Quantitative cross-species extrapolation between humans and fish: The case of the anti-depressant fluoxetine

This article has been made available through the Brunel Open Access Publishing Fund.Fish are an important model for the pharmacological and toxicological characterization of human pharmaceuticals in drug discovery, drug safety assessment and environmental toxicology. However, do fish respond to pharmaceuticals as humans do? To address this question, we provide a novel quantitative cross-species extrapolation approach (qCSE) based on the hypothesis that similar plasma concentrations of pharmaceuticals cause comparable target-mediated effects in both humans and fish at similar level of biological organization (Read-Across Hypothesis). To validate this hypothesis, the behavioural effects of the anti-depressant drug fluoxetine on the fish model fathead minnow (Pimephales promelas) were used as test case. Fish were exposed for 28 days to a range of measured water concentrations of fluoxetine (0.1, 1.0, 8.0, 16, 32, 64 μg/L) to produce plasma concentrations below, equal and above the range of Human Therapeutic Plasma Concentrations (HTPCs). Fluoxetine and its metabolite, norfluoxetine, were quantified in the plasma of individual fish and linked to behavioural anxiety-related endpoints. The minimum drug plasma concentrations that elicited anxiolytic responses in fish were above the upper value of the HTPC range, whereas no effects were observed at plasma concentrations below the HTPCs. In vivo metabolism of fluoxetine in humans and fish was similar, and displayed bi-phasic concentration-dependent kinetics driven by the auto-inhibitory dynamics and saturation of the enzymes that convert fluoxetine into norfluoxetine. The sensitivity of fish to fluoxetine was not so dissimilar from that of patients affected by general anxiety disorders. These results represent the first direct evidence of measured internal dose response effect of a pharmaceutical in fish, hence validating the Read-Across hypothesis applied to fluoxetine. Overall, this study demonstrates that the qCSE approach, anchored to internal drug concentrations, is a powerful tool to guide the assessment of the sensitivity of fish to pharmaceuticals, and strengthens the translational power of the cross-species extrapolation

Morbidity associated with "self-rated health" in epithelial ovarian cancer survivors

<p>Abstract</p> <p>Background</p> <p>Epithelial ovarian cancer survivors (EOCSs) frequently report multiple complaints after their treatment. The objective was to study somatic and mental morbidity in EOCSs associated with their Self- Rated Health (SRH) assessed by a single item.</p> <p>Findings were compared to age-matched controls from the general population.</p> <p>Methods</p> <p>In a cross -sectional follow-up design 189/287 (66%) EOCSs treated at The Norwegian Radiumhospital 1979–2003 responded to a mailed questionnaire on demographic data, and somatic and mental morbidity. SRH last week was rated on item #29 of the European Organization and Treatment of Cancer Quality of Life Questionnaire in 84/189 (97%) of responding EOCSs. For comparisons "good" and "poor" SRH groups were defined by the median score on the SRH item.</p> <p>Results</p> <p>EOCSs with "poor SRH" had higher level of somatic symptoms, anxiety, depression and fatigue than those with "good SRH" (p < .001). In multivariate analyses somatic symptoms, age and fatigue, were significantly associated with the SRH score in EOCSs, but not the cancer-related variables (FIGO stage, recurrence in < 6 months or chemotherapy ever). The model explained 70% of the variance in SRH in linear and 77% in logistic regression analyses. The distribution of the SRH scores in EOCSs did not differ significantly from that of normative controls; however a higher proportion of controls recorded a high SRH score.</p> <p>Conclusion</p> <p>SRH is strongly related to common somatic complaints, impairment and fatigue but not to cancer-related variables. A single question concerning SRH last week might be a quick screening method for collecting important information on symptoms in EOCSs, in addition to cancer – related questions.</p

Genome\u2011wide diversity and runs of homozygosity in the \u201cBraque Fran\ue7ais, type Pyr\ue9n\ue9es\u201d dog breed

Objective: Braque Fran\uc3\ua7ais, type Pyr\uc3\ua9n\uc3\ua9es is a French hunting-dog breed whose origin is traced back to old pointing gun-dogs used to assist hunters in finding and retrieving game. This breed is popular in France, but seldom seen elsewhere. Despite the ancient background, the literature on its genetic characterization is surprisingly scarce. A recent study looked into the demography and inbreeding using pedigree records, but there is yet no report on the use of molecular markers in this breed. The aim of this work was to genotype a population of Braque Fran\uc3\ua7ais, type Pyr\uc3\ua9n\uc3\ua9es dogs with the high-density SNP array to study the genomic diversity of the breed. Results: The average observed (HO) and expected (HE) heterozygosity were 0.371 (\uc2\ub1 0.142) and 0.359 (\uc2\ub1 0.124). Effective population size (NE) was 27.5635 runs of homozygosity (ROH) were identified with average length of 2.16 MB. A ROH shared by 75% of the dogs was detected at the beginning of chromosome 22. Inbreeding coefficients from marker genotypes were in the range FIS= [- 0.127, 0.172]. Inbreeding estimated from ROH (FROH) had mean 0.112 (\uc2\ub1 0.023), with range [0.0526, 0.225]. These results show that the Braque Fran\uc3\ua7ais, type Pyr\uc3\ua9n\uc3\ua9es breed is a relatively inbred population, but with still sufficient genetic variability for conservation and genetic improvement

The longitudinal relationship between job mobility, perceived organizational justice, and health

<p>Abstract</p> <p>Background</p> <p>The main purpose of the present study was to examine the 2-year longitudinal and reciprocal relationship between job mobility and health and burnout. A second aim was to elucidate the effects of perceived organizational justice and turnover intentions on the relationship between job mobility (non-, internally and externally mobile), and health (SF-36) and burnout (CBI).</p> <p>Methods</p> <p>The study used questionnaire data from 662 Swedish civil servants and the data were analysed with Structural Equation Modeling statistical methods.</p> <p>Results</p> <p>The results showed that job mobility was a better predictor of health and burnout, than health and burnout were as predictors of job mobility. The predictive effects were most obvious for psychosocial health and burnout, but negligible as far as physical health was concerned. Organizational justice was found to have a direct impact on health, but not on job mobility; whereas turnover intentions had a direct effect on job mobility.</p> <p>Conclusion</p> <p>The predictive relationship between job mobility and health has practical implications for health promotive actions in different organizations.</p

Single-copy nuclear genes resolve the phylogeny of the holometabolous insects

Background: Evolutionary relationships among the 11 extant orders of insects that undergo complete metamorphosis, called Holometabola, remain either unresolved or contentious, but are extremely important as a context for accurate comparative biology of insect model organisms. The most phylogenetically enigmatic holometabolan insects are Strepsiptera or twisted wing parasites, whose evolutionary relationship to any other insect order is unconfirmed. They have been controversially proposed as the closest relatives of the flies, based on rDNA, and a possible homeotic transformation in the common ancestor of both groups that would make the reduced forewings of Strepsiptera homologous to the reduced hindwings of Diptera. Here we present evidence from nucleotide sequences of six single-copy nuclear protein coding genes used to reconstruct phylogenetic relationships and estimate evolutionary divergence times for all holometabolan orders. Results: Our results strongly support Hymenoptera as the earliest branching holometabolan lineage, the monophyly of the extant orders, including the fleas, and traditionally recognized groupings of Neuropteroidea and Mecopterida. Most significantly, we find strong support for a close relationship between Coleoptera (beetles) and Strepsiptera, a previously proposed, but analytically controversial relationship. Exploratory analyses reveal that this relationship cannot be explained by long-branch attraction or other systematic biases. Bayesian divergence times analysis, with reference to specific fossil constraints, places the origin of Holometabola in the Carboniferous (355 Ma), a date significantly older than previous paleontological and morphological phylogenetic reconstructions. The origin and diversification of most extant insect orders began in the Triassic, but flourished in the Jurassic, with multiple adaptive radiations producing the astounding diversity of insect species for which these groups are so well known. Conclusion: These findings provide the most complete evolutionary framework for future comparative studies on holometabolous model organisms and contribute strong evidence for the resolution of the 'Strepsiptera problem', a long-standing and hotly debated issue in insect phylogenetics

Early Palaeozoic ocean anoxia and global warming driven by the evolution of shallow burrowing

The evolution of burrowing animals forms a defining event in the history of the Earth. It has been hypothesised that the expansion of seafloor burrowing during the Palaeozoic altered the biogeochemistry of the oceans and atmosphere. However, whilst potential impacts of bioturbation on the individual phosphorus, oxygen and sulphur cycles have been considered, combined effects have not been investigated, leading to major uncertainty over the timing and magnitude of the Earth system response to the evolution of bioturbation. Here we integrate the evolution of bioturbation into the COPSE model of global biogeochemical cycling, and compare quantitative model predictions to multiple geochemical proxies. Our results suggest that the advent of shallow burrowing in the early Cambrian contributed to a global low-oxygen state, which prevailed for ~100 million years. This impact of bioturbation on global biogeochemistry likely affected animal evolution through expanded ocean anoxia, high atmospheric CO2 levels and global warming

Seasonal variation in objectively measured physical activity, sedentary time, cardio-respiratory fitness and sleep duration among 8–11 year-old Danish children: a repeated-measures study

Abstract Background Understanding fluctuations in lifestyle indicators is important to identify relevant time periods to intervene in order to promote a healthy lifestyle; however, objective assessment of multiple lifestyle indicators has never been done using a repeated-measures design. The primary aim was, therefore, to examine between-season and within-week variation in physical activity, sedentary behaviour, cardio-respiratory fitness and sleep duration among 8–11 year-old children. Methods A total of 1021 children from nine Danish schools were invited to participate and 834 accepted. Due to missing data, 730 children were included in the current analytical sample. An accelerometer was worn for 7 days and 8 nights during autumn, winter and spring, from which physical activity, sedentary time and sleep duration were measured. Cardio-respiratory fitness was assessed using a 10-min intermittent running test. Results The children had 5% more sedentary time, 23% less time in moderate-to-vigorous physical activity and 2% longer sleep duration during winter compared to spring and cardio-respiratory fitness was 4% higher during spring compared to autumn (P < 0.001). Sedentary time was higher and total physical activity, moderate-to-vigorous physical activity and sleep duration (boys only) were lower during weekends at all seasons (P ≤ 0.01). Intraclass correlation coefficients between seasons ranged from 0.47-0.74, leaving 45-78% to seasonal variation. Conclusions Overall, sedentary time was higher and physical activity lower during winter and during weekends. The most accurate and unbiased estimates of physical activity came from autumn; however, the considerable intra-individual variation suggests that a single measurement may not adequately characterise children’s habitual sleep and activity

Analysis of a viral metagenomic library from 200 m depth in Monterey Bay, California constructed by direct shotgun cloning

<p>Abstract</p> <p>Background</p> <p>Viruses have a profound influence on both the ecology and evolution of marine plankton, but the genetic diversity of viral assemblages, particularly those in deeper ocean waters, remains poorly described. Here we report on the construction and analysis of a viral metagenome prepared from below the euphotic zone in a temperate, eutrophic bay of coastal California.</p> <p>Methods</p> <p>We purified viruses from approximately one cubic meter of seawater collected from 200m depth in Monterey Bay, CA. DNA was extracted from the virus fraction, sheared, and cloned with no prior amplification into a plasmid vector and propagated in <it>E. coli </it>to produce the MBv200m library. Random clones were sequenced by the Sanger method. Sequences were assembled then compared to sequences in GenBank and to other viral metagenomic libraries using BLAST analyses.</p> <p>Results</p> <p>Only 26% of the 881 sequences remaining after assembly had significant (E ≤ 0.001) BLAST hits to sequences in the GenBank nr database, with most being matches to bacteria (15%) and viruses (8%). When BLAST analysis included environmental sequences, 74% of sequences in the MBv200m library had a significant match. Most of these hits (70%) were to microbial metagenome sequences and only 0.7% were to sequences from viral metagenomes. Of the 121 sequences with a significant hit to a known virus, 94% matched bacteriophages (Families <it>Podo</it>-, <it>Sipho</it>-, and <it>Myoviridae</it>) and 6% matched viruses of eukaryotes in the Family <it>Phycodnaviridae </it>(5 sequences) or the Mimivirus (2 sequences). The largest percentages of hits to viral genes of known function were to those involved in DNA modification (25%) or structural genes (17%). Based on reciprocal BLAST analyses, the MBv200m library appeared to be most similar to viral metagenomes from two other bays and least similar to a viral metagenome from the Arctic Ocean.</p> <p>Conclusions</p> <p>Direct cloning of DNA from diverse marine viruses was feasible and resulted in a distribution of virus types and functional genes at depth that differed in detail, but were broadly similar to those found in surface marine waters. Targeted viral analyses are useful for identifying those components of the greater marine metagenome that circulate in the subcellular size fraction.</p