Multiple locus linkage analysis of genomewide expression in yeast.

With the ability to measure thousands of related phenotypes from a single biological sample, it is now feasible to genetically dissect systems-level biological phenomena. The genetics of transcriptional regulation and protein abundance are likely to be complex, meaning that genetic variation at multiple loci will influence these phenotypes. Several recent studies have investigated the role of genetic variation in transcription by applying traditional linkage analysis methods to genomewide expression data, where each gene expression level was treated as a quantitative trait and analyzed separately from one another. Here, we develop a new, computationally efficient method for simultaneously mapping multiple gene expression quantitative trait loci that directly uses all of the available data. Information shared across gene expression traits is captured in a way that makes minimal assumptions about the statistical properties of the data. The method produces easy-to-interpret measures of statistical significance for both individual loci and the overall joint significance of multiple loci selected for a given expression trait. We apply the new method to a cross between two strains of the budding yeast Saccharomyces cerevisiae, and estimate that at least 37% of all gene expression traits show two simultaneous linkages, where we have allowed for epistatic interactions. Pairs of jointly linking quantitative trait loci are identified with high confidence for 170 gene expression traits, where it is expected that both loci are true positives for at least 153 traits. In addition, we are able to show that epistatic interactions contribute to gene expression variation for at least 14% of all traits. We compare the proposed approach to an exhaustive two-dimensional scan over all pairs of loci. Surprisingly, we demonstrate that an exhaustive two-dimensional scan is less powerful than the sequential search used here. In addition, we show that a two-dimensional scan does not truly allow one to test for simultaneous linkage, and the statistical significance measured from this existing method cannot be interpreted among many traits

Tau-aggregation inhibitor therapy for Alzheimer's disease

Article Accepted Date: 9 December 2013 Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.Peer reviewedPublisher PD

Rationale for tau aggregation inhibitor therapy in Alzheimer's disease and other tauopathies

Preprin

Mapping gene expression quantitative trait loci by singular value decomposition and independent component analysis

<p>Abstract</p> <p>Background</p> <p>The combination of gene expression profiling with linkage analysis has become a powerful paradigm for mapping gene expression quantitative trait loci (eQTL). To date, most studies have searched for eQTL by analyzing gene expression traits one at a time. As thousands of expression traits are typically analyzed, this can reduce power because of the need to correct for the number of hypothesis tests performed. In addition, gene expression traits exhibit a complex correlation structure, which is ignored when analyzing traits individually.</p> <p>Results</p> <p>To address these issues, we applied two different multivariate dimension reduction techniques, the Singular Value Decomposition (SVD) and Independent Component Analysis (ICA) to gene expression traits derived from a cross between two strains of <it>Saccharomyces cerevisiae</it>. Both methods decompose the data into a set of meta-traits, which are linear combinations of all the expression traits. The meta-traits were enriched for several Gene Ontology categories including metabolic pathways, stress response, RNA processing, ion transport, retro-transposition and telomeric maintenance. Genome-wide linkage analysis was performed on the top 20 meta-traits from both techniques. In total, 21 eQTL were found, of which 11 are novel. Interestingly, both <it>cis </it>and <it>trans</it>-linkages to the meta-traits were observed.</p> <p>Conclusion</p> <p>These results demonstrate that dimension reduction methods are a useful and complementary approach for probing the genetic architecture of gene expression variation.</p

Crystal structures of four indole derivatives as possible cannabinoid allosteric antagonists

Acknowledgements We thank the EPSRC National Crystallography Service (University of Southampton) for the data collections and the EPSRC National Mass Spectrometry Service (University of Swansea) for the HRMS data. We thank John Low for carrying out the Cambridge Database survey.Peer reviewedPublisher PD

Electrically tunable selective reflection of light from ultraviolet to visible and infrared by heliconical cholesterics

Cholesteric liquid crystals with helicoidal molecular architecture are known for their ability to selectively reflect light with the wavelength that is determined by the periodicity of molecular orientations. Here we demonstrate that by using a cholesteric with oblique helicoidal(heliconical) structure, as opposed to the classic right-angle helicoid, one can vary the wavelength of selectively reflected light in a broad spectral range, from ultraviolet to visible and infrared (360-1520 nm for the same chemical composition) by simply adjusting the electric field applied parallel to the helicoidal axis. The effect exists in a wide temperature range (including the room temperatures) and thus can enable many applications that require dynamically controlled transmission and reflection of electromagnetic waves, from energy-saving smart windows to tunable organic lasers, reflective color display, and transparent see-through displays.Comment: 11 pages, 5figure

Ethyl 2-(5-bromo-2-iodo­anilino)cyclo­pent-1-ene-1-carboxyl­ate

Acknowledgements We thank the EPSRC National Crystallography Service (University of Southampton) for the data collection.Peer reviewedPublisher PD

Tau Aggregation Inhibitor Therapy : An Exploratory Phase 2 Study in Mild or Moderate Alzheimer's Disease

ACKNOWLEDGMENTS We thank patients and their caregivers for their participation in the study and are indebted to all the investigators involved in the study, particularly Drs. Douglas Fowlie and Donald Mowat for their helpful contributions to the clinical execution of the study in Scotland. We thank Sharon Eastwood, Parexel, for assistance in preparing initial drafts of the manuscript. We acknowledge constructive comments provided by Professors G. Wilcock and S. Gauthier on drafts of the article. CMW, CRH, and JMDS are officers of, and hold beneficial interests in, TauRx Therapeutics. RTS, PB, KK, and DJW are paid consultants to TauRx Therapeutics. The study was financed entirely by TauRx TherapeuticsPeer reviewedPublisher PD

A convenient one-pot synthesis, and characterisation of the ω-bromo-1-(4-cyanobiphenyl-4’-yl) alkanes (CBnBr)

Open access via T&F agreementPeer reviewedPublisher PD

Syntheses and Crystal Structures of Three Chiral Oxazolidinones with Different Ring Conformations

Funding: This research received no external funding. Acknowledgments: We thank the EPSRC National Crystallography Centre (University of Southampton) for the X-ray data collections.Peer reviewedPublisher PD