Statistical methods for analyzing immunosignatures

<p>Abstract</p> <p>Background</p> <p>Immunosignaturing is a new peptide microarray based technology for profiling of humoral immune responses. Despite new challenges, immunosignaturing gives us the opportunity to explore new and fundamentally different research questions. In addition to classifying samples based on disease status, the complex patterns and latent factors underlying immunosignatures, which we attempt to model, may have a diverse range of applications.</p> <p>Methods</p> <p>We investigate the utility of a number of statistical methods to determine model performance and address challenges inherent in analyzing immunosignatures. Some of these methods include exploratory and confirmatory factor analyses, classical significance testing, structural equation and mixture modeling.</p> <p>Results</p> <p>We demonstrate an ability to classify samples based on disease status and show that immunosignaturing is a very promising technology for screening and presymptomatic screening of disease. In addition, we are able to model complex patterns and latent factors underlying immunosignatures. These latent factors may serve as biomarkers for disease and may play a key role in a bioinformatic method for antibody discovery.</p> <p>Conclusion</p> <p>Based on this research, we lay out an analytic framework illustrating how immunosignatures may be useful as a general method for screening and presymptomatic screening of disease as well as antibody discovery.</p

Benzo-fused Lactams from a Diversity-oriented Synthesis (DOS) Library as Inhibitors of Scavenger Receptor BI (SR-BI)-mediated Lipid Uptake

We report a new series of 8-membered benzo-fused lactams that inhibit cellular lipid uptake from HDL particles mediated by Scavenger Receptor, Class B, Type I (SR-BI). The series was identified via a high-throughput screen of the National Institutes of Health Molecular Libraries Small Molecule Repository (NIH MLSMR), measuring the transfer of the fluorescent lipid DiI from HDL particles to CHO cells overexpressing SR-BI. The series is part of a previously reported diversity-oriented synthesis (DOS) library prepared via a build-couple-pair approach. Detailed structure–activity relationship (SAR) studies were performed with a selection of the original library, as well as additional analogs prepared via solution phase synthesis. These studies demonstrate that the orientation of the substituents on the aliphatic ring have a critical effect on activity. Additionally, a lipophilic group is required at the western end of the molecule, and a northern hydroxyl group and a southern sulfonamide substituent also proved to be optimal. Compound 2p was found to possess a superior combination of potency (av IC50 = 0.10 μM) and solubility (79 μM in PBS), and it was designated as probe ML312

Self-subduction of the Pangaean global plate

One of the most striking and rare occurrences in the Earth's history is the amalgamation of most of the continental lithosphere into one supercontinent. The most recent supercontinent, Pangaea, lasted from 320 to 200 million years ago. Here, we show that after the continental collisions that led to the formation of Pangaea, plate convergence continued in a large, wedge-shaped oceanic tract. We súggest that plate strain at the periphery of the supercontinent eventually resulted in self-subduction of the Pangaean global plate, when the ocean margin of the continent subducted beneath the continental edge at the other end of the same plate. Our scenario results in a stress regime within Pangaea that explains the development of a large fold structure near the apex of the Palaeotethys Ocean, extensive lower crustal heating and continental magmatism at the core of the continent as well as the development of radially arranged continental rifts in more peripheral regions of the plate

Biogeochemical and microbial seasonal dynamics between water column and sediment processes in a productive mountain lake: Georgetown Lake, MT, USA

This manuscript details investigations of a productive, mountain freshwater lake and examines the dynamic relationship between the chemical and stable isotopes and microbial composition of lake bed sediments with the geochemistry of the lake water column. A multidisciplinary approach was used in order to better understand the lake water- sediment interactions including quantification and sequencing of microbial 16S rRNA genes in a sediment core as well as stable isotope analysis of C, S, and N. One visit included the use of a pore water sampler to gain insight into the composition of dissolved solutes within the sediment matrix. Sediment cores showed a general decrease in total C with depth which included a decrease in the fraction of organic C combined with an increase in the fraction of inorganic C. One sediment core showed a maximum concentration of dissolved organic C, dissolved inorganic C, and dissolved methane in pore water at 4 cm depth which corresponded with a sharp increase in the abundance of 16S rRNA templates as a proxy for the microbial population size as well as the peak abundance of a sequence affiliated with a putative methanotroph. The isotopic separation between dissolved inorganic and dissolved organic carbon is consistent with largely aerobic microbial processes dominating the upper water column, while anaerobic microbial activity dominates the sediment bed. Using sediment core carbon concentrations, predictions were made regarding the breakdown and return of stored carbon per year from this temperate climate lake with as much as 1.3 Gg C yr(-1) being released in the form of CO2 and CH4