Beschreibung: Previously published literature reports various impacts of food on the oral bioavailability of piperaquine. The aim of this study was to use a population modeling approach to investigate the impact of concomitant intake of a small amount of food on piperaquine pharmacokinetics. This was an open, randomized comparison of piperaquine pharmacokinetics when administered as a fixed oral formulation once daily for 3 days with ( n = 15) and without ( n = 15) concomitant food to patients with uncomplicated Plasmodium falciparum malaria in Thailand. Nonlinear mixed-effects modeling was used to characterize the pharmacokinetics of piperaquine and the influence of concomitant food intake. A modified Monte Carlo mapped power approach was applied to evaluate the relationship between statistical power and various degrees of covariate effect sizes of the given study design. Piperaquine population pharmacokinetics were described well in fasting and fed patients by a three-compartment distribution model with flexible absorption. The final model showed a 25% increase in relative bioavailability per dose occasion during recovery from malaria but demonstrated no clinical impact of concomitant intake of a low-fat meal. Body weight and age were both significant covariates in the final model. The novel power approach concluded that the study was adequately powered to detect a food effect of at least 35%. This modified Monte Carlo mapped power approach may be a useful tool for evaluating the power to detect true covariate effects in mixed-effects modeling and a given study design. A small amount of food does not affect piperaquine absorption significantly in acute malaria.

Beschreibung: Transcriptional profiling is a useful strategy to study development and disease. Approaches to isolate RNA from specific cell types, or from specific cellular compartments, would extend the power of this strategy. Previous work has shown that isolation of genetically tagged ribosomes (translating ribosome affinity purification; TRAP) is an effective means...

Beschreibung: HPA-axis function and grey matter volume reductions: imaging the diathesis-stress model in individuals at ultra-high risk of psychosis Translational Psychiatry 6, e797 (May 2016). doi:10.1038/tp.2016.68 Authors: I Valli, N A Crossley, F Day, J Stone, S Tognin, V Mondelli, O Howes, L Valmaggia, C Pariante & P McGuire

Beschreibung: Rare earth element (REE)-rich breccia pipes (600,000 t @ 12% rare earth oxides) are preserved along the margins of the 136-million metric ton (Mt) Pea Ridge magnetite-apatite deposit, within Mesoproterozoic (~1.47 Ga) volcanic-plutonic rocks of the St. Francois Mountains terrane in southeastern Missouri, United States. The breccia pipes cut the rhyolite-hosted magnetite deposit and contain clasts of nearly all local bedrock and mineralized lithologies. Grains of monazite and xenotime were extracted from breccia pipe samples for SHRIMP U-Pb geochronology; both minerals were also dated in one polished thin section. Monazite forms two morphologies: (1) matrix granular grains composed of numerous small (〈50 μ m) crystallites intergrown with rare xenotime, thorite, apatite, and magnetite; and (2) coarse euhedral, glassy, bright-yellow grains similar to typical igneous or metamorphic monazite. Trace element abundances (including REE patterns) were determined on selected grains of monazite (both morphologies) and xenotime. Zircon grains from two samples of host rhyolite and two late felsic dikes collected underground at Pea Ridge were also dated. Additional geochronology done on breccia pipe minerals includes Re-Os on fine-grained molybdenite and 40 Ar/ 39 Ar on muscovite, biotite, and K-feldspar. Ages (±2 errors) obtained by SHRIMP U-Pb analysis are as follows: (1) zircon from the two host rhyolite samples have ages of 1473.6 ± 8.0 and 1472.7 ± 5.6 Ma; most zircon in late felsic dikes is interpreted as xenocrystic (age range ca. 1522–1455 Ma); a population of rare spongy zircon is likely of igneous origin and yields an age of 1441 ± 9 Ma; (2) pale-yellow granular monazite—1464.9 ± 3.3 Ma (no dated xenotime); (3) reddish matrix granular monazite—1462.0 ± 3.5 Ma and associated xenotime—1453 ± 11 Ma; (4) coarse glassy-yellow monazite—1464.8 ± 2.1, 1461.7 ± 3.7 Ma, with rims at 1447.2 ± 4.7 Ma; and (5) matrix monazite (in situ)—1464.1 ± 3.6 and 1454.6 ± 9.6 Ma, and matrix xenotime (in situ)—1468.0 ± 8.0 Ma. Two slightly older ages of cores are about 1478 Ma. The young age of rims on the coarse glassy monazite coincides with an Re-Os age of 1440.6 ± 9.2 Ma determined in this study for molybdenite intergrown with quartz and allanite, and with the age of monazite inclusions in apatite from the magnetite ore ( Neymark et al., 2016 ). A 40 Ar/ 39 Ar age of 1473 ± 1 Ma was obtained for muscovite from a breccia pipe sample. Geochronology and trace element geochemical data suggest that the granular matrix monazite and xenotime (in polygonal texture), and cores of coarse glassy monazite precipitated from hydrothermal fluids during breccia pipes formation at about 1465 Ma. The second episode of mineral growth at ca. 1443 Ma may be related to faulting and fluid flow that rebrecciated the pipes. The ca. 10-m.y. gap between the ages of host volcanic rocks and breccia pipe monazite and xenotime suggests that breccia pipe mineral formation cannot be related to the felsic magmatism represented by the rhyolitic volcanic rocks, and hence is linked to a different magmatic-hydrothermal system.

Beschreibung: Iron oxide-apatite and iron oxide-copper-gold deposits occur within ~1.48 to 1.47 Ga volcanic rocks of the St. Francois Mountains terrane near a regional boundary separating crustal blocks having contrasting depleted-mantle Sm-Nd model ages (T DM ). Major and trace element analyses and Nd and Pb isotope data were obtained to characterize the Pea Ridge deposit, improve identification of exploration targets, and better understand the regional distribution of mineralization with respect to crustal blocks. The Pea Ridge deposit is spatially associated with felsic volcanic rocks and plutons. Mafic to intermediate-composition rocks are volumetrically minor. Data for major element variations are commonly scattered and strongly suggest element mobility. Ratios of relatively immobile elements indicate that the felsic rocks are evolved subalkaline dacite and rhyolite; the mafic rocks are basalt to basaltic andesite. Granites and rhyolites display geochemical features typical of rocks produced by subduction. Rare earth element (REE) variations for the rhyolites are diagnostic of rocks affected by hydrothermal alteration and associated REE mineralization. The magnetite-rich rocks and REE-rich breccias show similar REE and mantle-normalized trace element patterns. Nd isotope compositions (age corrected) show that: (1) host rhyolites have Nd from 3.44 to 4.25 and T DM from 1.51 to 1.59 Ga; (2) magnetite ore and specular hematite rocks display Nd from 3.04 to 4.21 and T DM from 1.6 to 1.51 Ga, and Nd from 2.23 to 2.81, respectively; (3) REE-rich breccias have Nd from 3.04 to 4.11 and T DM from 1.6 to 1.51 Ga; and (4) mafic to intermediate-composition rocks range in Nd from 2.35 to 3.66 and in T DM from 1.66 to 1.56. The Nd values of the magnetite and specular hematite samples show that the REE mineralization is magmatic; no evidence exists for major overprinting by younger, crustal meteoric fluids, or by externally derived Nd. Host rocks, breccias, and magnetite ore shared a common origin from a similar source. Lead isotope ratios are diverse: (1) host rhyolite has 206 Pb/ 204 Pb from 24.261 to 50.091; (2) Pea Ridge and regional galenas have 206 Pb/ 204 Pb from 16.030 to 33.548; (3) REE-rich breccia, magnetite ore, and specular hematite rock are more radiogenic than galena; (4) REE-rich breccias have high 206 Pb/ 204 Pb (38.122–1277.61) compared to host rhyolites; and (5) REE-rich breccias are more radiogenic than magnetite ore and specular-hematite rock, having 206 Pb/ 204 Pb up to 230.65. Radiogenic 207 Pb/ 206 Pb age estimates suggest the following: (1) rhyolitic host rocks have ages of ~1.50 Ga, (2) magnetite ore is ~1.44 Ga, and (3) REE-rich breccias are ~1.48 Ga. These estimates are broadly consistent and genetically link the host rhyolite, REE-rich breccia, and magnetite ore as being contemporaneous. Alteration style and mineralogical or textural distinctions among the magnetite-rich rocks and REE-rich breccias do not correlate with different isotopic sources. In our model, magmatic fluids leached metals from the coeval felsic rocks (rhyolites), which provided the metal source reflected in the compositions of the REE-rich breccias and mineralized rocks. This model allows for the likelihood of contributions from other genetically related felsic and intermediate to more mafic rocks stored deeper in the crust. The deposit thus records an origin as a magmatic-hydrothermal system that was not affected by Nd and Pb remobilization processes, particularly if these processes also triggered mixing with externally sourced metal-bearing fluids. The Pea Ridge deposit was part of a single, widespread, homogeneous mixing system that produced a uniform isotopic composition, thus representing an excellent example of an igneous-dominated system that generated coeval magmatism and REE mineralization. Geochemical features suggest that components in the Pea Ridge deposit originated from sources in an orogenic margin. Basaltic magmatism produced by mantle decompression melting provided heat for extracting melts from the middle or lower crust. Continual addition of mafic magmas to the base of the subcontinental lithosphere, in a back-arc setting, remelted calc-alkaline rocks enriched in metals that were stored in the crust. The St. Francois Mountains terrane is adjacent to the regional T DM line (defined at a value of 1.55 Ga) that separates ~1600 Ma basement to the west, from younger basements to the east. Data for Pea Ridge straddle the T DM values proposed for the line. The Sm-Nd isotope system has been closed since formation of the deposit and the original igneous signatures have not been affected by cycles of alteration or superimposed mineralizing events. No evidence exists for externally derived Nd or Sm. The source region for metals within the Pea Ridge deposit had a moderate compositional variation and the REE-rich breccias and mineralized rocks are generally isotopically homogeneous. The Pea Ridge deposit thus constitutes a distinctive isotopic target for use as a model in identifying other mineralized systems that may share the same metal source in the St. Francois Mountains terrane and elsewhere in the eastern Granite-Rhyolite province.

Beschreibung: Defects in the acid phosphatase ACPT cause recessive hypoplastic amelogenesis imperfecta European Journal of Human Genetics advance online publication, May 17 2017. doi:10.1038/ejhg.2017.79 Authors: Claire EL Smith, Laura LE Whitehouse, James A Poulter, Steven J Brookes, Peter F Day, Francesca Soldani, Jennifer Kirkham, Chris F Inglehearn & Alan J Mighell

Beschreibung: Different APC genotypes in proximal and distal sporadic colorectal cancers suggest distinct WNT/β-catenin signalling thresholds for tumourigenesis Oncogene 32, 4675 (26 September 2013). doi:10.1038/onc.2012.486 Authors: M Christie, R N Jorissen, D Mouradov, A Sakthianandeswaren, S Li, F Day, C Tsui, L Lipton, J Desai, I T Jones, S McLaughlin, R L Ward, N J Hawkins, A R Ruszkiewicz, J Moore, A W Burgess, D Busam, Q Zhao, R L Strausberg, A J Simpson, I P M Tomlinson, P Gibbs & O M Sieber

Beschreibung: Whooping cough results from infection of the respiratory tract with Bordetella pertussis , and the secreted adenylate cyclase toxin (ACT) is essential for the bacterium to establish infection. Despite extensive study of the mechanism of ACT cytotoxicity and its effects over a range of concentrations in vitro , ACT has not been observed or quantified in vivo , and thus the concentration of ACT at the site of infection is unknown. The recently developed baboon model of infection mimics the prolonged cough and transmissibility of pertussis, and we hypothesized that measurement of ACT in nasopharyngeal washes (NPW) from baboons, combined with human and in vitro data, would provide an estimate of the ACT concentration in the airway during infection. NPW contained up to ~10 8 CFU/ml B. pertussis and 1 to 5 ng/ml ACT at the peak of infection. Nasal aspirate specimens from two human infants with pertussis contained bacterial concentrations similar to those in the baboons, with 12 to 20 ng/ml ACT. When ~10 8 CFU/ml of a laboratory strain of B. pertussis was cultured in vitro , ACT production was detected in 60 min and reached a plateau of ~60 ng/ml in 6 h. Furthermore, when bacteria were brought into close proximity to target cells by centrifugation, intoxication was increased 4-fold. Collectively, these data suggest that at the bacterium-target cell interface during infection of the respiratory tract, the concentration of ACT can exceed 100 ng/ml, providing a reference point for future studies of ACT and pertussis pathogenesis.

Beschreibung: We report the discovery of a peculiar L dwarf from the United Kingdom Infrared Deep Sky Survey Large Area Survey, ULAS J222711–004547. The very red infrared photometry (MKO J – K  = 2.79 ± 0.06, WISE W 1– W 2 = 0.65 ± 0.05) of ULAS J222711–004547 makes it one of the reddest brown dwarfs discovered so far. We obtained a moderate resolution spectrum of this target using the XSHOOTER spectrograph on the Very Large Telescope, and we classify it as L7pec, confirming its very red nature. Comparison to theoretical models suggests that the object could be a low-gravity L dwarf with a solar or higher than solar metallicity. Nonetheless, the match of such fits to the spectral energy distribution is rather poor, and this and other less red peculiar L dwarfs pose new challenges for the modelling of ultracool atmospheres, especially to the understanding of the effects of condensates and their sensitivity to gravity and metallicity. We determined the proper motion of ULAS J222711–004547 using the data available in the literature, and we find that its kinematics do not suggest membership of any of the known young associations. We show that applying a simple de-reddening curve to its spectrum allows it to resemble the spectra of the L7 spectroscopic standards without any spectral features that distinguish it as a low-metallicity or low-gravity dwarf. Given the negligible interstellar reddening of the field containing our target, we conclude that the reddening of the spectrum is mostly due to an excess of dust in the photosphere of the target. De-reddening the spectrum using extinction curves for different dust species gives surprisingly good results and suggests a characteristic grain size of ~0.5 μm. We show that by increasing the optical depth, the same extinction curves allow the spectrum of ULAS J222711–004547 to resemble the spectra of unusually blue L dwarfs and even slightly metal-poor L dwarfs. Grains of similar size also yield very good fits when de-reddening other unusually red L dwarfs in the L5–L7.5 range. These results suggest that the diversity in near-infrared colours and spectra seen in late L dwarfs could be due to differences in the optical thickness of the dust cloud deck.

Beschreibung: There is a large unmet need for a simple, accurate, noninvasive, quantitative, and high-resolution imaging modality to detect lung fibrosis at early stage and to monitor disease progression. Overexpression of collagen is a hallmark of organ fibrosis. Here, we describe the optimization of a collagen-targeted PET probe for staging pulmonary fibrosis. Methods: Six peptides were synthesized, conjugated to a copper chelator, and radiolabeled with 64 Cu. The collagen affinity of each probe was measured in a plate-based assay. The pharmacokinetics and metabolic stability of the probes were studied in healthy rats. The capacity of these probes to detect and stage pulmonary fibrosis in vivo was assessed in a mouse model of bleomycin-induced fibrosis using PET imaging. Results: All probes exhibited affinities in the low micromolar range (1.6 μM 〈 Kd 〈 14.6 μM) and had rapid blood clearance. The probes showed 2- to 8-fold-greater uptake in the lungs of bleomycin-treated mice than sham-treated mice, whereas the distribution in other organs was similar between bleomycin-treated and sham mice. The probe 64 Cu-CBP7 showed the highest uptake in fibrotic lungs and the highest target-to-background ratios. The superiority of 64 Cu-CBP7 was traced to a much higher metabolic stability compared with the other probes. The specificity of 64 Cu-CBP7 for collagen was confirmed by comparison with a nonbinding isomer. Conclusion: 64 Cu-CBP7 is a promising candidate for in vivo imaging of pulmonary fibrosis.