Evaluating a subset of ancestry informative SNPs for discriminating among Southwest Asian and circum-Mediterranean populations

AbstractMany different published sets of single nucleotide polymorphisms (SNPs) and/or insertion-deletion polymorphisms (InDels) can serve as ancestry informative markers (AIMs) to distinguish among continental regions of the world. For a focus on Southwest Asian ancestry we chose to start with the Kidd Lab panel of 55 ancestry-informative SNPs (AISNPs) because it already provided good global reference data (FROG-kb: frog.med.yale.edu) in a set of 73 population samples distinguishing at least 8 biogeographic clusters of populations. This panel serves as a good first tier ancestry panel. We are now interested in identifying region-specific second tier panels for more refined distinction among populations within each of the global regions. We have begun studying the global region centered on Southwest Asia and the region encompassing the Mediterranean Sea. We have incorporated 10 populations from North Africa, Turkey and Iran and included 31 of the original 73 populations and eleven 1000 Genomes Phase3 populations for a total of 3129 individuals from 52 populations, all typed for the 55 AISNPs. We have then identified the subset of the 55 AISNPs that are most informative for this region of the world using Heatmap, Fst, and Informativeness analyses to eliminate those SNPs essentially redundant or providing no information among populations in this region, reducing the number of SNPs to 32. STRUCTURE and PCA analyses show the remaining 32 SNPs identify the North African cluster and appropriately include the Turkish and Iranian samples with the Southwest Asian cluster. These markers provide the basis for building an improved, optimized panel of AISNPs that provides additional information on differences among populations in this part of the world. The data have also allowed an examination of the accuracy of the ancestry inference based on 32 SNPs for the newly studied populations from this region. The likelihood ratio approach to ancestry inference embodied in FROG-kb provides highly significant population assignments within one order of magnitude for each individual in the Turkish, Iranian, and Tunisian populations

Ga-68 DOTATATE Accumulation in Sarcoidosis

We aimed in this case series to show Ga-68 DOTATATE uptake in relation with disease activity in sarcoidosis cases. 8 patients with previous diagnosis of sarcoidosis were included to the study. Ga-68 DOTATATE PET/CT was performed to evaluate of disease activity. Disease activity was described clinically by chest disease specialist by evaluation of lung function tests, serum ACE measurements and thorax CT. Correlation between Ga-68 DOTATATE uptake and disease activity was analyzed. Ga-68 DOTATATE PET/CT as a combination of SSR scintigraphy and anatomical imaging might be beneficial in the evaluation of active sarcoidosis

Multiple subduction imprints in the mantle below Italy detected in a single lava flow

Post-collisional magmatism reflects the regional subduction history prior to collision but the link between the two is complex and often poorly understood. The collision of continents along a convergent plate boundary commonly marks the onset of a variety of transitional geodynamic processes. Typical responses include delamination of subducting lithosphere, crustal thickening in the overriding plate, slab detachment and asthenospheric upwelling, or the complete termination of convergence. A prominent example is the Western-Central Mediterranean, where the ongoing slow convergence of Africa and Europe (Eurasia) has been accommodated by a variety of spreading and subduction systems that dispersed remnants of subducted lithosphere into the mantle, creating a compositionally wide spectrum of magmatism. Using lead isotope compositions of a set of melt inclusions in magmatic olivine crystals we detect exceptional heterogeneity in the mantle domain below Central Italy, which we attribute to the presence of continental material, introduced initially by Alpine and subsequently by Apennine subduction. We show that superimposed subduction imprints of a mantle source can be tapped during a melting episode millions of years later, and are recorded in a single lava flow

Oral Migalastat HCl Leads to Greater Systemic Exposure and Tissue Levels of Active α-Galactosidase A in Fabry Patients when Co-Administered with Infused Agalsidase.

UnlabelledMigalastat HCl (AT1001, 1-Deoxygalactonojirimycin) is an investigational pharmacological chaperone for the treatment of α-galactosidase A (α-Gal A) deficiency, which leads to Fabry disease, an X-linked, lysosomal storage disorder. The currently approved, biologics-based therapy for Fabry disease is enzyme replacement therapy (ERT) with either agalsidase alfa (Replagal) or agalsidase beta (Fabrazyme). Based on preclinical data, migalastat HCl in combination with agalsidase is expected to result in the pharmacokinetic (PK) enhancement of agalsidase in plasma by increasing the systemic exposure of active agalsidase, thereby leading to increased cellular levels in disease-relevant tissues. This Phase 2a study design consisted of an open-label, fixed-treatment sequence that evaluated the effects of single oral doses of 150 mg or 450 mg migalastat HCl on the PK and tissue levels of intravenously infused agalsidase (0.2, 0.5, or 1.0 mg/kg) in male Fabry patients. As expected, intravenous administration of agalsidase alone resulted in increased α-Gal A activity in plasma, skin, and peripheral blood mononuclear cells (PBMCs) compared to baseline. Following co-administration of migalastat HCl and agalsidase, α-Gal A activity in plasma was further significantly increased 1.2- to 5.1-fold compared to agalsidase administration alone, in 22 of 23 patients (95.6%). Importantly, similar increases in skin and PBMC α-Gal A activity were seen following co-administration of migalastat HCl and agalsidase. The effects were not related to the administered migalastat HCl dose, as the 150 mg dose of migalastat HCl increased α-Gal A activity to the same extent as the 450 mg dose. Conversely, agalsidase had no effect on the plasma PK of migalastat. No migalastat HCl-related adverse events or drug-related tolerability issues were identified.Trial registrationClinicalTrials.gov NCT01196871

The Cytotoxicity and Insecticidal Activity of Extracts from Delphinium formosum Boiss. & Huet

Delphinium species are well-known toxic plants with diterpenoid alkaloid contents. There has been no previous investigation on the cytotoxicity of Delphinium formosum. The extracts of the different parts of D. formosum, an endemic species in Turkey, were investigated for their cytotoxic activity against the human liver carcinoma cell line (HepG2) and primary human umbilical vein endothelial cells (HUVEC). The cytotoxic effects of twelve extracts and subfractions were determined against HepG2 cells using the MTT assay. The only active extract was applied to the HUVEC as a model for healthy cells. Only one of the alkaloidcontaining extracts from the aerial parts was toxic (IC50=244,9 µg/mL against HepG2 and 144,4 µg/mL against HUVEC), while the root extracts were inactive. The results were improbable although it is predicted secondary metabolites, such as diterpene alkaloids (methyllycaconitine, browniine, lycoctonine, avardharidine, antranoyllycoctonine, delsemine A/B and lycoctonine). Based on previous studies in the literature, the cytotoxic plants were also expected to exhibit insecticidal activity. Therefore, the cytotoxic extract of D. formosum was examined for its adulticidal and larvicidal activity against the yellow fever, dengue fever and the Zika virus vector Aedes aegypti L

Reliability and stability challenges in ABCD task fMRI data

Trait stability of measures is an essential requirement for individual differences research. Functional MRI has been increasingly used in studies that rely on the assumption of trait stability, such as attempts to relate task related brain activation to individual differences in behavior and psychopathology. However, recent research using adult samples has questioned the trait stability of task-fMRI measures, as assessed by test-retest correlations. To date, little is known about trait stability of task fMRI in children. Here, we examined within-session reliability and long-term stability of individual differences in task-fMRI measures using fMRI measures of brain activation provided by the adolescent brain cognitive development (ABCD) Study Release v4.0 as an individual\u27s average regional activity, using its tasks focused on reward processing, response inhibition, and working memory. We also evaluated the effects of factors potentially affecting reliability and stability. Reliability and stability (quantified as the ratio of non-scanner related stable variance to all variances) was poor in virtually all brain regions, with an average value of 0.088 and 0.072 for short term (within-session) reliability and long-term (between-session) stability, respectively, in regions of interest (ROIs) historically-recruited by the tasks. Only one reliability or stability value in ROIs exceeded the \u27poor\u27 cut-off of 0.4, and in fact rarely exceeded 0.2 (only 4.9%). Motion had a pronounced effect on estimated reliability/stability, with the lowest motion quartile of participants having a mean reliability/stability 2.5 times higher (albeit still \u27poor\u27) than the highest motion quartile. Poor reliability and stability of task-fMRI, particularly in children, diminishes potential utility of fMRI data due to a drastic reduction of effect sizes and, consequently, statistical power for the detection of brain-behavior associations. This essential issue urgently needs to be addressed through optimization of task design, scanning parameters, data acquisition protocols, preprocessing pipelines, and data denoising methods