General patterns and asymptotic dose in the design of coated stents

Stents are used in interventional cardiology to keep a diseased vessel open. New stents are coated with a medicinal agent to prevent early reclosure due to the proliferation of smooth muscle cells. It is recognised that it is the dose of the agent that effectively controls the growth. This paper focusses on the asymptotic behaviour of the dose for general families of coated stents under a fixed ratio between the coated region of the stent and the targeted region of the vessel and set therapeutic bounds on the dose. It generalises the results of Delfour, Garon and Longo for stents made of a sequence of thin equally spaced rings to stents with an arbitrary pattern. It gives the equation of the asymptotic dose for a normal tiling of the target region using the theory of tilings, patterns and motifs on a cylinder.     

Parasitism drives host genome evolution: Insights from the Pasteuria ramosa–Daphnia magna system

Because parasitism is thought to play a major role in shaping host genomes, it has been predicted that genomic regions associated with resistance to parasites should stand out in genome scans, revealing signals of selection above the genomic background. To test whether parasitism is indeed such a major factor in host evolution and to better understand host–parasite interaction at the molecular level, we studied genome‐wide polymorphisms in 97 genotypes of the planktonic crustacean Daphnia magna originating from three localities across Europe. Daphnia magna is known to coevolve with the bacterial pathogen Pasteuria ramosa for which host genotypes (clonal lines) are either resistant or susceptible. Using association mapping, we identified two genomic regions involved in resistance to P. ramosa, one of which was already known from a previous QTL analysis. We then performed a naïve genome scan to test for signatures of positive selection and found that the two regions identified with the association mapping further stood out as outliers. Several other regions with evidence for selection were also found, but no link between these regions and phenotypic variation could be established. Our results are consistent with the hypothesis that parasitism is driving host genome evolution.     

DNA methylation of the X chromosomes of the human female: an in situ semi-quantitative analysis

We present an in situ semi-quantitative analysis of the global DNA methylation of the X chromosomes of the human female using antibodies raised against 5-methylcytosine. The antibodies were revealed by immunofluorescence. Images were recorded by a CCD camera and the difference in intensity of fluorescence between active (early replicating) and inactive (late-replicating) X chromosomes was measured. Global hypomethylation of the late-replicating X chromosomal DNA was observed in three cases of fibroblast primary cultures that were characterized by numerical and structural aberrations of the X chromosomes [46,X,ter rea(X;X), 48,XXXX and 46,X,t(X;15)]. In these cases, the difference between early and late-replicating X chromosomes was significantly greater than the intrametaphasic variations, measured for a pair of autosomes, that result from experimental procedures. In cells with normal karyotypes, the differneces between the two X chromosomes were in the range of experimental variation. These results demonstrated that late replication and facultative heterochromatinization of the inactive X are two processes that are not related to global hypermethylation of the DNA     

Nuclear interactions of wild type and variant glucocorticoid receptors

Nuclease digestion of nuclei from glucocorticoid sensitive and resistant lymphoma cell lines was used to study the nuclear compartmentalization of wild type and variant glucocorticoid receptors. In comparison with wild type, the variant line (S49 143r) had an increased capacity to translocate to the nucleus (nti), but was more completely released from nuclei by nuclease digestion. Approximately 20% of the receptor in wild type nuclei was resistant to release by DNase I digestion, while only less than 5% of the receptor from nti nuclei was retained under the same conditions. Studies with wild type nuclei show that the nuclease resistant portion of receptors was also more resistant to release by increased ionic strength.     

DNA binding properties of glucocorticosteroid receptors bound to the steroid antagonist RU-486.

RU-486 is an anti-fertility steroid which also has anti-glucocorticosteroid effects. RU-486 is shown to be a strong antagonist of the glucocorticosteroid-induced cytolytic response of the murine thymoma lines W7TB and T1M1b , and of the induction of mouse mammary tumor virus (MMTV) mRNA in T1M1b cells. The glucocorticosteroid receptor of W7 cells has high affinity for RU-486 (Kd = 3 X 10(-9) M) but the complex formed has low nuclear transfer capacity. Binding of RU-486, as compared with the glucocorticosteroid agonist triamcinolone acetonide, to mouse receptor results in a decreased affinity for DNA in general and a reduced specific recognition of a site in the promoter region of MMTV proviral DNA. The RU-486 complex formed with rat liver receptor exhibits the same behavior; in addition, it is shown that only a fraction of these complexes are activated by temperature and these form highly salt-sensitive interactions with DNA. These results indicate that the binding of RU-486 to glucocorticosteroid receptors mimics pharmacologically the properties of a class of receptor variants (nt-) which are non-functional and have reduced nuclear transfer and altered DNA binding capacity. These results substantiate the importance of DNA binding in receptor function.