Synthesis and biological evaluation of novel, selective, nonsteroidal glucocorticoid receptor antagonists

We report the discovery of a novel class of glucocorticoid receptor (GR) antagonists based on the chromene molecular scaffold. The compounds exhibit good functional potency and an improved receptor selectivity profile for GR over other steroid receptors when compared to the classical steroidal GR-antagonist, RU-486.     

Short tandem repeat polymorphic markers for the rat genome from marker-selected libraries

In an effort to generate a genome-wide set of high-quality polymorphic markers for the rat, we used the marker-selection method, which has already been proven useful for the development of markers, especially for the human genome. Small-insert (300–900 bp) rat genomic libraries were constructed with an estimated complexity of three genome equivalents and enriched for short tandem repeat sequences (STRs). The enriched libraries were found to contain 45% (CA)_n and 27% (GATA)_n, representing at least a 50-fold enrichment over unselected small insert genomic libraries. A subset of 2160 STR-containing clones, primarily of the (GATA)_n class of repeats, were sequenced. PCR primers flanking the repeats were synthesized from some of the sequences from the (CA)_n and (GATA)_n classes of STRs and tested for polymorphism in a panel of eight inbred rat strains. This strategy yielded 147 polymorphic markers, which mapped with high odds to all chromosomes by linkage in three F₂ populations. The integration of these STR markers with other rat genetic markers and mapping reagents will facilitate the mapping of disease genes in the rat and the identification of loci associated with complex mammalian phenotypes. Received: 6 May 1998 / Accepted: 6 August 1998     

Continuous Steady-State Method Using Tenax for Delivering Tetrachloroethene to Chloro-Respiring Bacteria

Tenax-TA, a solid-phase sorbent, was used as an alternative to hexadecane for continuous delivery of tetrachloroethene (PCE) to Desulfuromonas strain BB1, a chloro-respiring microorganism. In both batch and bioreactor configurations, Tenax not only maintained low, steady-state concentrations of PCE in an active culture for several months but also adsorbed the product of dechlorination, cis-1,2-dichloroethene, before it approached toxic levels.     

Re-Constructing Historical Adélie Penguin Abundance Estimates by Retrospectively Accounting for Detection Bias

Seabirds and other land-breeding marine predators are considered to be useful and practical indicators of the state of marine ecosystems because of their dependence on marine prey and the accessibility of their populations at breeding colonies. Historical counts of breeding populations of these higher-order marine predators are one of few data sources available for inferring past change in marine ecosystems. However, historical abundance estimates derived from these population counts may be subject to unrecognised bias and uncertainty because of variable attendance of birds at breeding colonies and variable timing of past population surveys. We retrospectively accounted for detection bias in historical abundance estimates of the colonial, land-breeding Adélie penguin through an analysis of 222 historical abundance estimates from 81 breeding sites in east Antarctica. The published abundance estimates were de-constructed to retrieve the raw count data and then re-constructed by applying contemporary adjustment factors obtained from remotely operating time-lapse cameras. The re-construction process incorporated spatial and temporal variation in phenology and attendance by using data from cameras deployed at multiple sites over multiple years and propagating this uncertainty through to the final revised abundance estimates. Our re-constructed abundance estimates were consistently higher and more uncertain than published estimates. The re-constructed estimates alter the conclusions reached for some sites in east Antarctica in recent assessments of long-term Adélie penguin population change. Our approach is applicable to abundance data for a wide range of colonial, land-breeding marine species including other penguin species, flying seabirds and marine mammals.     

Circulating MicroRNAs as Non-Invasive Biomarkers for Early Detection of Non-Small-Cell Lung Cancer

BackgroundDetection of lung cancer at an early stage by sensitive screening tests could be an important strategy to improving prognosis. Our objective was to identify a panel of circulating microRNAs in plasma that will contribute to early detection of lung cancer.ResultsWe identified a panel of 24 microRNAs with optimum classification performance. The combination of these 24 microRNAs alone could discriminate lung cancer cases from non-cancer controls with an AUC of 0.92 (95% CI: 0.87-0.95). This classification improved to an AUC of 0.94 (95% CI: 0.90-0.97) following addition of sex, age and smoking status to the model. Internal validation of the model suggests that the discriminatory power of the panel will be high when applied to independent samples with a corrected AUC of 0.78 for the 24-miRNA panel alone.ConclusionOur 24-microRNA predictor improves lung cancer prediction beyond that of known risk factors.     

The Clinical Performance of an Office-Based Risk Scoring System for Fatal Cardiovascular Diseases in North-East of Iran

BackgroundCardiovascular diseases (CVD) are becoming major causes of death in developing countries. Risk scoring systems for CVD are needed to prioritize allocation of limited resources. Most of these risk score algorithms have been based on a long array of risk factors including blood markers of lipids. However, risk scoring systems that solely use office-based data, not including laboratory markers, may be advantageous. In the current analysis, we validated the office-based Framingham risk scoring system in Iran.MethodsThe study used data from the Golestan Cohort in North-East of Iran. The following risk factors were used in the development of the risk scoring method: sex, age, body mass index, systolic blood pressure, hypertension treatment, current smoking, and diabetes. Cardiovascular risk functions for prediction of 10-year risk of fatal CVDs were developed.ResultsA total of 46,674 participants free of CVD at baseline were included. Predictive value of estimated risks was examined. The resulting Area Under the ROC Curve (AUC) was 0.774 (95% CI: 0.762-0.787) in all participants, 0.772 (95% CI: 0.753-0.791) in women, and 0.763 (95% CI: 0.747-0.779) in men. AUC was higher in urban areas (0.790, 95% CI: 0.766-0.815). The predicted and observed risks of fatal CVD were similar in women. However, in men, predicted probabilities were higher than observed.ConclusionThe AUC in the current study is comparable to results of previous studies while lipid profile was replaced by body mass index to develop an office-based scoring system. This scoring algorithm is capable of discriminating individuals at high risk versus low risk of fatal CVD.     

MIiSR: Molecular Interactions in Super-Resolution Imaging Enables the Analysis of Protein Interactions,Dynamics and Formation of Multi-protein Structures

Our current understanding of the molecular mechanisms which regulate cellular processes such as vesicular trafficking has been enabled by conventional biochemical and microscopy techniques. However, these methods often obscure the heterogeneity of the cellular environment, thus precluding a quantitative assessment of the molecular interactions regulating these processes. Herein, we present Molecular Interactions in Super Resolution (MIiSR) software which provides quantitative analysis tools for use with super-resolution images. MIiSR combines multiple tools for analyzing intermolecular interactions, molecular clustering and image segmentation. These tools enable quantification, in the native environment of the cell, of molecular interactions and the formation of higher-order molecular complexes. The capabilities and limitations of these analytical tools are demonstrated using both modeled data and examples derived from the vesicular trafficking system, thereby providing an established and validated experimental workflow capable of quantitatively assessing molecular interactions and molecular complex formation within the heterogeneous environment of the cell.