Efficient Bayesian-based Multi-View Deconvolution

Light sheet fluorescence microscopy is able to image large specimen with high resolution by imaging the sam- ples from multiple angles. Multi-view deconvolution can significantly improve the resolution and contrast of the images, but its application has been limited due to the large size of the datasets. Here we present a Bayesian- based derivation of multi-view deconvolution that drastically improves the convergence time and provide a fast implementation utilizing graphics hardware.Comment: 48 pages, 20 figures, 1 table, under review at Nature Method

SPSmart: adapting population based SNP genotype databases for fast and comprehensive web access

<p>Abstract</p> <p>Background</p> <p>In the last five years large online resources of human variability have appeared, notably HapMap, Perlegen and the CEPH foundation. These databases of genotypes with population information act as catalogues of human diversity, and are widely used as reference sources for population genetics studies. Although many useful conclusions may be extracted by querying databases individually, the lack of flexibility for combining data from within and between each database does not allow the calculation of key population variability statistics.</p> <p>Results</p> <p>We have developed a novel tool for accessing and combining large-scale genomic databases of single nucleotide polymorphisms (SNPs) in widespread use in human population genetics: SPSmart (SNPs for Population Studies). A fast pipeline creates and maintains a data mart from the most commonly accessed databases of genotypes containing population information: data is mined, summarized into the standard statistical reference indices, and stored into a relational database that currently handles as many as 4 × 10⁹genotypes and that can be easily extended to new database initiatives. We have also built a web interface to the data mart that allows the browsing of underlying data indexed by population and the combining of populations, allowing intuitive and straightforward comparison of population groups. All the information served is optimized for web display, and most of the computations are already pre-processed in the data mart to speed up the data browsing and any computational treatment requested.</p> <p>Conclusion</p> <p>In practice, SPSmart allows populations to be combined into user-defined groups, while multiple databases can be accessed and compared in a few simple steps from a single query. It performs the queries rapidly and gives straightforward graphical summaries of SNP population variability through visual inspection of allele frequencies outlined in standard pie-chart format. In addition, full numerical description of the data is output in statistical results panels that include common population genetics metrics such as heterozygosity, <it>Fst </it>and <it>In</it>.</p

Real Talk: A Realist Dialogic Approach in a Realist Evaluation

Realist evaluation is a method increasingly adopted to provide an understanding of how and why a program works, for whom, and under what circumstances. Initial program theories (IPT) are the crucial starting point of any realist evaluation, however descriptions about how they are developed in practice remain under-reported in the published literature. This article argues for the value of genuine research-group conversations using David Bohm’s concept of dialogue in realist research. We label it the realist dialogic approach. We draw out the relational qualities as well as the contextual circumstances of dialogue through our development of IPT and interview guides for a research study on the implementation and scaling of a large-system value-based program to transform complex health services. We selected the relevant middle-range theories, conducted a literature review, and drew on informal discussions with key stakeholders, to develop IPT through research-group conversations. The benefits of this approach were: 1) development of rigorous, novel, deep and well-tailored IPT, 2) detailed understanding of the complex intervention under investigation and development of rapport and networks with participants, 3) empirically grounded Context-Mechanism-Outcome (CMO) configurations, predicated on suitable abstract and contextually-contingent middle-range theories, and 4) productive research team interactions which supported the entire research process. The challenges of this approach include: 1) establishing and retaining a sense of humility across the research team, 2) contextual circumstances can hinder dialogic relationship, and 3) time and resource heavy. This paper uses middle-range theory and ethnographic insights to advance the existing practice of realist evaluations and offer transferable lessons to other scholars considering similar approaches. Moreover, we content that the use of middle-range theory to extend the methodological literature is a novel contribution to realist work

Expression of Drug Targets in Patients Treated with Sorafenib, Carboplatin and Paclitaxel

Introduction: Sorafenib, a multitarget kinase inhibitor, targets members of the mitogen-activated protein kinase (MAPK) pathway and VEGFR kinases. Here we assessed the association between expression of sorafenib targets and biomarkers of taxane sensitivity and response to therapy in pre-treatment tumors from patients enrolled in ECOG 2603, a phase III comparing sorafenib, carboplatin and paclitaxel (SCP) to carboplatin, paclitaxel and placebo (CP). Methods: Using a method of automated quantitative analysis (AQUA) of in situ protein expression, we quantified expression of VEGF-R2, VEGF-R1, VEGF-R3, FGF-R1, PDGF-Rβ, c-Kit, B-Raf, C-Raf, MEK1, ERK1/2, STMN1, MAP2, EB1 and Bcl-2 in pretreatment specimens from 263 patients. Results: An association was found between high FGF-R1 and VEGF-R1 and increased progression-free survival (PFS) and overall survival (OS) in our combined cohort (SCP and CP arms). Expression of FGF-R1 and VEGF-R1 was higher in patients who responded to therapy ((CR+PR) vs. (SD+PD+ un-evaluable)). Conclusions: In light of the absence of treatment effect associated with sorafenib, the association found between FGF-R1 and VEGF-R1 expression and OS, PFS and response might reflect a predictive biomarker signature for carboplatin/paclitaxel-based therapy. Seeing that carboplatin and pacitaxel are now widely used for this disease, corroboration in another cohort might enable us to improve the therapeutic ratio of this regimen. © 2013 Jilaveanu et al

Superconductivity in HfTe5 across weak to strong topological insulator transition induced via pressures

Recently, theoretical studies show that layered HfTe5 is at the boundary of weak & strong topological insulator (TI) and might crossover to a Dirac semimetal state by changing lattice parameters. The topological properties of 3D stacked HfTe5 are expected hence to be sensitive to pressures tuning. Here, we report pressure induced phase evolution in both electronic & crystal structures for HfTe5 with a culmination of pressure induced superconductivity. Our experiments indicated that the temperature for anomaly resistance peak (Tp) due to Lifshitz transition decreases first before climbs up to a maximum with pressure while the Tp minimum corresponds to the transition from a weak TI to strong TI. The HfTe5 crystal becomes superconductive above ~5.5 GPa where the Tp reaches maximum. The highest superconducting transition temperature (Tc) around 5 K was achieved at 20 GPa. Crystal structure studies indicate that HfTe5 transforms from a Cmcm phase across a monoclinic C2/m phase then to a P-1 phase with increasing pressure. Based on transport, structure studies a comprehensive phase diagram of HfTe5 is constructed as function of pressure. The work provides valuable experimental insights into the evolution on how to proceed from a weak TI precursor across a strong TI to superconductors

The Structure of Tumor Endothelial Marker 8 (TEM8) Extracellular Domain and Implications for Its Receptor Function for Recognizing Anthrax Toxin

Anthrax toxin, which is released from the Gram-positive bacterium Bacillus anthracis, is composed of three proteins: protective antigen (PA), lethal factor (LF), and edema factor (EF). PA binds a receptor on the surface of the target cell and further assembles into a homo-heptameric pore through which EF and LF translocate into the cytosol. Two distinct cellular receptors for anthrax toxin, TEM8/ANTXR1 and CMG2/ANTXR2, have been identified, and it is known that their extracellular domains bind PA with low and high affinities, respectively. Here, we report the crystal structure of the TEM8 extracellular vWA domain at 1.7 Å resolution. The overall structure has a typical integrin fold and is similar to that of the previously published CMG2 structure. In addition, using structure-based mutagenesis, we demonstrate that the putative interface region of TEM8 with PA (consisting of residues 56, 57, and 154–160) is responsible for the PA-binding affinity differences between the two receptors. In particular, Leu56 was shown to be a key factor for the lower affinity of TEM8 towards PA compared with CMG2. Because of its high affinity for PA and low expression in normal tissues, an isolated extracellular vWA domain of the L56A TEM8 variant may serve as a potent antitoxin and a potential therapeutic treatment for anthrax infection. Moreover, as TEM8 is often over-expressed in tumor cells, our TEM8 crystal structure may provide new insights into how to design PA mutants that preferentially target tumor cells

The quality control theory of aging

The quality control (QC) theory of aging is based on the concept that aging is the result of a reduction in QC of cellular systems designed to maintain lifelong homeostasis. Four QC systems associated with aging are 1) inadequate protein processing in a distressed endoplasmic reticulum (ER); 2) histone deacetylase (HDAC) processing of genomic histones and gene silencing; 3) suppressed AMPK nutrient sensing with inefficient energy utilization and excessive fat accumulation; and 4) beta-adrenergic receptor (BAR) signaling and environmental and emotional stress. Reprogramming these systems to maintain efficiency and prevent aging would be a rational strategy for increased lifespan and improved health. The QC theory can be tested with a pharmacological approach using three well-known and safe, FDA-approved drugs: 1) phenyl butyric acid, a chemical chaperone that enhances ER function and is also an HDAC inhibitor, 2) metformin, which activates AMPK and is used to treat type 2 diabetes, and 3) propranolol, a beta blocker which inhibits BAR signaling and is used to treat hypertension and anxiety. A critical aspect of the QC theory, then, is that aging is associated with multiple cellular systems that can be targeted with drug combinations more effectively than with single drugs. But more importantly, these drug combinations will effectively prevent, delay, or reverse chronic diseases of aging that impose such a tremendous health burden on our society

Tumor Endothelium Marker-8 Based Decoys Exhibit Superiority over Capillary Morphogenesis Protein-2 Based Decoys as Anthrax Toxin Inhibitors

Anthrax toxin is the major virulence factor produced by Bacillus anthracis. The toxin consists of three protein subunits: protective antigen (PA), lethal factor, and edema factor. Inhibition of PA binding to its receptors, tumor endothelium marker-8 (TEM8) and capillary morphogenesis protein-2 (CMG2) can effectively block anthrax intoxication, which is particularly valuable when the toxin has already been overproduced at the late stage of anthrax infection, thus rendering antibiotics ineffectual. Receptor-like agonists, such as the mammalian cell-expressed von Willebrand factor type A (vWA) domain of CMG2 (sCMG2), have demonstrated potency against the anthrax toxin. However, the soluble vWA domain of TEM8 (sTEM8) was ruled out as an anthrax toxin inhibitor candidate due to its inferior affinity to PA. In the present study, we report that L56A, a PA-binding-affinity-elevated mutant of sTEM8, could inhibit anthrax intoxication as effectively as sCMG2 in Fisher 344 rats. Additionally, pharmacokinetics showed that L56A and sTEM8 exhibit advantages over sCMG2 with better lung-targeting and longer plasma retention time, which may contribute to their enhanced protective ability in vivo. Our results suggest that receptor decoys based on TEM8 are promising anthrax toxin inhibitors and, together with the pharmacokinetic studies in this report, may contribute to the development of novel anthrax drugs

Molecular and Antigenic Characterization of Reassortant H3N2 Viruses from Turkeys with a Unique Constellation of Pandemic H1N1 Internal Genes

Triple reassortant (TR) H3N2 influenza viruses cause varying degrees of loss in egg production in breeder turkeys. In this study we characterized TR H3N2 viruses isolated from three breeder turkey farms diagnosed with a drop in egg production. The eight gene segments of the virus isolated from the first case submission (FAV-003) were all of TR H3N2 lineage. However, viruses from the two subsequent case submissions (FAV-009 and FAV-010) were unique reassortants with PB2, PA, nucleoprotein (NP) and matrix (M) gene segments from 2009 pandemic H1N1 and the remaining gene segments from TR H3N2. Phylogenetic analysis of the HA and NA genes placed the 3 virus isolates in 2 separate clades within cluster IV of TR H3N2 viruses. Birds from the latter two affected farms had been vaccinated with a H3N4 oil emulsion vaccine prior to the outbreak. The HAl subunit of the H3N4 vaccine strain had only a predicted amino acid identity of 79% with the isolate from FAV-003 and 80% for the isolates from FAV-009 and FAV-0010. By comparison, the predicted amino acid sequence identity between a prototype TR H3N2 cluster IV virus A/Sw/ON/33853/2005 and the three turkey isolates from this study was 95% while the identity between FAV-003 and FAV-009/10 isolates was 91%. When the previously identified antigenic sites A, B, C, D and E of HA1 were examined, isolates from FAV-003 and FAV-009/10 had a total of 19 and 16 amino acid substitutions respectively when compared with the H3N4 vaccine strain. These changes corresponded with the failure of the sera collected from turkeys that received this vaccine to neutralize any of the above three isolates in vitro