultivars). Expectations and practices of producers selling on a local market (i.e., direct sale) differ radically from those of producers selling to long food supply chains. This study showed that the availability and use of organic seeds have significantly improved over the last three years. A vast majority of organic producers willingly use organic seeds, with, on average, 45-70 % (cereals), and 75%-100 % (vegetables) of organic seeds being planted on farms. However, the total number of derogations remained quite high: there is still space for improvement in organic seed use and supply in France. Several limiting factors and levers were identified during the study, as well as farmers’ expectations for the future on cereals, forage crops and vegetables. This study described an action plan, which must be carefully implemented. The organic sector depends on the development of a wide and adapted range of organic seeds

Prioritisation of Anti-SARS-Cov-2 Drug Repurposing Opportunities Based on Plasma and Target Site Concentrations Derived from their Established Human Pharmacokinetics.

There is a rapidly expanding literature on the in vitro antiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against SARS-CoV-2. However, this has not been accompanied by a comprehensive evaluation of the target plasma and lung concentrations of these drugs following approved dosing in humans. Accordingly, EC90 values recalculated from in vitro anti-SARS-CoV-2 activity data was expressed as a ratio to the achievable maximum plasma concentrations (Cmax) at an approved dose in humans (Cmax/EC90 ratio). Only 14 of the 56 analysed drugs achieved a Cmax/EC90 ratio above 1. A more in-depth assessment demonstrated that only nitazoxanide, nelfinavir, tipranavir (ritonavir-boosted) and sulfadoxine achieved plasma concentrations above their reported anti-SARS-CoV-2 activity across their entire approved dosing interval. An unbound lung to plasma tissue partition coefficient (Kp Ulung ) was also simulated to derive a lung Cmax/EC50 as a better indicator of potential human efficacy. Hydroxychloroquine, chloroquine, mefloquine, atazanavir (ritonavir-boosted), tipranavir (ritonavir-boosted), ivermectin, azithromycin and lopinavir (ritonavir-boosted) were all predicted to achieve lung concentrations over 10-fold higher than their reported EC50 . Nitazoxanide and sulfadoxine also exceeded their reported EC50 by 7.8- and 1.5-fold in lung, respectively. This analysis may be used to select potential candidates for further clinical testing, while deprioritising compounds unlikely to attain target concentrations for antiviral activity. Future studies should focus on EC90 values and discuss findings in the context of achievable exposures in humans, especially within target compartments such as the lung, in order to maximise the potential for success of proposed human clinical trials

MHC Class I Endosomal and Lysosomal Trafficking Coincides with Exogenous Antigen Loading in Dendritic Cells

BACKGROUND: Cross-presentation by dendritic cells (DCs) is a crucial prerequisite for effective priming of cytotoxic T-cell responses against bacterial, viral and tumor antigens; however, this antigen presentation pathway remains poorly defined. METHODOLOGY/PRINCIPAL FINDINGS: In order to develop a comprehensive understanding of this process, we tested the hypothesis that the internalization of MHC class I molecules (MHC-I) from the cell surface is directly involved in cross-presentation pathway and the loading of antigenic peptides. Here we provide the first examination of the internalization of MHC-I in DCs and we demonstrate that the cytoplasmic domain of MHC-I appears to act as an addressin domain to route MHC-I to both endosomal and lysosomal compartments of DCs, where it is demonstrated that loading of peptides derived from exogenously-derived proteins occurs. Furthermore, by chasing MHC-I from the cell surface of normal and transgenic DCs expressing mutant forms of MHC-I, we observe that a tyrosine-based endocytic trafficking motif is required for the constitutive internalization of MHC-I molecules from the cell surface into early endosomes and subsequently deep into lysosomal peptide-loading compartments. Finally, our data support the concept that multiple pathways of peptide loading of cross-presented antigens may exist depending on the chemical nature and size of the antigen requiring processing. CONCLUSIONS/SIGNIFICANCE: We conclude that DCs have 'hijacked' and adapted a common vacuolar/endocytic intracellular trafficking pathway to facilitate MHC I access to the endosomal and lysosomal compartments where antigen processing and loading and antigen cross-presentation takes place

ISG15 Is Critical in the Control of Chikungunya Virus Infection Independent of UbE1L Mediated Conjugation

Chikungunya virus (CHIKV) is a re-emerging alphavirus that has caused significant disease in the Indian Ocean region since 2005. During this outbreak, in addition to fever, rash and arthritis, severe cases of CHIKV infection have been observed in infants. Challenging the notion that the innate immune response in infants is immature or defective, we demonstrate that both human infants and neonatal mice generate a robust type I interferon (IFN) response during CHIKV infection that contributes to, but is insufficient for, the complete control of infection. To characterize the mechanism by which type I IFNs control CHIKV infection, we evaluated the role of ISG15 and defined it as a central player in the host response, as neonatal mice lacking ISG15 were profoundly susceptible to CHIKV infection. Surprisingly, UbE1L−/− mice, which lack the ISG15 E1 enzyme and therefore are unable to form ISG15 conjugates, displayed no increase in lethality following CHIKV infection, thus pointing to a non-classical role for ISG15. No differences in viral loads were observed between wild-type (WT) and ISG15−/− mice, however, a dramatic increase in proinflammatory cytokines and chemokines was observed in ISG15−/− mice, suggesting that the innate immune response to CHIKV contributes to their lethality. This study provides new insight into the control of CHIKV infection, and establishes a new model for how ISG15 functions as an immunomodulatory molecule in the blunting of potentially pathologic levels of innate effector molecules during the host response to viral infection

SMF-1, SMF-2 and SMF-3 DMT1 Orthologues Regulate and Are Regulated Differentially by Manganese Levels in C. elegans

Manganese (Mn) is an essential metal that can exert toxic effects at high concentrations, eventually leading to Parkinsonism. A major transporter of Mn in mammals is the divalent-metal transporter (DMT1). We characterize here DMT1-like proteins in the nematode C. elegans, which regulate and are regulated by Mn and iron (Fe) content. We identified three new DMT1-like genes in C. elegans: smf-1, smf-2 and smf-3. All three can functionally substitute for loss of their yeast orthologues in S. cerevisiae. In the worm, deletion of smf-1 or smf-3 led to an increased Mn tolerance, while loss of smf-2 led to increased Mn sensitivity. smf mRNA levels measured by QRT-PCR were up-regulated upon low Mn and down-regulated upon high Mn exposures. Translational GFP-fusions revealed that SMF-1 and SMF-3 strongly localize to partially overlapping apical regions of the gut epithelium, suggesting a differential role for SMF-1 and SMF-3 in Mn nutritional intake. Conversely, SMF-2 was detected in the marginal pharyngeal epithelium, possibly involved in metal-sensing. Analysis of metal content upon Mn exposure in smf mutants revealed that SMF-3 is required for normal Mn uptake, while smf-1 was dispensable. Higher smf-2 mRNA levels correlated with higher Fe content, supporting a role for SMF-2 in Fe uptake. In smf-1 and smf-3 but not in smf-2 mutants, increased Mn exposure led to decreased Fe levels, suggesting that both metals compete for transport by SMF-2. Finally, SMF-3 was post-translationally and reversibly down-regulated following Mn-exposure. In sum, we unraveled a complex interplay of transcriptional and post-translational regulations of 3 DMT1-like transporters in two adjacent tissues, which regulate metal-content in C. elegans

Remnants of premetamorphic fluid and oxygen isotopic signatures in eclogites and garnet clinopyroxenite from the Dabie-Sulu terranes, eastern China

A combined oxygen-isotope and fluid-inclusion study has been carried out on high- and ultrahigh-pressure metamorphic (HP/UHPM) eclogites and garnet clinopyroxenite from the Dabie-Sulu terranes in eastern China. Coesite-bearing eclogites/garnet clinopyroxenite and quartz eclogites have a wide range in whole-rock δ18OVSMOW, from 0 to 11‰. The high-T oxygen-isotope fractionations preserved between quartz and garnet preclude significant retrograde isotope exchange during exhumation, and the wide range in whole-rock oxygen-isotope composition is thought to be a presubduction signature of the precursors. Aqueous fluids with variable salinities and gas species (N2-, CO2-, or CH4-rich), are trapped as primary inclusions in garnet, omphacite and epidote, and in quartz blebs enclosed within eclogitic minerals. In high-δ18O HP/UHPM rocks from Hujialin and Shima, high-salinity brine and/or N2 inclusions occur in garnet porphyroblasts, which also contain inclusions of coesite, Cl-rich blue amphibole and dolomite. In contrast, in low-δ18O eclogites from Qinglongshan and Huangzhen, the Cl concentrations in amphibole are very low, < 0.2 wt.%, and low-salinity aqueous inclusions occur in quartz inclusions in epidote porphyroblasts and in epidote cores. These low-salinity fluid inclusions are believed to be remnants of meteoric water, although the fluid composition was modified during pre- and syn-peak HP/UHPM. Eclogites at Houshuichegou and Hetang contain CH4-rich fluid inclusions, coexisting with high-salinity brine inclusions. Methane was probably formed under the influence of CO2-rich aqueous fluids during serpentinisation of mantle-derived peridotites prior to or during plate subduction. Remnants of premetamorphic low- to high-salinity aqueous fluid with minor N2 and/or other gas species preserved in the Dabie-Sulu HP/UHPM eclogites and garnet clinopyroxenite indicate a great diversity of initial fluid composition in the precursors, implying very limited fluid–rock interaction during syn- and post-peak HP/UHPM