Bor and Cukaru Peki are world-class porphyry deposits spatially and genetically associated with the Cretaceous Timok magmatic complex. This research was conducted to determine the age and geochemical affinity of the magmatic rocks that formed these ore deposits. Our new geochemical analyses of magmatic rocks from Bor and Cukaru Peki deposits imply they comprise adakite-like compositions that have undergone the amphibole fractionation and sulphide saturation processes. The zircon ages indicate that the Bor system was formed in the age span between 84.5?82 Ma, while the Cukaru Peki system was created in the age span between 86.5?85 Ma.

PPI-1011 is a synthetic plasmalogen precursor in development as a treatment for multiple plasmalogen-deficiency disorders. Previous work has demonstrated the ability of PPI-1011 to augment plasmalogens and its effects in vitro and in vivo, however, the precise uptake and distribution across tissues in vivo has not been investigated. The purpose of this study was to evaluate the pharmacokinetics, mass balance, and excretion of [14C]PPI-1011 following a single oral administration at 100 mg/kg in Sprague-Dawley rats. Further tissue distribution was examined using quantitative whole-body autoradiography after both single and repeat daily doses at 100 mg/kg/day. Non-compartmental analysis showed that following a single dose, PPI-1011 exhibited peak levels between 6 and 12 h but also a long half-life with mean t1/2 of 40 h. Mass balance showed that over 50% of the compound-associated radioactivity was absorbed by the body, while approximately 40% was excreted in the feces, 2.5% in the urine, and 10% in expired air within the first 24 h. Quantitative whole-body autoradiography following a single dose showed uptake to nearly all tissues, with the greatest initial uptake in the intestines, liver, and adipose tissue, which decreased time-dependently throughout 168 h post-dose. Following 15 consecutive daily doses, uptake was significantly higher across the entire body at 24 h compared to single dose and remained high out to 96 h where 75% of the initially-absorbed compound-associated radioactivity was still present. The adipose tissue remained particularly high, suggesting a possible reserve of either plasmalogens or alkyl diacylglycerols that the body can pull from for plasmalogen biosynthesis. Uptake to the brain was also definitively confirmed, proving PPI-1011’s ability to cross the blood-brain barrier. In conclusion, our results suggest that oral administration of PPI-1011 results in high uptake across the body, and that repeated dosing over time represents a viable therapeutic strategy for treating plasmalogen deficiencies.

The primary aim of mineral exploration is to focus the search space from regional scale (1000 s km2) to prospect scale (1–10 km2), identify areas that warrant further investigation, and ultimately drill a target. Mineral deposits typically display geochemical anomalism related to the conditions of their formation, or the weathering and mass transport of sediment away from a mineral deposit. However, this anomalism can be obscured in soil-sample surveys due to background variations in host bedrock chemistry and the transformation and redistribution of original minerals during surface weathering, regolith development, and supergene processes. This contribution uses machine-learnt map products to aid in the interpretation of a regional-scale soil-sample dataset. ASTER (satellite spectral) data were combined with airborne radiometric data using Self-Organising Maps (SOM) to generate a map of regolith type. A map of bedrock geology was previously derived by the authors from airborne geophysical data using Random Forests. These two products are used to classify soil samples with an objective bedrock-geology and regolith-type classification. A z-score normalisation was implemented on the soil-sample geochemical data, using two different matrices (regolith type and bedrock geology) to remove the bias of bedrock geology and regolith type from the soil sample chemistry. The signal that remains likely reflects metasomatic processes, and associated elemental anomalism, potentially linked to mineralisation. These data can then be plotted to provide maps of (pathfinder) element anomalies, thus identifying potential exploration targets. We explore this approach to normalise geochemical data in a dataset of 9,924 soil samples collected over an area of 1,028 km2, from Kerkasha, Eritrea (Nubian Shield). The Kerkasha project is an early-stage exploration project, with a limited understanding of the local geology and mineral deposit types; however, it contains many Au and Cu prospects that have received minimal exploration work.

BackgroundRhizomelic chondrodysplasia punctata (RCDP) is an inherited ultra-rare disease which results in severely impaired physical and mental development. Mutations in one of five genes involved in plasmalogen biosynthesis have been reported to drive disease pathology. Estimates of disease incidence have been extremely challenging due to the rarity of the disorder, preventing an understanding of the unmet medical need. To address this, we have prepared a disease incidence and prevalence model based on genetic epidemiology approaches to estimate the total number of RCDP patients affected, and their demographic characteristics.ResultsExtraction of allelic frequencies for known and predicted pathogenic variants in PEX7, GNPAT, AGPS, FAR1, PEX5 (limited to the PTS2 domain encoding region) genes, from large-scale human genetic diversity datasets (TopMed and gnomAD) revealed the mutational landscape contributing to the RCDP patient population in the US and Europe. We computed genetic prevalence to derive birth incidence for RCDP and modeled the impact to life expectancy to obtain high confidence estimates of disease prevalence. Our population genetics-based model indicates PEX7 variants are expected to contribute to the majority of RCDP cases in both the US and Europe; closely aligning with clinical reports. Furthermore, this model provides estimates for RCDP subtypes due to mutations in other genes, including exceedingly rare subtypes.ConclusionIn total, the estimated number of RCDP patients in the US and the five largest European countries (UK, Germany, France, Italy and Spain) is between 516 and 847 patients, all under the age of 35 years old. This model provides a quantitative framework for better understanding the unmet medical need in RCDP, to help guide disease awareness and diagnosis efforts for this specific patient group.

We present an integrated study combining detailed field, geochronological and geochemical data of a Neoproterozoic intra-oceanic arc systems exposed in the Pan-African belt of the Moroccan Anti-Atlas. The arc rock units exposed in Bou Azzer and Sirwa inliers consist of a tectonic patchwork of back-arc ophiolitic sequences to the north thrusted onto accreted arc complexes to the south. Arc complexes are composed of amphibolite, granodioritic and granitic gneisses intruded by various undeformed hydrous ultramafic (hornblendite), mafic (hornblende-gabbro, diorite) and felsic (granodiorite, tonalite, granite) arc lithologies. We show that these complexes are remnants of a long-lived (120 Myr) Neoproterozoic oceanic arc, punctuated by three successive magmatic episodes (760–730 Ma, 710–690 Ma, 660–640 Ma respectively) interspersed with periods of magmatic quiescence. The typical geochemical arc signature and positive ƐNdt values for the igneous rocks emplaced during each magmatic episode (medians at +7.1, +5.4 and +5.7, from older to younger) attest that their parental magmas derived from a depleted mantle source without substantial assimilation by the WAC older crustal basement. Trace-element geochemistry, i.e. Sr/Y, La/Yb, of intermediate to felsic arc rocks produced during each magmatic pulse suggests that the arc crust was thickened (>30–35 km) over a short time period between the first and second magmatic episodes (730–710 Ma) which coincides with an important regional shortening event. Soft-docking of the oceanic arc on a buoyant transitional margin is invoked to explain tectonic inversion in overriding plate, leading to shortening and related thickening of the arc crust. Concomitant magmatic shutdown resulting from a reorganization of subduction dynamics (i.e. change in slab geometry, flip in subduction polarity). A non-tectonic critical thickening of the arc crust is invoked to explain the second magmatic shutdown (680–660 Ma), by freezing the subarc mantle influx. This lull period is followed by a third magmatic episode which is likely triggered by delamination of the dense lower crust and reactivation of subarc mantle flow. This is supported by the bimodal chemical signature of evolved magmatic products, suggesting two distinct sources partial melts from the foundered lower crust and new magmatic products which differentiated from a post-delamination thinned crust.

ABSTRACTRhizomelic chondrodysplasia punctata (RCDP) is a rare genetic disorder caused by mutations in peroxisomal genes essential for plasmalogen biosynthesis. Plasmalogens are a class of membrane glycerophospholipids containing a vinyl-ether-linked fatty alcohol at the sn-1 position that affect functions including vesicular transport, membrane protein function and free radical scavenging. A logical rationale for the treatment of RCDP is therefore the therapeutic augmentation of plasmalogens. The objective of this work was to provide a preliminary characterization of a novel vinyl-ether synthetic plasmalogen, PPI-1040, in support of its potential utility as an oral therapeutic option for RCDP. First, wild-type mice were treated with 13C6-labeled PPI-1040, which showed that the sn-1 vinyl-ether and the sn-3 phosphoethanolamine groups remained intact during digestion and absorption. Next, a 4-week treatment of adult plasmalogen-deficient Pex7hypo/null mice with PPI-1040 showed normalization of plasmalogen levels in plasma, and variable increases in plasmalogen levels in erythrocytes and peripheral tissues (liver, small intestine, skeletal muscle and heart). Augmentation was not observed in brain, lung and kidney. Functionally, PPI-1040 treatment normalized the hyperactive behavior observed in the Pex7hypo/null mice as determined by open field test, with a significant inverse correlation between activity and plasma plasmalogen levels. Parallel treatment with an equal amount of ether plasmalogen precursor, PPI-1011, did not effectively augment plasmalogen levels or reduce hyperactivity. Our findings show, for the first time, that a synthetic vinyl-ether plasmalogen is orally bioavailable and can improve plasmalogen levels in an RCDP mouse model. Further exploration of its clinical utility is warranted.This article has an associated First Person interview with the joint first authors of the paper.

A regional bedrock map provides a foundation from which to build geological interpretations. However, rapid and accurate bedrock mapping in an area that lacks outcrop is a common problem, especially in regions with sparse data. A historic bedrock map from an Au and base metal project in the Kerkasha district, Eritrea, is significantly improved by predicting bedrock distribution in areas previously mapped as transported overburden. Publicly-available remote sensing data (DTM and ASTER) were combined with airborne geophysical data (magnetics and radiometrics) to provide features for bedrock prediction. Remote sensing data were pre-processed using Principal Components Analysis (PCA) to yield an equal number of principal components (PC) as input features. Four iterations were trialled, using different combinations of remote sensing PC features. The two initial trials used all available remote sensing data but compared results when feature ranking and selection is applied to reduce the number of PCs used for training and classification. The subsequent two trials used subsets of available remote-sensing data, selected based on domain expertise (i.e., the domain-specific knowledge of a geologist), with all respective PCs were retained. Five-fold cross-validation scores were highest when a DTM, magnetics, and radiometrics data were included as input features. However, qualitative visual appraisal of predicted results across trials, complemented by maps of class membership uncertainty (using a measure of entropy), indicate that geologically-meaningful results are also produced when radiometrics are omitted and only the DTM and magnetics are used. The study concludes with a generalised workflow to assist geologists who are seeking to improve the bedrock interpretation of areas under cover in a single area of interest. Domain expertise is shown to be critical for the selection of appropriate input features and validation of results during predictive lithologic mapping.

Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide. It is typically associated with motor symptoms originating from the degeneration of nigrostriatal dopamine (DA) neurons. Early stages of PD have been associated with an alteration in DA production in intestinal DAergic neurons along with inflammation. Interestingly, decreased serum concentrations of ethanolamine plasmalogens (PlsEtn) have been reported in PD patients. Ethanolamine plasmalogens play a role in vesicular fusion and release during neurotransmission, and store neuroprotective polyunsaturated fatty acids, such as docosahexaenoic acid (DHA) and are strong anti-oxidants, highlighting areas of potential therapeutic interest. Docosahexaenoic acid is known to play important roles in both the central nervous and peripheral systems, in addition to acting as a precursor of several molecules that regulate the resolution of inflammation. The present study investigated the neuroprotective and anti-inflammatory properties of the DHA-containing PlsEtn precursor, PPI-1011, in the intestine of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. Treatment with PPI-1011 prevented the MPTP-induced decrease in PlsEtn levels. In addition it prevented the loss of tyrosine hydroxylase (TH) expression and reduced the infiltration of macrophages in the myenteric plexus of MPTP-treated mice. The protective effects of PPI-1011 were observed regardless of whether it was administered pre- or post- MPTP treatment. These results suggest that PPI-1011 has neuroprotective and anti-inflammatory properties in the gut and indicate its potential utility as a treatment for both early and more advanced stages of PD.

Cleft palate is a common congenital abnormality that results from defective secondary palate (SP) formation. The Sine oculis-related homeobox 2 (Six2) gene has been linked to abnormalities of craniofacial and kidney development. Our current study examined, for the first time, the specific role of Six2 in embryonic mouse SP development. Six2 mRNA and protein expression were identified in the palatal shelves from embryonic days (E)12.5 to E15.5, with peak levels during early stages of palatal shelf outgrowth. Immunohistochemical staining (IHC) showed that Six2 protein is abundant throughout the mesenchyme in the oral half of each palatal shelf, whereas there is a pronounced decline in Six2 expression by mesenchyme cells in the nasal half of the palatal shelf by stages E14.5–15.5. An opposite pattern was observed in the surface epithelium of the palatal shelf. Six2 expression was prominent at all stages in the epithelial cell layer located on the nasal side of each palatal shelf but absent from the epithelium located on the oral side of the palatal shelf. Six2 is a putative downstream target of transcription factor Hoxa2 and we previously demonstrated that Hoxa2 plays an intrinsic role in embryonic palate formation. We therefore investigated whether Six2 expression was altered in the developing SP of Hoxa2 null mice. Reverse transcriptase PCR and Western blot analyses revealed that Six2 mRNA and protein levels were upregulated in Hoxa2−/− palatal shelves at stages E12.5–14.5. Moreover, the domain of Six2 protein expression in the palatal mesenchyme of Hoxa2−/− embryos was expanded to include the entire nasal half of the palatal shelf in addition to the oral half. The palatal shelves of Hoxa2−/− embryos displayed a higher density of proliferating, Ki-67 positive palatal mesenchyme cells, as well as a higher density of Six2/Ki-67 double-positive cells. Furthermore, Hoxa2−/− palatal mesenchyme cells in culture displayed both increased proliferation and elevated Cyclin D1 expression relative to wild-type cultures. Conversely, siRNA-mediated Six2 knockdown restored proliferation and Cyclin D1 expression in Hoxa2−/− palatal mesenchyme cultures to near wild-type levels. Our findings demonstrate that Six2 functions downstream of Hoxa2 as a positive regulator of mesenchymal cell proliferation during SP development.

Ethanolamine plasmalogens (PlsEtn) are a class of glycerophospholipids characterized by a vinyl-ether bond at the sn-1 position that play an important role in the structure and function of membranes. Previous reports have suggested a link between reduced blood and brain PlsEtn levels and Parkinson’s disease (PD). We recently reported that the DHA containing plasmalogen precursor PPI-1011 protected striatal dopamine (DA) against MPTP toxicity in mice. In this paper, we further investigate the specificity requirements of the lipid side chains by testing the oleic acid-containing plasmalogen precursor PPI-1025. Male mice were treated for 10days with daily oral administration of PPI-1025 (10, 50 or 200mg/kg). On day 5 mice received MPTP and were sacrificed on Day 11. Treatment with PPI-1025 prevented MPTP-induced decrease of DA and serotonin, as well as their metabolites. In addition, PPI-1025 treatment prevented the MPTP-induced decrease of the striatal dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) specific binding. Significant positive correlations were measured between striatal DA concentrations and DAT or VMAT2 specific binding, as well as with serum plasmalogen concentrations. The neuroprotective effect of PPI-1025 displayed a bell-curve dose-dependency losing effect at the highest dose tested. The similar protective response of oleic and docosahexaenoic acid (DHA)-containing plasmalogen precursors suggests that the neuroprotection observed is not only due to DHA but to the oleic substituent and the plasmalogen backbone.