A novel unstable duplication upstream of HAS2 predisposes to a breed-defining skin phenotype and a periodic fever syndrome in Chinese Shar-Pei dogs

Hereditary periodic fever syndromes are characterized by recurrent episodes of fever and inflammation with no known pathogenic or autoimmune cause. In humans, several genes have been implicated in this group of diseases, but the majority of cases remain unexplained. A similar periodic fever syndrome is relatively frequent in the Chinese Shar-Pei breed of dogs. In the western world, Shar-Pei have been strongly selected for a distinctive thick and heavily folded skin. In this study, a mutation affecting both these traits was identified. Using genome-wide SNP analysis of Shar-Pei and other breeds, the strongest signal of a breed-specific selective sweep was located on chromosome 13. The same region also harbored the strongest genome-wide association (GWA) signal for susceptibility to the periodic fever syndrome (p_raw = 2.3×10⁻⁶, p_genome = 0.01). Dense targeted resequencing revealed two partially overlapping duplications, 14.3 Kb and 16.1 Kb in size, unique to Shar-Pei and upstream of the Hyaluronic Acid Synthase 2 (HAS2) gene. HAS2 encodes the rate-limiting enzyme synthesizing hyaluronan (HA), a major component of the skin. HA is up-regulated and accumulates in the thickened skin of Shar-Pei. A high copy number of the 16.1 Kb duplication was associated with an increased expression of HAS2 as well as the periodic fever syndrome (p<0.0001). When fragmented, HA can act as a trigger of the innate immune system and stimulate sterile fever and inflammation. The strong selection for the skin phenotype therefore appears to enrich for a pleiotropic mutation predisposing these dogs to a periodic fever syndrome. The identification of HA as a major risk factor for this canine disease raises the potential of this glycosaminoglycan as a risk factor for human periodic fevers and as an important driver of chronic inflammation.     

Detection, properties, and frequency of local calcium release from the sarcoplasmic reticulum in teleost cardiomyocytes

Calcium release from the sarcoplasmic reticulum (SR) plays a central role in the regulation of cardiac contraction and rhythm in mammals and humans but its role is controversial in teleosts. Since the zebrafish is an emerging model for studies of cardiovascular function and regeneration we here sought to determine if basic features of SR calcium release are phylogenetically conserved. Confocal calcium imaging was used to detect spontaneous calcium release (calcium sparks and waves) from the SR. Calcium sparks were detected in 16 of 38 trout atrial myocytes and 6 of 15 ventricular cells. The spark amplitude was 1.45±0.03 times the baseline fluorescence and the time to half maximal decay of sparks was 27±3 ms. Spark frequency was 0.88 sparks µm⁻¹ min⁻¹ while calcium waves were 8.5 times less frequent. Inhibition of SR calcium uptake reduced the calcium transient (F/F₀) from 1.77±0.17 to 1.12±0.18 (p = 0.002) and abolished calcium sparks and waves. Moreover, elevation of extracellular calcium from 2 to 10 mM promoted early and delayed afterdepolarizations (from 0.6±0.3 min⁻¹ to 8.1±2.0 min⁻¹, p = 0.001), demonstrating the ability of SR calcium release to induce afterdepolarizations in the trout heart. Calcium sparks of similar width and duration were also observed in zebrafish ventricular myocytes. In conclusion, this is the first study to consistently report calcium sparks in teleosts and demonstrate that the basic features of calcium release through the ryanodine receptor are conserved, suggesting that teleost cardiac myocytes is a relevant model to study the functional impact of abnormal SR function.     

Ecology of phlebotomine sand flies in the rural community of Mont Rolland (Thiès region, Senegal): area of transmission of canine leishmaniasis

Background

Different epidemiological studies previously indicated that canine leishmaniasis is present in the region of Thiès (Senegal). However, the risks to human health, the transmission cycle and particularly the implicated vectors are unknown.

Methodology/Principal Findings

To improve our knowledge on the population of phlebotomine sand flies and the potential vectors of canine leishmaniasis, sand flies were collected using sticky traps, light traps and indoor spraying method using pyrethroid insecticides in 16 villages of the rural community of Mont Rolland (Thiès region) between March and July 2005. The 3788 phlebotomine sand flies we collected (2044 males, 1744 females) were distributed among 9 species of which 2 belonged to the genus Phlebotomus: P. duboscqi (vector of cutaneous leishmaniasis in Senegal) and P. rodhaini. The other species belonged to the genus Sergentomyia: S. adleri, S. clydei, S. antennata, S. buxtoni, S. dubia, S. schwetzi and S. magna. The number of individuals and the species composition differed according to the type of trap, suggesting variable, species-related degrees of endophily or exophily. The two species of the genus Phlebotomus were markedly under-represented in comparison to the species of the genus Sergentomyia. This study also shows a heterogeneous spatial distribution within the rural community that could be explained by the different ecosystems and particularly the soil characteristics of this community. Finally, the presence of the S. dubia species appeared to be significantly associated with canine leishmaniasis seroprevalence in dogs.

Conclusions/Significance

Our data allow us to hypothesize that the species of the genus Sergentomyia and particularly the species S. dubia and S. schwetzi might be capable of transmitting canine leishmaniasis. These results challenge the dogma that leishmaniasis is exclusively transmitted by species of the genus Phlebotomus in the Old World. This hypothesis should be more thoroughly evaluated.     

Mechanisms underlying the bioindicator notion: spatial association between individual sexual performance and community diversity

The bioindicator notion is an appealing concept that has received more support in applied than in basic ecology, mostly due to the difficulty in deriving general ecological rules applicable to all target organisms. However, recognizing the mechanisms that determine the association between a particular species and the well-being of many other species is important for understanding the functioning of ecosystems and the relationship among different biological levels. We examined here the processes at the individual level that cause an association between species performance and biodiversity value, by analyzing attributes that can be studied in a variety of animals with sexual reproduction, namely breeding site selection and condition-dependent sexual signals. Our study model was the Capercaillie, an indicator of forest functioning and diversity, and the associated bird community, used here as a surrogate of broader forest biodiversity. At a regional scale Capercaillie occurrence was not associated with the most diverse forest patches, but at the scale of male spring territories the sexual display grounds (arenas) were located in the oldest and less disturbed forest portions, which also hosted the richest local bird communities. Social mechanisms and conspecific cueing likely concurred with habitat-driven processes in determining the long-term persistence of traditional display grounds, which were appealing to many other species because of their structural composition. Characteristics of male vocal display that honestly advertize male quality (low frequencies and rapid song rates) were significantly correlated with high diversity values, resulting in a spatial association between individual and community performances. Costly or risky activities such as reproductive or social behaviors, which more than other attributes match gradients in habitat quality, are therefore contributing to functionally connect individuals with ecosystem health.     

Protective role of selenium in wheat seedlings subjected to enhanced UV-B radiation

Selenium (Se) is beneficial for some plants and is able to increase resistance and antioxidant capacity of plants subjected to stressful environment. In this work, the effects of enhanced ultraviolet-B (UV-B) radiation, Se supply, and their combination on growth and physiological traits of wheat (Triticum aestivum L., cv. Han NO.7086) seedlings were studied. The objective was to elucidate whether Se could alleviate the expected adverse effects of UV-B stress on seedlings. UV-B treatment caused a marked decline in growth parameters and total chlorophyll content and changed biomass allocation between aboveground and underground parts, which led to an increase in the root/shoot ratio. UV-B treatment also increased MDA content and the rate of superoxide radical (O₂^·−) production, although it increased some antioxidant (proline, phenolic compounds, and flavonoids) content and activity of antioxidant enzymes (peroxidase, superoxide dimutase, catalase (CAT)). Se treatment only increased total chlorophyll content and CAT activity. Compared with UV-B treatment alone, the combined treatment with UV-B and Se induced a significant increase in the biomass, total chlorophyll content, antioxidant content, and activity of antioxidant enzymes, and an evident decrease in MDA content and the rate of O₂^·− production. The results of this study demonstrated that Se alleviated the damage caused by UV-B to wheat seedlings to some extent by increasing antioxidant enzyme activity and antioxidant content.     

Dihydroartemisinin Exerts Its Anticancer Activity through Depleting Cellular Iron via Transferrin Receptor-1

Artemisinin and its main active metabolite dihydroartemisinin, clinically used antimalarial agents with low host toxicity, have recently shown potent anticancer activities in a variety of human cancer models. Although iron mediated oxidative damage is involved, the mechanisms underlying these activities remain unclear. In the current study, we found that dihydroartemisinin caused cellular iron depletion in time- and concentration-dependent manners. It decreased iron uptake and disturbed iron homeostasis in cancer cells, which were independent of oxidative damage. Moreover, dihydroartemisinin reduced the level of transferrin receptor-1 associated with cell membrane. The regulation of dihydroartemisinin to transferrin receptor-1 could be reversed by nystatin, a cholesterol-sequestering agent but not the inhibitor of clathrin-dependent endocytosis. Dihydroartemisinin also induced transferrin receptor-1 palmitoylation and colocalization with caveolin-1, suggesting a lipid rafts mediated internalization pathway was involved in the process. Also, nystatin reversed the influences of dihydroartemisinin on cell cycle and apoptosis related genes and the siRNA induced downregulation of transferrin receptor-1 decreased the sensitivity to dihydroartemisinin efficiently in the cells. These results indicate that dihydroartemisinin can counteract cancer through regulating cell-surface transferrin receptor-1 in a non-classical endocytic pathway, which may be a new action mechanism of DHA independently of oxidative damage.     

Reproductive toxicity in boron exposed workers in Bandirma, Turkey

Boric acid and sodium borates have been considered as being “toxic to reproduction and development”, following results of animal studies with high doses. However unfavorable effects of boron exposure on reproduction and development have not been proved in epidemiological studies so far. The aim of the present study was to investigate the reproductive toxicity indicators in highly exposed workers employed in a boric acid production plant in Band?rma, Turkey. Two hundred and four workers participated in this study. The mean blood boron concentration of the high exposure group of workers was 223.89 ± 69.49 (152.82–454.02) ng/g. Unfavorable effects of boron exposure on the reproductive toxicity indicators were not observed.