Up-regulation of ryanodine receptor expression increases the calcium-induced calcium release and spontaneous calcium signals in cerebral arteries from hindlimb unloaded rats

Microgravity induces a redistribution of blood volume. Consequently, astronauts' body pressure is modified so that the upright blood pressure gradient is abolished, thereby inducing a modification in cerebral blood pressure. This effect is mimicked in the hindlimb unloaded rat model. After a duration of 8 days of unloading, Ca²⁺ signals activated by depolarization and inositol-1,4,5-trisphosphate intracellular release were increased in cerebral arteries. In the presence of ryanodine and thapsigargin, the depolarization-induced Ca²⁺ signals remained increased in hindlimb suspended animals, indicating that Ca²⁺ influx and Ca²⁺-induced Ca²⁺ release mechanism were both increased. Spontaneous Ca²⁺ waves and localized Ca²⁺ events were also investigated. Increases in both amplitude and frequency of spontaneous Ca²⁺ waves were measured in hindlimb suspension conditions. After pharmacological segregation of Ca²⁺ sparks and Ca²⁺ sparklets, their kinetic parameters were characterized. Hindlimb suspension induced an increase in the frequencies of both Ca²⁺ localized events, suggesting an increase of excitability. Labeling with bodipy compounds suggested that voltage-dependent Ca²⁺ channels and ryanodine receptor expressions were increased. Finally, the expression of the ryanodine receptor subtype 1 (RyR1) was increased in hindlimb unloading conditions. Taken together, these results suggest that RyR1 expression and voltage-dependent Ca²⁺ channels activity are the focal points of the regulation of Ca²⁺ signals activated by vasoconstriction in rat cerebral arteries with an increase of the voltage-dependent Ca²⁺ influx

Guest editorial: fatigue design and material defects

This issue of Fatigue and Fracture of Engineering Materials and Structures contains a collection of manuscripts presented at the Second International Symposium on Fatigue Design and Material Defects (FDMD II) held in Paris, France, on June 11 – 13, 2014 organized by the French Society for Metallurgy and Materials (SF2M) and the German Association for Materials Research and Testing (DVM)

Inhibition of bone turnover by milk intake in postmenopausal women

Increased postmenopausal bone turnover leads to bone loss and fragility fracture risk. In the absence of osteoporosis, risk preventive measures, particularly those modifying nutritional lifestyle, are appropriate. We tested the hypothesis that milk supplementation affects bone turnover related to biochemical markers in a direction that, in the long term, may be expected to reduce postmenopausal bone loss. Thirty healthy postmenopausal women aged 59·3 (sd 3·3) years were enrolled in a prospective crossover trial of 16 weeks. After a 4-week period of adaptation with diet providing 600mg calcium plus 300mg ingested as 250ml semi-skimmed milk, participants were maintained during 6 weeks under the same 600mg calcium diet and randomized to receive either 500ml semi-skimmed milk, thus providing a total of 1200mg calcium, or no milk supplement. In the next 6 weeks they were switched to the alternative regimen. At the end of the each period, i.e. after 4, 10 and 16 weeks, blood and urinary samples were collected. The changes in blood variables between the periods of 6 weeks without and with milk supplementation were: for parathyroid hormone, −3·2pg/ml (P=0·0054); for crosslinked telopeptide of type I collagen, −624pg/ml (P<0·0001); for propeptide of type I procollagen, −5·5ng/ml (P=0·0092); for osteocalcin, −2·8ng/ml (P=0·0014). In conclusion, a 6-week period of milk supplementation induced a decrease in several biochemical variables compatible with diminished bone turnover mediated by reduction in parathyroid hormone secretion. This nutritional approach to postmenopausal alteration in bone metabolism may be a valuable measure in the primary prevention of osteoporosi

Dissecting genetic architecture of grape proanthocyanidin composition through quantitative trait locus mapping

<p>Abstract</p> <p>Background</p> <p>Proanthocyanidins (PAs), or condensed tannins, are flavonoid polymers, widespread throughout the plant kingdom, which provide protection against herbivores while conferring organoleptic and nutritive values to plant-derived foods, such as wine. However, the genetic basis of qualitative and quantitative PA composition variation is still poorly understood. To elucidate the genetic architecture of the complex grape PA composition, we first carried out quantitative trait locus (QTL) analysis on a 191-individual pseudo-F1 progeny. Three categories of PA variables were assessed: total content, percentages of constitutive subunits and composite ratio variables. For nine functional candidate genes, among which eight co-located with QTLs, we performed association analyses using a diversity panel of 141 grapevine cultivars in order to identify causal SNPs.</p> <p>Results</p> <p>Multiple QTL analysis revealed a total of 103 and 43 QTLs, respectively for seed and skin PA variables. Loci were mainly of additive effect while some loci were primarily of dominant effect. Results also showed a large involvement of pairwise epistatic interactions in shaping PA composition. QTLs for PA variables in skin and seeds differed in number, position, involvement of epistatic interaction and allelic effect, thus revealing different genetic determinisms for grape PA composition in seeds and skin. Association results were consistent with QTL analyses in most cases: four out of nine tested candidate genes (<it>VvLAR1</it>, <it>VvMYBPA2</it>, <it>VvCHI1</it>, <it>VvMYBPA1</it>) showed at least one significant association with PA variables, especially <it>VvLAR1 </it>revealed as of great interest for further functional investigation. Some SNP-phenotype associations were observed only in the diversity panel.</p> <p>Conclusions</p> <p>This study presents the first QTL analysis on grape berry PA composition with a comparison between skin and seeds, together with an association study. Our results suggest a complex genetic control for PA traits and different genetic architectures for grape PA composition between berry skin and seeds. This work also uncovers novel genomic regions for further investigation in order to increase our knowledge of the genetic basis of PA composition.</p

Dynamics of MBD2 deposition across methylated DNA regions during malignant transformation of human mammary epithelial cells

DNA methylation is thought to induce transcriptional silencing through the combination of two mechanisms: the repulsion of transcriptional activators unable to bind their target sites when methylated, and the recruitment of transcriptional repressors with specific affinity for methylated DNA. The Methyl CpG Binding Domain proteins MeCP2, MBD1 and MBD2 belong to the latter category. Here, we present MBD2 ChIPseq data obtained from the endogenous MBD2 in an isogenic cellular model of oncogenic transformation of human mammary cells. In immortalized (HMEC-hTERT) or transformed (HMLER) cells, MBD2 was found in a large proportion of methylated regions and associated with transcriptional silencing. A redistribution of MBD2 on methylated DNA occurred during oncogenic transformation, frequently independently of local DNA methylation changes. Genes downregulated during HMEC-hTERT transformation preferentially gained MBD2 on their promoter. Furthermore, depletion of MBD2 induced an upregulation of MBD2-bound genes methylated at their promoter regions, in HMLER cells. Among the 3,160 genes downregulated in transformed cells, 380 genes were methylated at their promoter regions in both cell lines, specifically associated by MBD2 in HMLER cells, and upregulated upon MBD2 depletion in HMLER. The transcriptional MBD2-dependent downregulation occurring during oncogenic transformation was also observed in two additional models of mammary cell transformation. Thus, the dynamics of MBD2 deposition across methylated DNA regions was associated with the oncogenic transformation of human mammary cells

PTX3 Polymorphisms and Invasive Mold Infections After Solid Organ Transplant

Donor PTX3 polymorphisms were shown to influence the risk of invasive aspergillosis among hematopoietic stem cell transplant recipients. Here, we show that PTX3 polymorphisms are independent risk factors for invasive mold infections among 1101 solid organ transplant recipients, thereby strengthening their role in mold infection pathogenesis and patients' risk stratificatio