The evolution of XY recombination: sexually antagonistic selection versus deleterious mutation load.

Recombination arrest between X and Y chromosomes, driven by sexually antagonistic genes, is expected to induce their progressive differentiation. However, in contrast to birds and mammals (which display the predicted pattern), most cold-blooded vertebrates have homomorphic sex chromosomes. Two main hypotheses have been proposed to account for this, namely high turnover rates of sex-determining systems and occasional XY recombination. Using individual-based simulations, we formalize the evolution of XY recombination (here mediated by sex reversal; the "fountain-of-youth" model) under the contrasting forces of sexually antagonistic selection and deleterious mutations. The shift between the domains of elimination and accumulation occurs at much lower selection coefficients for the Y than for the X. In the absence of dosage compensation, mildly deleterious mutations accumulating on the Y depress male fitness, thereby providing incentives for XY recombination. Under our settings, this occurs via "demasculinization" of the Y, allowing recombination in XY (sex-reversed) females. As we also show, this generates a conflict with the X, which coevolves to oppose sex reversal. The resulting rare events of XY sex reversal are enough to purge the Y from its load of deleterious mutations. Our results support the "fountain of youth" as a plausible mechanism to account for the maintenance of sex-chromosome homomorphy.

Main results of the Monte Carlo studies carried out for nuclear medicine practices within the ORAMED project

The aim of ORAMED work package 4 was the optimization of the medical practices in nuclear medicine during the preparation of radiopharmaceuticals and their administration to the patient. During the project a wide campaign of measurements was performed in the nuclear medicine departments of the collaborating hospitals. Such data were intrinsically characterized by a large variability that depended on the procedure, the employed techniques and the operator's habits. That variability could easily hide some important parameter, for example, the effectiveness of the adopted shielding (for syringe and vial) or the effect of the distances from the source. This information is necessary for a valuable optimization purpose of radiation protection. To this end a sensitivity analysis was carried out through Monte Carlo simulations employing voxel models, representing operator's hand during the considered practices. Such analysis allowed understanding at what extent the range of personal dose equivalent evaluated during measurements can be considered intrinsically related to the procedures. Furthermore, with the Monte Carlo simulations it was possible to study the appropriateness of the shielding usually utilized in these practices.

Studying the micro-angels approach to micro-investment decisions

Purpose: The paper analyzes the micro-angels investment behaviour, looking both to the criteria used in the selection of their investment projects and to the characteristics of their guidance role during the investment period. Design/Methodology/Approach: The paper focuses on a double bottom line movement of French micro-angels clubs that has been operating since 1983. Our primary source of data is an online survey carried out during March 2012, asking members of clubs all over France for different aspects of their procedures. Findings: Our findings suggest that micro-angels are interested in small, socially or environmentally friendly projects having the potential to contribute to the development of their neighbourhood. We find that women are even more interested than men in such projects. Educated micro-angels value entrepreneurial motivation and understanding of the project more than less-educated micro-angels. We also point out the factors that micro-angels consider important in accompanying enterprises. Here we find that gender makes little difference. However, retired micro-angels value financial diagnosis made conjointly with entrepreneurs, while both active micro-angels and educated micro-angels value more the use of their network to help micro-entrepreneurs. Practical/Social Implications: Given the potential benefits of micro-angels investing and guiding the development of micro-enterprises, a social micro-angel investment on a major scale in developing countries could help in tackling some of the problems faced by the development of microfinance, such as the over-indebtedness of micro-entrepreneurs. Practitioners and new initiatives would gain from understanding what adaptations need to be made. Originality/value: We expect to add to the venture capital theory to take into account non-economic motives.

Contribution of major cardiovascular risk factors to familial premature coronary artery disease: the GENECARD project.

OBJECTIVES: This study was designed to assess the prevalence of major cardiovascular risk factors in familial premature coronary artery disease (P-CAD), affecting two or more siblings within one sibship. BACKGROUND: Premature CAD has a genetic component. It remains to be established whether familial P-CAD is due to genes acting independently from major cardiovascular risk factors. METHODS: We recruited 213 P-CAD survivors from 103 sibships diagnosed before age <or=50 (men) or <or=55 (women) years old. Hypertension, hypercholesterolemia, obesity, and smoking were documented at the time of the event in 163 patients (145 men and 18 women). Each patient was compared with two individuals of the same age and gender, diagnosed with sporadic (nonfamilial) P-CAD, and three individuals randomly sampled from the general population. RESULTS: Compared with the general population, patients with sporadic P-CAD had a higher prevalence of hypertension (29% vs. 14%, p < 0.001), hypercholesterolemia (54% vs. 33%, p < 0.001), obesity (20% vs. 13%, p < 0.01), and smoking (76% vs. 39%, p < 0.001). These risk factors were equally or even more prevalent in patients with familial P-CAD (43% [p < 0.05 vs. sporadic P-CAD], 58% [p = 0.07], 21% and 72%, respectively). Overall, only 7 (4%) of 163 of patients with familial P-CAD and 22 (7%) of 326 of patients with sporadic P-CAD had none of these conditions, as compared with 167 (34%) of 489 patients in the general population. CONCLUSIONS: Classic, remediable risk factors are highly prevalent in patients with familial P-CAD. Accordingly, a major contribution of genes acting in the absence of these risk factors is unlikely.

Development of a Manual Crack Quantification and Automated Crack Measurment System, Project TR-457 Final Report, 2005

Final report produced by DOT on development of manual crack quantification and automatic crack measurment system.

Optimal Usage of De-Icing Chemicals when Scraping Ice, Final Report of Project HR 391, 2003

Optimal Usage of De-Icing Chemicals when Scraping Ice, Final Report of Project HR 391

Inter-rater agreement and reliability of the COSMIN (COnsensus-based Standards for the selection of health status Measurement Instruments) Checklist

Background: The COSMIN checklist is a tool for evaluating the methodological quality of studies on measurement properties of health-related patient-reported outcomes. The aim of this study is to determine the inter-rater agreement and reliability of each item score of the COSMIN checklist (n = 114). Methods: 75 articles evaluating measurement properties were randomly selected from the bibliographic database compiled by the Patient-Reported Outcome Measurement Group, Oxford, UK. Raters were asked to assess the methodological quality of three articles, using the COSMIN checklist. In a one-way design, percentage agreement and intraclass kappa coefficients or quadratic-weighted kappa coefficients were calculated for each item. Results: 88 raters participated. Of the 75 selected articles, 26 articles were rated by four to six participants, and 49 by two or three participants. Overall, percentage agreement was appropriate (68% was above 80% agreement), and the kappa coefficients for the COSMIN items were low (61% was below 0.40, 6% was above 0.75). Reasons for low inter-rater agreement were need for subjective judgement, and accustom to different standards, terminology and definitions.Conclusions: Results indicated that raters often choose the same response option, but that it is difficult on item level to distinguish between articles. When using the COSMIN checklist in a systematic review, we recommend getting some training and experience, completing it by two independent raters, and reaching consensus on one final rating. Instructions for using the checklist are improved.

Distribution of events of positive selection and population differentiation in a metabolic pathway: the case of asparagine N-glycosylation

Background: Asparagine N-Glycosylation is one of the most important forms of protein post-translational modification in eukaryotes. This metabolic pathway can be subdivided into two parts: an upstream sub-pathway required for achieving proper folding for most of the proteins synthesized in the secretory pathway, and a downstream sub-pathway required to give variability to trans-membrane proteins, and involved in adaptation to the environment andinnate immunity. Here we analyze the nucleotide variability of the genes of this pathway in human populations, identifying which genes show greater population differentiation and which genes show signatures of recent positive selection. We also compare how these signals are distributed between the upstream and the downstream parts of the pathway, with the aim of exploring how forces of population differentiation and positive selection vary among genes involved in the same metabolic pathway but subject to different functional constraints. Results:Our results show that genes in the downstream part of the pathway are more likely to show a signature of population differentiation, while events of positive selection are equally distributed among the two parts of the pathway. Moreover, events of positive selection arefrequent on genes that are known to be at bifurcation points, and that are identified as beingin key position by a network-level analysis such as MGAT3 and GCS1.Conclusions: These findings indicate that the upstream part of the Asparagine N-Glycosylation pathway has lower diversity among populations, while the downstream part is freer to tolerate diversity among populations. Moreover, the distribution of signatures of population differentiation and positive selection can change between parts of a pathway, especially between parts that are exposed to different functional constraints. Our results support the hypothesis that genes involved in constitutive processes can be expected to show lower population differentiation, while genes involved in traits related to the environment should show higher variability. Taken together, this work broadens our knowledge on how events of population differentiation and of positive selection are distributed among different parts of a metabolic pathway.

Signatures of selection in the human olfactory receptor OR5I1 gene

The human olfactory receptor repertoire is reduced in comparison to other mammalsand to other non-human primates. Nonetheless, this olfactory decline opens an opportunity forevolutionary innovation and improvement. In the present study, we focus on an olfactoryreceptor gene, OR5I1, which had previously been shown to present an excess of amino acidreplacement substitutions between humans and chimpanzees. We analyze the geneticvariation in OR5I1 in a large worldwide human panel and find an excess of derived allelessegregating at relatively high frequencies in all populations. Additional evidence for selectionincludes departures from neutrality in allele frequency spectra tests but no unusually extendedhaplotype structure. Moreover, molecular structural inference suggests that one of thenonsynonymous polymorphisms defining the presumably adaptive protein form of OR5I1may alter the functional binding properties of the olfactory receptor. These results arecompatible with positive selection having modeled the pattern of variation found in the OR5I1gene and with a relatively ancient, mild selective sweep predating the “Out of Africa”expansion of modern humans.

EGASP: the human ENCODE Genome Annotation Assessment Project

Background: We present the results of EGASP, a community experiment to assess the state-ofthe-art in genome annotation within the ENCODE regions, which span 1% of the human genomesequence. The experiment had two major goals: the assessment of the accuracy of computationalmethods to predict protein coding genes; and the overall assessment of the completeness of thecurrent human genome annotations as represented in the ENCODE regions. For thecomputational prediction assessment, eighteen groups contributed gene predictions. Weevaluated these submissions against each other based on a ‘reference set’ of annotationsgenerated as part of the GENCODE project. These annotations were not available to theprediction groups prior to the submission deadline, so that their predictions were blind and anexternal advisory committee could perform a fair assessment.Results: The best methods had at least one gene transcript correctly predicted for close to 70%of the annotated genes. Nevertheless, the multiple transcript accuracy, taking into accountalternative splicing, reached only approximately 40% to 50% accuracy. At the coding nucleotidelevel, the best programs reached an accuracy of 90% in both sensitivity and specificity. Programsrelying on mRNA and protein sequences were the most accurate in reproducing the manuallycurated annotations. Experimental validation shows that only a very small percentage (3.2%) of the selected 221 computationally predicted exons outside of the existing annotation could beverified.Conclusions: This is the first such experiment in human DNA, and we have followed thestandards established in a similar experiment, GASP1, in Drosophila melanogaster. We believe theresults presented here contribute to the value of ongoing large-scale annotation projects and shouldguide further experimental methods when being scaled up to the entire human genome sequence.

Development of a Method to Determine Pavement Damage Due to Detours, Project 02-105, Apirl 2005

The research presented in this report provides the basis for the development of a new procedure to be used by the Iowa DOT and cities and counties in the state to deal with detours. Even though the project initially focused on investigating new tools to determine condition and compensation, the focus was shifted to traffic and the gas tax method to set the basis for the new procedure. It was concluded that the condition-based approach, even though accurate and consistent condition evaluations can be achieved, is not feasible or cost effective because of the current practices of data collection (two-year cycle) and also the logistics of the procedure (before and after determination). The gas tax method provides for a simple, easy to implement, and consistent approach to dealing with compensation for use of detours. It removes the subjectivity out of the current procedures and provides for a more realistic (traffic based) approach to the compensation determination.

Early maternal investment in mice: no evidence for compatible-genes sexual selection despite hybrid vigor.

Confronting a recently mated female with a strange male can induce a pregnancy block ('Bruce effect'). The physiology of this effect is well studied, but its functional significance is still not fully understood. The 'anticipated infanticide hypothesis' suggests that the pregnancy block serves to avoid the cost of embryogenesis and giving birth to offspring that are likely to be killed by a new territory holder. Some 'compatible-genes sexual selection hypotheses' suggest that the likelihood of a pregnancy block is also dependent on the female's perception of the stud's and the stimulus male's genetic quality. We used two inbred strains of mice (C57BL/6 and BALB/c) to test all possible combinations of female strain, stud strain, and stimulus strain under experimental conditions (N(total) = 241 mated females). As predicted from previous studies, we found increased rates of pregnancy blocks if stud and stimulus strains differed, and we found evidence for hybrid vigour in offspring of between-strain mating. Despite the observed heterosis, pregnancies of within-strain matings were not more likely to be blocked than pregnancies of between-strain matings. A power analysis revealed that if we missed an existing effect (type-II error), the effect must be very small. If a female gave birth, the number and weight of newborns were not significantly influenced by the stimulus males. In conclusion, we found no support for the 'compatible-genes sexual selection hypotheses'.

Synthesis of Best Practice for Increasing Protection and Visibility of Highway Maintenance Vehicles, CTRE Final Report Iowa DOT Project TR-475, August 2002

The purpose of this research project is to study current practices in enhancing visibility and protection of highway maintenance vehicles involved in moving operations such as snow removal and shoulder operations, crack sealing, and pothole patching. The results will enable the maintenance staff to adequately assess the applicability and impact of each strategy to their use and budget. The report’s literature review chapter examines the use of maintenance vehicle warning lights, retroreflective tapes, shadow vehicles and truck-mounted attenuators, and advanced vehicle control systems, as well as other practices to improve visibility for both snowplow operators and vehicles. The chapter concludes that the Manual on Uniform Traffic Control Devices does not specify what color or kind of warning lights to use. Thus, a wide variety of lights are being used on maintenance vehicles. The study of the relevant literatures also suggests that there are no clear guidelines for moving work zones at this time. Two types of surveys were conducted to determine current practices to improve visibility and safety in moving work zones across the country and in the state of Iowa. In the first survey of state departments of transportation, most indicated using amber warning lights on their maintenance vehicles. Almost all the responding states indicated using some form of reflective material on their vehicles to make them more visible. Most participating states indicated that the color of their vehicles is orange. Most states indicated using more warning lights on snow removal vehicles than their other maintenance vehicles. All responding state agencies indicated using shadow vehicles and/or truck-mounted attenuators during their moving operations. In the second survey of Iowa counties, most indicated using very similar traffic control and warning devices during their granular road maintenance and snow removal operations. Mounting warning signs and rotating or strobe lights on the rear of maintenance vehicles is common for Iowa counties. The most common warning devices used during the counties’ snow removal operations are reflective tapes, warning flags, strobe lights, and auxiliary headlamps.

Design and evaluation of a panel os single-nucleotide polymorphisms in microRNA genomic regions for association studies in human disease

MicroRNAs (miRNA) are recognized posttranscriptional gene repressors involved in the control of almost every biological process. Allelic variants in these regions may be an important source of phenotypic diversity and contribute to disease susceptibility. We analyzed the genomic organization of 325 human miRNAs (release 7.1, miRBase) to construct a panel of 768 single-nucleotide polymorphisms (SNPs) covering approximately 1 Mb of genomic DNA, including 131 isolated miRNAs (40%) and 194 miRNAs arranged in 48 miRNA clusters, as well as their 5-kb flanking regions. Of these miRNAs, 37% were inside known protein-coding genes, which were significantly associated with biological functions regarding neurological, psychological or nutritional disorders. SNP coverage analysis revealed a lower SNP density in miRNAs compared with the average of the genome, with only 24 SNPs located in the 325 miRNAs studied. Further genotyping of 340 unrelated Spanish individuals showed that more than half of the SNPs in miRNAs were either rare or monomorphic, in agreement with the reported selective constraint on human miRNAs. A comparison of the minor allele frequencies between Spanish and HapMap population samples confirmed the applicability of this SNP panel to the study of complex disorders among the Spanish population, and revealed two miRNA regions, hsa-mir-26a-2 in the CTDSP2 gene and hsa-mir-128-1 in the R3HDM1 gene, showing geographical allelic frequency variation among the four HapMap populations, probably because of differences in natural selection. The designed miRNA SNP panel could help to identify still hidden links between miRNAs and human disease.

Evolutionary analysis of genes of two pathways involved in placental malaria infection

Placental malaria is a special form of malaria that causes up to 200,000 maternal and infant deaths every year. Previous studies show that two receptor molecules, hyaluronic acid and chondroitin sulphate A, are mediating the adhesion of parasite-infected erythrocytes in the placenta of patients, which is believed to be a key step in the pathogenesis of the disease. In this study, we aimed at identifying sites of malaria-induced adaptation by scanning for signatures of natural selection in 24 genes in the complete biosynthesis pathway of these two receptor molecules. We analyzed a total of 24 Mb of publicly available polymorphism data from the International HapMap project for three human populations with European, Asian and African ancestry, with the African population from a region of presently and historically high malaria prevalence. Using the methods based on allele frequency distributions, genetic differentiation between populations, and on long-range haplotype structure, we found only limited evidence for malaria-induced genetic adaptation in this set of genes in the African population; however, we identified one candidate gene with clear evidence of selection in the Asian population. Although historical exposure to malaria in this population cannot be ruled out, we speculate that it might be caused by other pathogens, as there is growing evidence that these molecules are important receptors in a variety of host-pathogen interactions. We propose to use the present methods in a systematic way to help identify candidate regions under positive selection as a consequence of malaria.