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Oxygen isotope ratios of quartz inclusions (QI) within garnet from granulite and amphibolite facies gneisses in the Adirondack Mountains, NY were analysed and used to determine metamorphic temperatures. Primary QI for eight of 12 samples have δ18O values significantly lower than matrix quartz (MQ). The primary QI retain δ18O values representative of thermal conditions during garnet crystallization, whereas the δ18O values of MQ were raised by diffusive exchange with other matrix minerals (e.g. mica and feldspar) during cooling. The δ18O differences between QI and MQ show that garnet (a mineral with slow diffusion of oxygen) can armour QI from isotopic exchange with surrounding matrix, even during slow cooling. These differences between δ18O in MQ and QI can further be used to test cooling rates by Fast Grain Boundary diffusion modelling. Criteria for identifying QI that preserve primary compositions and are suitable for thermometry were developed based on comparative tests. Relations between δ18O and inclusion size, distance of inclusion to host-garnet rim, core-rim zonation of individual inclusions, and presence or absence of petrological features (healed cracks in QI, inclusions in contact with garnet cracks lined by secondary minerals, and secondary minerals along the inclusion grain boundary) were investigated. In this study, 61% of QI preserve primary δ18O and 39% were associated with features that were linked to reset δ18O values. If δ18O in garnet is homogeneous and inclusions are removed, laser-fluorination δ18O values of bulk garnet are more precise, more accurate, and best for thermometry. Intragrain δ18O(Grt) profiles measured in situ by ion microprobe show no δ18O zonation. Almandine-rich garnet (Alm60-75) from each sample was measured by laser-fluorination mass-spectrometry ( LF- MS) for δ18O and compared with ion microprobe measurements of δ18O in QI for thermometry. The Δ18O(Qz-Grt) values for Adirondack samples range from 2.66 to 3.24‰, corresponding to temperatures of 640-740 °C (A[Qz-Alm] = 2.71). Out of 12 samples that were used for thermometry, nine are consistent with previous estimates of peak temperature (625-800 °C) based on petrological and carbon-isotope thermometry for regional granulite and upper amphibolite facies metamorphism. The three samples that disagree with independent thermometry for peak metamorphism are from the anorthosite-mangerite-charnockite-granite suite in the central Adirondacks and yield temperatures of 640-665 °C, ~100 °C lower than previous estimates. These low temperatures could be interpreted as thermal conditions during late (post-peak) crystallization of garnet on the retrograde path. [ABSTRACT FROM AUTHOR]

Malaria, caused by Plasmodium parasites, continues to be a devastating global health issue. Despite a decline in malaria related deaths over the last decade, overall progress has plateaued. Key challenges to malaria prevention and control include the lack of a broadly effective vaccine and parasite drug resistance, including to the current gold standard artemisinin combination therapies (ACTs). New drugs with unique modes of action are therefore a priority for both the treatment and prevention of malaria. Unlike treatment drugs which need to kill parasites quickly to reduce or prevent clinical symptoms, compounds that kill parasites more slowly may be an option for malaria prevention. Natural products and natural product derived compounds have historically been an excellent source of antimalarial drugs, including the artemisinin component of ACTs. In this study, 424 natural product derived compounds were screened for in vitro activity against P. falciparum in assays designed to detect slow action activity, with 46 hit compounds identified as having >50% inhibition at 10 μM. Dose response assays revealed nine compounds with submicromolar activity, with slow action activity confirmed for two compounds, alstonine and himbeline (50% inhibitory concentration (IC 50 ) 0.17 and 0.58 μM, respectively). Both compounds displayed >140-fold better activity against P. falciparum versus two human cell lines (Selectivity Index (SI) >1,111 and > 144, respectively). Importantly, P. falciparum multi-drug resistant lines showed no cross-resistance to alstonine or himbeline, with some resistant lines being more sensitive to these two compounds compared to the drug sensitive line. In addition, alstonine displayed cross-species activity against the zoonotic species, P. knowelsi (IC 50 ~1 μM). Outcomes of this study provide a starting point for further investigations into these compounds as antiplasmodial drug candidates and the investigation of their molecular targets., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A plethora of studies indicate that iron metabolism is dysregulated in Parkinson's disease (PD). The literature reveals well-documented alterations consistent with established dogma, but also intriguing paradoxical observations requiring mechanistic dissection. An important fact is the iron loading in dopaminergic neurons of the substantia nigra pars compacta (SNpc), which are the cells primarily affected in PD. Assessment of these changes reveal increased expression of proteins critical for iron uptake, namely transferrin receptor 1 and the divalent metal transporter 1 (DMT1), and decreased expression of the iron exporter, ferroportin-1 (FPN1). Consistent with this is the activation of iron regulator protein (IRP) RNA-binding activity, which is an important regulator of iron homeostasis, with its activation indicating cytosolic iron deficiency. In fact, IRPs bind to iron-responsive elements (IREs) in the 3ꞌ untranslated region (UTR) of certain mRNAs to stabilize their half-life, while binding to the 5ꞌ UTR prevents translation. Iron loading of dopaminergic neurons in PD may occur through these mechanisms, leading to increased neuronal iron and iron-mediated reactive oxygen species (ROS) generation. The "gold standard" histological marker of PD, Lewy bodies, are mainly composed of α-synuclein, the expression of which is markedly increased in PD. Of note, an atypical IRE exists in the α-synuclein 5ꞌ UTR that may explain its up-regulation by increased iron. This dysregulation could be impacted by the unique autonomous pacemaking of dopaminergic neurons of the SNpc that engages L-type Ca +2 channels, which imparts a bioenergetic energy deficit and mitochondrial redox stress. This dysfunction could then drive alterations in iron trafficking that attempt to rescue energy deficits such as the increased iron uptake to provide iron for key electron transport proteins. Considering the increased iron-loading in PD brains, therapies utilizing limited iron chelation have shown success. Greater therapeutic advancements should be possible once the exact molecular pathways of iron processing are dissected., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

A near-shore marine intertidal environment-associated Streptomyces isolate (USC-633) from the Sunshine Coast Region of Queensland, Australia, cultivated under a range of chemically defined and complex media to determine optimal parameters resulting in the secretion of diverse array of secondary metabolites with antimicrobial properties against various antibiotic resistant bacteria. Following extraction, fractioning and re-testing of active metabolites resulted in persistent antibacterial activity against Escherichia coli (Migula) (ATCC 13706) and subsequent Nuclear Magnetic Resonance (NMR) analysis of the active fractions confirmed the induction of metabolites different than the ones in fractions which did not display activity against the same bacterial species. Overall findings again confirmed the value of One Strain-Many Compounds (OSMAC) approach that tests a wide range of growth parameters to trigger bioactive compound secretion increasing the likelihood of finding novel therapeutic agents. The isolate was found to be adaptable to both marine and terrestrial conditions corresponding to its original near-shore marine intertidal environment. Wide variations in its morphology, sporulation and diffusible pigment production were observed when different growth media were used.

Transplantation of peripheral glia is being trialled for neural repair therapies, and identification of compounds that enhance the activity of glia is therefore of therapeutic interest. We have previously shown that curcumin potently stimulates the activity of olfactory glia. We have now examined the effect of curcumin on Schwann cell (SC) activities including proliferation, migration and the expression of protein markers. SCs were treated with control media and with different concentrations of curcumin (0.02-20 μM). Cell proliferation was determined by MTS assay and migration changes were determined by single live cell migration tracking. We found that small doses of curcumin (40 nM) dramatically increased the proliferation and migration in SCs within just one day. When compared with olfactory glia, curcumin stimulated SC proliferation more rapidly and at lower concentrations. Curcumin significantly increased the migration of SCs, and also increased the dynamic activity of lamellipodial waves which are essential for SC migration. Expression of the activated form of the MAP kinase p38 (p-p38) was significantly decreased in curcumin-treated SCs. These results show that curcumin's effects on SCs differ remarkably to its effects on olfactory glia, suggesting that subtypes of closely related glia can be differentially stimulated by curcumin. Overall these results demonstrate that the therapeutically beneficial activities of glia can be differentially enhanced by curcumin which could be used to improve outcomes of neural repair therapies., (Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.)