Novel 2-amino-isoflavones exhibit aryl hydrocarbon receptor agonist or antagonist activity in a species/cell-specific context

The aryl hydrocarbon receptor (AhR) mediates the induction of a variety of xenobiotic metabolism genes. Activation of the AhR occurs through binding to a group of structurally diverse compounds, most notably dioxins, which are exogenous ligands. Isoflavones are part of a family which include some well characterised endogenous AhR ligands. This paper analysed a novel family of these compounds, based on the structure of 2-amino-isoflavone. Initially two luciferase-based cell models, mouse H1L6.1c2 and human HG2L6.1c3, were used to identify whether the compounds had AhR agonistic and/or antagonistic properties. This analysis showed that some of the compounds were weak agonists in mouse and antagonists in human. Further analysis of two of the compounds, Chr-13 and Chr-19, was conducted using quantitative real-time PCR in rat H4IIE and human MCF-7 cells. The results indicated that Chr-13 was an agonist in rat but an antagonist in human cells. Chr-19 was shown to be an agonist in rat but more interestingly, a partial agonist in human. Luciferase induction results not only revealed that subtle differences in the structure of the compound could produce species-specific differences in response but also dictated the ability of the compound to be an AhR agonist or antagonist. Substituted 2-amino-isoflavones represent a novel group of AhR ligands that must differentially interact with the AhR ligand binding domain to produce their species-specific agonist or antagonist activity and future ligand binding analysis and docking studies with these compounds may provide insights into the differential mechanisms of action of structurally similar compounds

In Vitro and In Silico Characterization of the Aggregation of Thrombi on Ventricular Assist Device Cannula

The unacceptably high stroke rate of HeartMate III VAD without signs of adherent pump thrombosis is hypothesized to be the result of the thrombi originating on the inflow cannula, ingesting and ejecting emboli from the VAD. Therefore, inflow cannula thrombosis has been an emerging focus. The inflow cannula of contemporary VADs, which incorporate both polished and rough regions serve as useful benchmarks to study the effects of roughness and shear on thrombogenesis. An in vitro study was conducted to emulate the micro-hemodynamic condition on a sintered inflow cannula, and to observe the deposition and detachment patterns. Together with a computational fluid dynamic tool, this study aimed to provide insight into the optimization of inflow cannula and potentially reducing adverse neurological events due to upstream thrombus

Wideband gyro-amplifiers

Gyro-amplifiers using helically corrugated waveguides have shown exceptional gain, power, bandwidth, and efficiency performance at cm and mm wavelengths. The performance of a long pulse (and therefore high vacuum) system is strongly influenced by factors other than the intrinsic bandwidth of the interaction. We shall discuss these and other challenges, along with their mitigation in high average power wideband amplifiers

Assessing the role of insulin-like growth factors and binding proteins in prostate cancer using Mendelian randomization:genetic variants as instruments for circulating levels

Circulating insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are associated with prostate cancer. Using genetic variants as instruments for IGF peptides, we investigated whether these associations are likely to be causal. We identified from the literature 56 single nucleotide polymorphisms (SNPs) in the IGF axis previously associated with biomarker levels (8 from a genome-wide association study [GWAS] and 48 in reported candidate genes). In ∼700 men without prostate cancer and two replication cohorts (N∼900 and ∼9,000), we examined the properties of these SNPS as instrumental variables (IVs) for IGF-I, IGF-II, IGFBP-2 and IGFBP-3. Those confirmed as strong IVs were tested for association with prostate cancer risk, low (< 7) vs high (≥ 7) Gleason grade, localised vs advanced stage, and mortality, in 22,936 controls and 22,992 cases. IV analysis was used in an attempt to estimate the causal effect of circulating IGF peptides on prostate cancer. Published SNPs in the IGFBP1/IGFBP3 gene region, particularly rs11977526, were strong instruments for IGF-II and IGFBP-3, less so for IGF-I. Rs11977526 was associated with high (vs low) Gleason grade (OR per IGF-II/IGFBP-3 level-raising allele 1.05; 95% CI 1.00, 1.10). Using rs11977526 as an IV we estimated the causal effect of a one SD increase in IGF-II (∼265 ng/ml) on risk of high vs low grade disease as 1.14 (95% CI 1.00, 1.31). Because of the potential for pleiotropy of the genetic instruments, these findings can only causally implicate the IGF pathway in general, not any one specific biomarker. This article is protected by copyright. All rights reserved

Usage Bibliometrics

Scholarly usage data provides unique opportunities to address the known shortcomings of citation analysis. However, the collection, processing and analysis of usage data remains an area of active research. This article provides a review of the state-of-the-art in usage-based informetric, i.e. the use of usage data to study the scholarly process.Comment: Publisher's PDF (by permission). Publisher web site: books.infotoday.com/asist/arist44.shtm

High salt-induced excess reactive oxygen species production resulted in heart tube malformation during gastrulation

An association has been proved between high salt consumption and cardiovascular mortality. In vertebrates, the heart is the first functional organ to be formed. However, it is not clear whether high‐salt exposure has an adverse impact on cardiogenesis. Here we report high‐salt exposure inhibited basement membrane breakdown by affecting RhoA, thus disturbing the expression of Slug/E‐cadherin/N‐cadherin/Laminin and interfering with mesoderm formation during the epithelial‐mesenchymal transition(EMT). Furthermore, the DiI+ cell migration trajectory in vivo and scratch wound assays in vitro indicated that high‐salt exposure restricted cell migration of cardiac progenitors, which was caused by the weaker cytoskeleton structure and unaltered corresponding adhesion junctions at HH7. Besides, down‐regulation of GATA4/5/6, Nkx2.5, TBX5, and Mef2c and up‐regulation of Wnt3a/β‐catenin caused aberrant cardiomyocyte differentiation at HH7 and HH10. High‐salt exposure also inhibited cell proliferation and promoted apoptosis. Most importantly, our study revealed that excessive reactive oxygen species(ROS)generated by high salt disturbed the expression of cardiac‐related genes, detrimentally affecting the above process including EMT, cell migration, differentiation, cell proliferation and apoptosis, which is the major cause of malformation of heart tubes

Amorphous and Polycrystalline Photoconductors for Direct Conversion Flat Panel X-Ray Image Sensors

In the last ten to fifteen years there has been much research in using amorphous and polycrystalline semiconductors as x-ray photoconductors in various x-ray image sensor applications, most notably in flat panel x-ray imagers (FPXIs). We first outline the essential requirements for an ideal large area photoconductor for use in a FPXI, and discuss how some of the current amorphous and polycrystalline semiconductors fulfill these requirements. At present, only stabilized amorphous selenium (doped and alloyed a-Se) has been commercialized, and FPXIs based on a-Se are particularly suitable for mammography, operating at the ideal limit of high detective quantum efficiency (DQE). Further, these FPXIs can also be used in real-time, and have already been used in such applications as tomosynthesis. We discuss some of the important attributes of amorphous and polycrystalline x-ray photoconductors such as their large area deposition ability, charge collection efficiency, x-ray sensitivity, DQE, modulation transfer function (MTF) and the importance of the dark current. We show the importance of charge trapping in limiting not only the sensitivity but also the resolution of these detectors. Limitations on the maximum acceptable dark current and the corresponding charge collection efficiency jointly impose a practical constraint that many photoconductors fail to satisfy. We discuss the case of a-Se in which the dark current was brought down by three orders of magnitude by the use of special blocking layers to satisfy the dark current constraint. There are also a number of polycrystalline photoconductors, HgI2 and PbO being good examples, that show potential for commercialization in the same way that multilayer stabilized a-Se x-ray photoconductors were developed for commercial applications. We highlight the unique nature of avalanche multiplication in a-Se and how it has led to the development of the commercial HARP video-tube. An all solid state version of the HARP has been recently demonstrated with excellent avalanche gains; the latter is expected to lead to a number of novel imaging device applications that would be quantum noise limited. While passive pixel sensors use one TFT (thin film transistor) as a switch at the pixel, active pixel sensors (APSs) have two or more transistors and provide gain at the pixel level. The advantages of APS based x-ray imagers are also discussed with examples

Organotypical tissue cultures from adult murine colon as an in vitro model of intestinal mucosa

Together with animal experiments, organotypical cell cultures are important models for analyzing cellular interactions of the mucosal epithelium and pathogenic mechanisms in the gastrointestinal tract. Here, we introduce a three-dimensional culture model from the adult mouse colon for cell biological investigations in an in vivo-like environment. These explant cultures were cultured for up to 2 weeks and maintained typical characteristics of the intestinal mucosa, including a high-prismatic epithelium with specific epithelial cell-to-cell connections, a basal lamina and various connective tissue cell types, as analyzed with immunohistological and electron microscopic methods. The function of the epithelium was tested by treating the cultures with dexamethasone, which resulted in a strong upregulation of the serum- and glucocorticoid-inducible kinase 1 similar to that found in vivo. The culture system was investigated in infection experiments with the fungal pathogen Candida albicans. Wildtype but not Δcph1/Δefg1-knockout Candida adhered to, penetrated and infiltrated the epithelial barrier. The results demonstrate the potential usefulness of this intestinal in vitro model for studying epithelial cell-cell interactions, cellular signaling and microbiological infections in a three-dimensional cell arrangement