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

L-DOPA Neurotoxicity Is Mediated by Up-Regulation of DMT1−IRE Expression

2008-2009 > Academic research: refereed > Publication in refereed journalpublished_fina

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

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

Fluid inclusions in coesite-bearing eclogites and jadeite quartzite at Shuanghe, Dabie Shan (China).

Fluid inclusions in coesite-bearing eclogites and jadeite quartzite at Shuanghe in Dabie Shan, East-central China, have preserved remnants of early, prograde and/or peak metamorphic fluids, reset during post-UHP (ultrahigh-pressure) metamorphic uplift. Inclusions occur in several minerals (e.g. omphacite and epidote), notably as isolated, primary inclusions in quartz included in various host minerals. Two major fluid types have been identified: non-polar fluid species (

Petrology, isotopic and fluid inclusion studies of eclogites from Sujiahe, NW Dabie Shan (China), July 1 2002

In addition to the Triassic Hong'an low-T–high-P eclogite and the Xinxian coesite-bearing kyanite-glaucophane eclogite, Silurian coesite-free amphibole eclogites occur in the Sujiahe region, NW Dabie Shan of central China. A comprehensive study of petrology, Nd–Sr, O–H isotopes and fluid inclusions has been carried out for the Sujiahe eclogites. Geothermobarometry of mineral assemblages gave peak P–T conditions of 600–730 °C and 14–19 kbar, and retrograde metamorphism of 530–685 °C and 6 kbar. The eclogites have high radical •Nd(t) values of −1.9 to 5.8, indicating that their protoliths were derived from oceanic basalts. Whole-rock δ18O values for eclogites at Xiongdian and at Hujiawan range from 8.8‰ to 11.2‰, whereas δ18O value of the Yangchong eclogite is as low as 4.3‰. Whole-rock δD values range from −55‰ to −75‰. The results exclude that the eclogite protoliths were isotopically exchanged with ancient meteoric water prior to plate subduction, thus distinguishing them from the other Dabie–Sulu eclogites. Fluid inclusions show the presence of early highly saline brine and late low-salinity aqueous fluids in the Sujiahe eclogites during the high-P metamorphism. The isotopic data suggest that the Sujiahe eclogite protolith was metamorphosed during subduction of an oceanic plate beneath the Sino-Korean Craton in the Middle Paleozoic, different from the other eclogites in the Dabie–Sulu orogen which were formed by the ultrahigh pressure metamorphism during the Triassic