Snagger: A user-friendly program for incorporating additional information for tagSNP selection

<p>Abstract</p> <p>Background</p> <p>There has been considerable effort focused on developing efficient programs for tagging single-nucleotide polymorphisms (SNPs). Many of these programs do not account for potential reduced genomic coverage resulting from genotyping failures nor do they preferentially select SNPs based on functionality, which may be more likely to be biologically important.</p> <p>Results</p> <p>We have developed a user-friendly and efficient software program, Snagger, as an extension to the existing open-source software, Haploview, which uses pairwise <it>r</it>²linkage disequilibrium between single nucleotide polymorphisms (SNPs) to select tagSNPs. Snagger distinguishes itself from existing SNP selection algorithms, including Tagger, by providing user options that allow for: (1) prioritization of tagSNPs based on certain characteristics, including platform-specific design scores, functionality (i.e., coding status), and chromosomal position, (2) efficient selection of SNPs across multiple populations, (3) selection of tagSNPs outside defined genomic regions to improve coverage and genotyping success, and (4) picking of surrogate tagSNPs that serve as backups for tagSNPs whose failure would result in a significant loss of data. Using HapMap genotype data from ten ENCODE regions and design scores for the Illumina platform, we show similar coverage and design score distribution and fewer total tagSNPs selected by Snagger compared to the web server Tagger.</p> <p>Conclusion</p> <p>Snagger improves upon current available tagSNP software packages by providing a means for researchers to select tagSNPs that reliably capture genetic variation across multiple populations while accounting for significant genotyping failure risk and prioritizing on SNP-specific characteristics.</p

A variable near-infrared counterpart to the neutron-star low-mass X-ray binary 4U 1705-440

We report the discovery of a near-infrared (nIR) counterpart to the persistent neutron-star low-mass X-ray binary 4U 1705-440, at a location consistent with its recently determined Chandra X-ray position. The nIR source is highly variable, with K_s-band magnitudes varying between 15.2 and 17.3 and additional J- and H-band observations revealing color variations. A comparison with contemporaneous X-ray monitoring observations shows that the nIR brightness correlates well with X-ray flux and X-ray spectral state. We also find possible indications for a change in the slope of the nIR/X-ray flux relation between different X-ray states. We discuss and test various proposed mechanisms for the nIR emission from neutron-star low-mass X-ray binaries and conclude that the nIR emission in 4U 1705-440 is most likely dominated by X-ray heating of the outer accretion disk and the secondary star.Comment: Accepted for publication in Ap

International Guillain-Barré Syndrome Outcome Study (IGOS): protocol of a prospective observational cohort study on clinical and biological predictors of disease course and outcome in Guillain-Barré syndrome

Guillain-Barré syndrome (GBS) is an acute polyradiculoneuropathy with a highly variable clinical presentation, course, and outcome. The factors that determine the clinical variation of GBS are poorly understood which complicates the care and treatment of individual patients. The protocol of the ongoing International GBS Outcome Study (IGOS), a prospective, observational, multi-centre cohort study that aims to identify the clinical and biological determinants and predictors of disease onset, subtype, course and outcome of GBS is presented here. Patients fulfilling the diagnostic criteria for GBS, regardless of age, disease severity, variant forms, or treatment, can participate if included within two weeks after onset of weakness. Information about demography, preceding infections, clinical features, diagnostic findings, treatment, course and outcome is collected. In addition, cerebrospinal fluid and serial blood samples for serum and DNA is collected at standard time points. The original aim was to include at least 1000 patients with a follow-up of 1-3 years. Data are collected via a web-based data entry system and stored anonymously. IGOS started in May 2012 and by January 2017 included more than 1400 participants from 143 active centres in 19 countries across 5 continents. The IGOS data/biobank is available for research projects conducted by expertise groups focusing on specific topics including epidemiology, diagnostic criteria, clinimetrics, electrophysiology, antecedent events, antibodies, genetics, prognostic modelling, treatment effects and long-term outcome of GBS. The IGOS will help to standardize the international collection of data and biosamples for future research of GBS. ClinicalTrials.gov Identifier: NCT01582763

The Nature and Conceptualisation of Career Transitions in Sport

First paragraph: While an athlete’s sports career may seem to develop in a smooth and continuous way from beginning to end, it is in fact characterized by specific phases and transitions. Asked to describe its development, athletes highlight their athletic career, for example, in terms of specific moments or situations which occurred throughout their career (Wylleman & De Knop, 1997a,b). These moments or situations do not only require athletes to cope with specific changes, but are also perceived by the athletes to influence the quality of their participation at their current competitive level. The occurrence of phases and transitions in the athletic career can also be illustrated by chronologically pin-pointing athletes’ sport achievements (e.g., a first national championship title) and selections (e.g., selection for the national team). Comparison of such developmental data has revealed many similarities in (elite) athletes’ athletic careers (Stambulova, 1998; Wylleman & De Knop, 1998): athletes start out in their sport at the ages of approximately 8 to 12 years-of-age; one or two years later athletes start competing at club level, and go, some three to four years later on to national level; a first selection for a national team occurs somewhere between 17-19 years-of-age, while a first Olympic selection is achieved during their early twenties; and finally, athletes do end their involvement in highlevel competitive sport at approximately 30 years-of-age (3). In fact, researchers have been able to identify a sequence of career developmental phases, not only with elite level athletes, but with talented performers in general, namely an initiation, a development, a mastery, and a post-career phase (e.g., Bloom, 1985; Salmela; 1994)

Polymorphisms in genes involved in estrogen and progesterone metabolism and mammographic density changes in women randomized to postmenopausal hormone therapy: results from a pilot study

INTRODUCTION: Mammographic density is a strong independent risk factor for breast cancer, and can be modified by hormonal exposures. Identifying genetic variants that determine increases in mammographic density in hormone users may be important in understanding hormonal carcinogenesis of the breast. METHODS: We obtained mammograms and DNA from 232 postmenopausal women aged 45 to 75 years who had participated in one of two randomized, double-blind clinical trials with estrogen therapy (104 women, taking 1 mg/day of micronized 17β-estradiol, E2), combined estrogen and progestin therapy (34 women, taking 17β-estradiol and 5 mg/day of medroxyprogesterone acetate for 12 days/month) or matching placebos (94 women). Mammographic percentage density (MPD) was measured on baseline and 12-month mammograms with a validated computer-assisted method. We evaluated polymorphisms in genes involved in estrogen metabolism (catechol-O-methyltransferase (COMT (Val158Met)), cytochrome P450 1B1 (CYP1B1 (Val432Leu)), UDP-glucuronosyltransferase 1A1 (UGT1A1 (<7/≥ 7 TA repeats))) and progesterone metabolism (aldo-keto reductase 1C4 (AKR1C4 (Leu311Val))) with changes in MPD. RESULTS: The adjusted mean change in MPD was +4.6% in the estrogen therapy arm and +7.2% in the combined estrogen and progestin therapy arm, compared with +0.02% in the placebo arm (P = 0.0001). None of the genetic variants predicted mammographic density changes in women using estrogen therapy. Both the AKR1C4 and the CYP1B1 polymorphisms predicted mammographic density change in the combined estrogen and progestin therapy group (P < 0.05). In particular, the eight women carrying one or two low-activity AKR1C4 Val alleles showed a significantly greater increase in MPD (16.7% and 29.3%) than women homozygous for the Leu allele (4.0%). CONCLUSION: Although based on small numbers, these findings suggest that the magnitude of the increase in mammographic density in women using combined estrogen and progestin therapy may be greater in those with genetically determined lower activity of enzymes that metabolize estrogen and progesterone

KAI407, a potent non-8-aminoquinoline compound that kills Plasmodium cynomolgi early dormant liver stage parasites in vitro.

Preventing relapses of Plasmodium vivax malaria through a radical cure depends on use of the 8-aminoquinoline primaquine, which is associated with safety and compliance issues. For future malaria eradication strategies, new, safer radical curative compounds that efficiently kill dormant liver stages (hypnozoites) will be essential. A new compound with potential radical cure activity was identified using a low-throughput assay of in vitro-cultured hypnozoite forms of Plasmodium cynomolgi (an excellent and accessible model for Plasmodium vivax). In this assay, primary rhesus hepatocytes are infected with P. cynomolgi sporozoites, and exoerythrocytic development is monitored in the presence of compounds. Liver stage cultures are fixed after 6 days and stained with anti-Hsp70 antibodies, and the relative proportions of small (hypnozoite) and large (schizont) forms relative to the untreated controls are determined. This assay was used to screen a series of 18 known antimalarials and 14 new non-8-aminoquinolines (preselected for blood and/or liver stage activity) in three-point 10-fold dilutions (0.1, 1, and 10 μM final concentrations). A novel compound, designated KAI407 showed an activity profile similar to that of primaquine (PQ), efficiently killing the earliest stages of the parasites that become either primary hepatic schizonts or hypnozoites (50% inhibitory concentration [IC50] for hypnozoites, KAI407, 0.69 μM, and PQ, 0.84 μM; for developing liver stages, KAI407, 0.64 μM, and PQ, 0.37 μM). When given as causal prophylaxis, a single oral dose of 100 mg/kg of body weight prevented blood stage parasitemia in mice. From these results, we conclude that KAI407 may represent a new compound class for P. vivax malaria prophylaxis and potentially a radical cure

The relationship between natural outdoor environments and cognitive functioning and its mediators

Background Urban residents may experience cognitive fatigue and little opportunity for mental restoration due to a lack of access to nature. Natural outdoor environments (NOE) are thought to be beneficial for cognitive functioning, but underlying mechanisms are not clear. Objectives To investigate the long-term association between NOE and cognitive function, and its potential mediators. Methods This cross-sectional study was based on adult participants of the Positive Health Effects of the Natural Outdoor Environment in Typical Populations in Different Regions in Europe (PHENOTYPE) project. Data were collected in Barcelona, Spain; Doetinchem, the Netherlands; and Stoke-on-Trent, United Kingdom. We assessed residential distance to NOE, residential surrounding greenness, perceived amount of neighborhood NOE, and engagement with NOE. Cognitive function was assessed with the Color Trails Test (CTT). Mediation analysis was undertaken following Baron and Kenny. Results Each 100 m increase in residential distance to NOE was associated with a longer CTT completion time of 1.50% (95% CI 0.13, 2.89). No associations were found for other NOE indicators and cognitive function. Neighborhood social cohesion was (marginally) significantly associated with both residential distance to NOE and CTT completion time, but no evidence for mediation was found. Nor were there indications for mediation by physical activity, social interaction with neighbors, loneliness, mental health, air pollution worries, or noise annoyance. Conclusions Our findings provide some indication that proximity to nature may benefit cognitive function. We could not establish which mechanisms may explain this relationship

Comparison of LDL fatty acid and carotenoid concentrations and oxidative resistance of LDL in volunteers from countries with different rates of cardiovascular disease

Within Europe there are differences in cardiovascular disease (CVD) risk between countries and this might be related to dietary habits. Oxidative modification of LDL is suggested to increase the risk of CVD and both the fatty acid and antioxidant content of LDL can affect its oxidation. In the present study, concentration of LDL fatty acid and antioxidant micronutrients (tocopherols and carotenoids) and ex vivo oxidative resistance of LDL (lag phase) was compared in volunteers from five countries with different fruit and vegetable intakes and reported rates of CVD. Eighty volunteers (forty males, forty females per centre), age range 25-45 years, were recruited from France, Northern Ireland, UK, Republic of Ireland, The Netherlands, and Spain, and their LDL composition and lag phase were measured. There were some differences in LDL carotenoid and α-tocopherol concentrations between countries. α-Tocopherol was low and β- + γ-tocopherol were high (P<0·001) in the Dutch subjects. β-Carotene concentrations were significantly different between the French and Spanish volunteers, with French showing the highest and Spanish the lowest concentration. LDL lycopene was not different between centres in contrast to lutein, which was highest in French (twofold that in the Dutch and Spanish and threefold that in Northern Ireland and the Republic of Ireland, P<0·001). However absolute LDL saturated, monounsaturated, polyunsaturated and total unsaturated fatty acid concentrations were different between countries (P<0·001, total unsaturated highest in Northern Ireland) there was little difference in unsaturated:saturated fatty acid concentration ratios and no difference in polyunsaturated:saturated fatty acid concentration ratios. LDL from the Republic of Ireland (a region with a high rate of CVD) had greater resistance to Cu-stimulated oxidation than samples obtained from volunteers in other countries. In conclusion, LDL composition did not predict resistance to Cu-stimulated oxidation, nor is there evidence that LDL from volunteers in countries with lower rates of CVD have greater resistance to oxidatio