Palaeoproterozoic to Eoarchaean crustal growth in southern Siberia: a Nd-isotope synthesis

Nd-isotope analyses from 114 rock samples are reported from the southern part of the Siberian craton to establish a first-order crustal formation scheme for the region. The Nd-isotopedata show considerable variability within and among different cratonic units. In many cases this variability reflects differing degrees of mixing between juvenile and older (up to Eoarchaean) crustal components. The fragments of Palaeoproterozoic juvenile crust within the studied segment of the Siberian craton margin have Nd-model ages of 2.0-2.3 Ga. Voluminous Palaeoproterozoicgranites ( 1.85 Ga) were intruded into cratonic fragments and suture zones. These granites mark the stabilization of the southern Siberian craton. The complexity in the Nd data indicatea long history of crustal development, extending from the Eoarchaean to the Palaeoproterozoiceras, which is interpreted to reflect the amalgamation of distinct Archaean crustal fragments, with differing histories, during Palaeoproterozoic accretion at 1.9-2.0 Ga and subsequent cratonic stabilization at 1.85 Ga. Such a model temporally coincides with important orogenic events on nearly every continent and suggests that the Siberian craton participated in the formation of a Palaeoproterozoic supercontinent at around 1.9 Ga

A flavin-inspired covalent organic framework for photocatalytic alcohol oxidation

Covalent organic frameworks (COFs) offer a number of key properties that predestine them to be used as heterogeneous photocatalysts, including intrinsic porosity, long-range order, and light absorption. Since COFs can be constructed from a practically unlimited library of organic building blocks, these properties can be precisely tuned by choosing suitable linkers. Herein, we report the construction and use of a novel COF (FEAx-COF) photocatalyst, inspired by natural flavin cofactors. We show that the functionality of the alloxazine chromophore incorporated into the COF backbone is retained and study the effects of this heterogenization approach by comparison with similar molecular photocatalysts. We find that the integration of alloxazine chromophores into the framework significantly extends the absorption spectrum into the visible range, allowing for photocatalytic oxidation of benzylic alcohols to aldehydes even with low-energy visible light. In addition, the activity of the heterogeneous COF photocatalyst is less dependent on the chosen solvent, making it more versatile compared to molecular alloxazines. Finally, the use of oxygen as the terminal oxidant renders FEAx-COF a promising and “green” heterogeneous photocatalyst

Computerized clinical decision support systems for therapeutic drug monitoring and dosing: A decision-maker-researcher partnership systematic review

<p>Abstract</p> <p>Background</p> <p>Some drugs have a narrow therapeutic range and require monitoring and dose adjustments to optimize their efficacy and safety. Computerized clinical decision support systems (CCDSSs) may improve the net benefit of these drugs. The objective of this review was to determine if CCDSSs improve processes of care or patient outcomes for therapeutic drug monitoring and dosing.</p> <p>Methods</p> <p>We conducted a decision-maker-researcher partnership systematic review. Studies from our previous review were included, and new studies were sought until January 2010 in MEDLINE, EMBASE, Evidence-Based Medicine Reviews, and Inspec databases. Randomized controlled trials assessing the effect of a CCDSS on process of care or patient outcomes were selected by pairs of independent reviewers. A study was considered to have a positive effect (<it>i.e.</it>, CCDSS showed improvement) if at least 50% of the relevant study outcomes were statistically significantly positive.</p> <p>Results</p> <p>Thirty-three randomized controlled trials were identified, assessing the effect of a CCDSS on management of vitamin K antagonists (14), insulin (6), theophylline/aminophylline (4), aminoglycosides (3), digoxin (2), lidocaine (1), or as part of a multifaceted approach (3). Cluster randomization was rarely used (18%) and CCDSSs were usually stand-alone systems (76%) primarily used by physicians (85%). Overall, 18 of 30 studies (60%) showed an improvement in the process of care and 4 of 19 (21%) an improvement in patient outcomes. All evaluable studies assessing insulin dosing for glycaemic control showed an improvement. In meta-analysis, CCDSSs for vitamin K antagonist dosing significantly improved time in therapeutic range.</p> <p>Conclusions</p> <p>CCDSSs have potential for improving process of care for therapeutic drug monitoring and dosing, specifically insulin and vitamin K antagonist dosing. However, studies were small and generally of modest quality, and effects on patient outcomes were uncertain, with no convincing benefit in the largest studies. At present, no firm recommendation for specific systems can be given. More potent CCDSSs need to be developed and should be evaluated by independent researchers using cluster randomization and primarily assess patient outcomes related to drug efficacy and safety.</p

Individual crypt genetic heterogeneity and the origin of metaplastic glandular epithelium in human Barrett’s oesophagus

OBJECTIVES: Current models of clonal expansion in human Barrett's oesophagus are based upon heterogenous, flow-purified biopsy analysis taken at multiple segment levels. Detection of identical mutation fingerprints from these biopsy samples led to the proposal that a mutated clone with a selective advantage can clonally expand to fill an entire Barrett's segment at the expense of competing clones (selective sweep to fixation model). We aimed to assess clonality at a much higher resolution by microdissecting and genetically analysing individual crypts. The histogenesis of Barrett's metaplasia and neo-squamous islands has never been demonstrated. We investigated the oesophageal gland squamous ducts as the source of both epithelial sub-types. METHODS: Individual crypts across Barrett's biopsy and oesophagectomy blocks were dissected. Determination of tumour suppressor gene loss of heterozygosity patterns, p16 and p53 point mutations were carried out on a crypt-by-crypt basis. Cases of contiguous neo-squamous islands and columnar metaplasia with oesophageal squamous ducts were identified. Tissues were isolated by laser capture microdissection and genetically analysed. RESULTS: Individual crypt dissection revealed mutation patterns that were masked in whole biopsy analysis. Dissection across oesophagectomy specimens demonstrated marked clonal heterogeneity, with multiple independent clones present. We identified a p16 point mutation arising in the squamous epithelium of the oesophageal gland duct, which was also present in a contiguous metaplastic crypt, whereas neo-squamous islands arising from squamous ducts were wild-type with respect to surrounding Barrett's dysplasia. CONCLUSIONS: By studying clonality at the crypt level we demonstrate that Barrett's heterogeneity arises from multiple independent clones, in contrast to the selective sweep to fixation model of clonal expansion previously described. We suggest that the squamous gland ducts situated throughout the oesophagus are the source of a progenitor cell that may be susceptible to gene mutation resulting in conversion to Barrett's metaplastic epithelium. Additionally, these data suggest that wild-type ducts may be the source of neo-squamous islands

Impact of the Gut Microbiota on Atorvastatin Mediated Effects on Blood Lipids

Background and aims: The mechanisms of interindividual variation of lipid regulation by statins, such as the low-density lipoprotein cholesterol (LDL) lowering effects, are not fully understood yet. Here, we used a gut microbiota depleted mouse model to investigate the relation between the gut microbiota and the regulatory property of atorvastatin on blood lipids. Methods: Mice (C57BL/6) with intact gut microbiota or antibiotic induced abiotic mice (ABS) were put on standard chow diet (SCD) or high fat diet (HFD) for six weeks. Atorvastatin (10 mg/kg body weight/day) or a control vehicle were applied per gavage for the last four weeks of dietary treatment. Blood lipids including total cholesterol, very low-density lipoprotein, low-density lipoprotein, high-density lipoprotein and sphingolipids were measured to probe microbiota-dependent effects of atorvastatin. The expression of genes involved in hepatic and intestinal cholesterol metabolism was analyzed with qRT-PCR. The alteration of the microbiota profile was examined using 16S rRNA qPCR in mice with intact gut microbiota. Results: HFD feeding significantly increased total blood cholesterol and LDL levels, as compared to SCD in both mice with intact and depleted gut microbiota. The cholesterol lowering effect of atorvastatin was significantly attenuated in mice with depleted gut microbiota. Moreover, we observed a global shift in the abundance of several sphingolipids upon atorvastatin treatment which was absent in gut microbiota depleted mice. The regulatory effect of atorvastatin on the expression of distinct hepatic and intestinal cholesterol-regulating genes, including Ldlr, Srebp2 and Npc1l1 was altered upon depletion of gut microbiota. In response to HFD feeding, the relative abundance of the bacterial phyla Bacteroidetes decreased, while the abundance of Firmicutes increased. The altered ratio between Firmicutes to Bacteroidetes was partly reversed in HFD fed mice treated with atorvastatin. Conclusions: Our findings support a regulatory impact of atorvastatin on the gut microbial profile and, in turn, demonstrate a crucial role of the gut microbiome for atorvastatin-related effects on blood lipids. These results provide novel insights into potential microbiota-dependent mechanisms of lipid regulation by statins, which may account for variable response to statin treatment

First bounds on the very high energy gamma-ray emission from Arp 220

Using the Major Atmospheric Gamma Imaging Cherenkov Telescope (MAGIC), we have observed the nearest ultra-luminous infrared galaxy Arp 220 for about 15 hours. No significant signal was detected within the dedicated amount of observation time. The first upper limits to the very high energy $\gamma$-ray flux of Arp 220 are herein reported and compared with theoretical expectations.Comment: Accepted for publication in Ap

Constraints on the steady and pulsed very high energy gamma-ray emission from observations of PSR B1951+32/CTB 80 with the MAGIC Telescope

We report on very high energy gamma-observations with the MAGIC Telescope of the pulsar PSR B1951+32 and its associated nebula, CTB 80. Our data constrain the cutoff energy of the pulsar to be less than 32 GeV, assuming the pulsed gamma-ray emission to be exponentially cut off. The upper limit on the flux of pulsed gamma-ray emission above 75 GeV is 4.3*10^-11 photons cm^-2 sec^-1, and the upper limit on the flux of steady emission above 140 GeV is 1.5*10^-11 photons cm^-2 sec^-1. We discuss our results in the framework of recent model predictions and other studies.Comment: 7 pages, 7 figures, replaced with published versio