Evidence of positive selection at codon sites localized in extracellular domains of mammalian CC motif chemokine receptor proteins

<p>Abstract</p> <p>Background</p> <p>CC chemokine receptor proteins (CCR1 through CCR10) are seven-transmembrane G-protein coupled receptors whose signaling pathways are known for their important roles coordinating immune system responses through targeted trafficking of white blood cells. In addition, some of these receptors have been identified as fusion proteins for viral pathogens: for example, HIV-1 strains utilize CCR5, CCR2 and CCR3 proteins to obtain cellular entry in humans. The extracellular domains of these receptor proteins are involved in ligand-binding specificity as well as pathogen recognition interactions.</p> <p>In mammals, the majority of chemokine receptor genes are clustered together; in humans, seven of the ten genes are clustered in the 3p21-24 chromosome region. Gene conversion events, or exchange of DNA sequence between genes, have been reported in chemokine receptor paralogs in various mammalian lineages, especially between the cytogenetically closely located pairs CCR2/5 and CCR1/3. Datasets of mammalian orthologs for each gene were analyzed separately to minimize the potential confounding impact of analyzing highly similar sequences resulting from gene conversion events.</p> <p>Molecular evolution approaches and the software package Phylogenetic Analyses by Maximum Likelihood (PAML) were utilized to investigate the signature of selection that has acted on the mammalian CC chemokine receptor (<it>CCR</it>) gene family. The results of neutral vs. adaptive evolution (positive selection) hypothesis testing using Site Models are reported. In general, positive selection is defined by a ratio of nonsynonymous/synonymous nucleotide changes (dN/dS, or ω) >1.</p> <p>Results</p> <p>Of the ten mammalian CC motif chemokine receptor sequence datasets analyzed, only <it>CCR2 </it>and <it>CCR3 </it>contain amino acid codon sites that exhibit evidence of positive selection using site based hypothesis testing in PAML. Nineteen of the twenty codon sites putatively indentified as likely to be under positive selection code for amino acid residues located in extracellular domains of the receptor protein products.</p> <p>Conclusions</p> <p>These results suggest that amino acid residues present in intracellular and membrane-bound domains are more selectively constrained for functional signal transduction and homo- or heterodimerization, whereas amino acid residues in extracellular domains of these receptor proteins evolve more quickly, perhaps due to heightened selective pressure resulting from ligand-binding and pathogen interactions of extracellular domains.</p

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Investigating undergraduate health sciences students’ acceptance of evolution using MATE and GAENE

Abstract Background Despite the overwhelming agreement among scientists regarding the fundamental importance of evolution to all areas of biology, a lack of evolution understanding and acceptance has been reported in studies of students, educators, and members of society. In the present study, we investigate and report evolution acceptance in a population of undergraduate health sciences students enrolled in a first-year foundational biology course. Two published instruments—The Measure of Acceptance of the Theory of Evolution (MATE) and the Generalized Acceptance of Evolution Evaluation (GAENE)—were used to quantify evolution acceptance. A confirmatory factor analysis (CFA) was performed on both instruments to test whether the items measured the underlying construct sufficiently. Additionally, Rasch scaling was used to investigate fit between the data and the measurement model, and to determine if the MATE should be treated as a unidimensional or bidimensional instrument. Using correlation and regression analysis, we examined the relationships between the two measures of evolution acceptance, and between measures of evolution acceptance with other student variables of interest. Results The health sciences students in this study demonstrated high acceptance of evolution at the start of term, as well as a significant increase in evolution acceptance from pre- to post-test. CFA and Rasch scaling provided some evidence that the MATE is a bidimensional instrument, but considering MATE as a bidimensional instrument provided little additional insight compared to treating MATE as a unidimensional instrument. Measures of evolution acceptance resulting from the MATE and GAENE instruments were significantly and strongly correlated. Multiple regression modeling identified underrepresented minority status as a demographic variable predictive of evolution acceptance, and provided further evidence of the strong association between the MATE and GAENE instruments. Conclusions The undergraduate health sciences students in this study demonstrated a significant increase in evolution acceptance from pre- to post-test after one semester of instruction in general biology. Measures of evolution acceptance from the MATE and GAENE instruments were strongly correlated whether MATE was treated as a unidimensional or bidimensional instrument. This work provides initial indications that the MATE and GAENE instruments perform comparably as measures of evolution acceptance. Although the instruments are closely related, this work found more psychometric evidence for interpreting and using GAENE scores than MATE scores as a measure of evolution acceptance

Repurposing “old” blood tests to replace costly interim analysis/imaging of Hodgkin lymphoma in low and middle-income settings

PostprintPeer reviewe

Precision Electroweak Measurements on the Z resonance.

We report on the final electroweak measurements performed with data taken at the Z resonance by the experiments operating at the electron–positron colliders SLC and LEP. The data consist of 17 million Z decays accumulated by the ALEPH, DELPHI, L3 and OPAL experiments at LEP, and 600 thousand Z decays by the SLD experiment using a polarised beam at SLC. The measurements include cross-sections, forward–backward asymmetries and polarised asymmetries. The mass and width of the Z boson, mZ and ΓZ, and its couplings to fermions, for example the ρ parameter and the effective electroweak mixing angle for leptons, are precisely measured: The number of light neutrino species is determined to be 2.9840±0.0082, in agreement with the three observed generations of fundamental fermions. The results are compared to the predictions of the Standard Model (SM). At the Z-pole, electroweak radiative corrections beyond the running of the QED and QCD coupling constants are observed with a significance of five standard deviations, and in agreement with the Standard Model. Of the many Z-pole measurements, the forward–backward asymmetry in b-quark production shows the largest difference with respect to its SM expectation, at the level of 2.8 standard deviations. Through radiative corrections evaluated in the framework of the Standard Model, the Z-pole data are also used to predict the mass of the top quark, , and the mass of the W boson, . These indirect constraints are compared to the direct measurements, providing a stringent test of the SM. Using in addition the direct measurements of mt and mW, the mass of the as yet unobserved SM Higgs boson is predicted with a relative uncertainty of about 50% and found to be less than at 95% confidence level