Project description:While the vertebrate body plan is highly conserved amongst all species of this taxon, extreme variations thereof can be documented in snakes, which display both an absence of limbs and an unusually elongated trunk. As Hox genes are strong candidates both for the making and the evolution of this body plan, their comparative study in such a morphologically diverged group is informative regarding their potential causative importance in these processes. In this work we use an interspecies comparative approach where different aspects of regulation at the HoxD locus are investigated. We find that although spatial collinearity and associated epigenetic mark dynamics are conserved in the corn snake, other regulatory modalities have been largely restructured. A BAC transgenic approach indeed revealed that, while the majority of mesodermal enhancers in vertebrates appear to be mostly located outside of the cluster, the corn snake contains most mesodermal trunk enhancers within the HoxD cluster. We also find that, despite the absence of limbs and an altered Hoxd gene regulation in external genitalia, the bimodal chromatin structure at the corn snake HoxD locus is maintained. The analysis of particular enhancer sequences initially defined in the mouse and further isolated at the snake orthologous locus showed differences in their specificities for the limb and genital bud expression. Of particular interest, a snake counterpart of a mouse limb-only enhancer sequence evolved into a genital-only enhancer. Such a regulatory exaptation suggests that enhancer versatility may have been an important factor to accompany the transition towards the snake body plan. These results show that vertebrate morphological evolution is likely to have been associated with extensive reorganization at the HoxD regulatory landscapes while respecting a very conserved general regulatory framework.
Project description:Our genomic, bulk and single-cell transcriptomic, functional, and developmental characterization of the Terrazzo corn snake color morph and the extensive comparison with wild-type snakes puts forward the dual role of PMEL in snake skin coloration, both in the differentiation of chromatophores during embryogenesis and the melanogenesis in melanophores.
Project description:Our genomic, bulk and single-cell transcriptomic, functional, and developmental characterization of the Terrazzo corn snake color morph and the extensive comparison with wild-type snakes puts forward the dual role of PMEL in snake skin coloration, both in the differentiation of chromatophores during embryogenesis and the melanogenesis in melanophores.
Project description:While the vertebrate body plan is highly conserved amongst all species of this taxon, extreme variations thereof can be documented in snakes, which display both an absence of limbs and an unusually elongated trunk. As Hox genes are strong candidates both for the making and the evolution of this body plan, their comparative study in such a morphologically diverged group is informative regarding their potential causative importance in these processes. In this work we use an interspecies comparative approach where different aspects of regulation at the HoxD locus are investigated. We find that although spatial collinearity and associated epigenetic mark dynamics are conserved in the corn snake, other regulatory modalities have been largely restructured. A BAC transgenic approach indeed revealed that, while the majority of mesodermal enhancers in vertebrates appear to be mostly located outside of the cluster, the corn snake contains most mesodermal trunk enhancers within the HoxD cluster. We also find that, despite the absence of limbs and an altered Hoxd gene regulation in external genitalia, the bimodal chromatin structure at the corn snake HoxD locus is maintained. The analysis of particular enhancer sequences initially defined in the mouse and further isolated at the snake orthologous locus showed differences in their specificities for the limb and genital bud expression. Of particular interest, a snake counterpart of a mouse limb-only enhancer sequence evolved into a genital-only enhancer. Such a regulatory exaptation suggests that enhancer versatility may have been an important factor to accompany the transition towards the snake body plan. These results show that vertebrate morphological evolution is likely to have been associated with extensive reorganization at the HoxD regulatory landscapes while respecting a very conserved general regulatory framework.
Project description:To determine the miRNA expression pattern in RBCs, we isolated miRNA from RBCs of healthy blood donors, who were homozygous or heterozygous carriers of different AB0 blood groups. We first analyzed miRNA expression by microarray chip analysis. In average, we found 873 miRNAs to be present in RBCs with a partially differential expression pattern depending on the blood group genotype. 148 out of these 873 miRNAs were significantly up- or downregulated in RBCs of blood group 0 and of heterozygous genotypes, as compared to homozygous genotypes.
Project description:Interventions: Administraion of CPT-11 is twice for 4 weeks on days 1 and 15. CPT-11 is reconstituted in >=250 mL of normal saline or 5% dextrose in water and infuse 90min on day 1 for pharmacokinetics, and 90min over on day15. CPT-11 adjusted dosage is determined from 50,75,100,125 or 150mg/sqm in the heterozygous group and the homozygous group by continual reassessment method. CPT-11 dosage is fixed at 150mg/sqm in the wild group.Definision of UGT1A1 polymorphisms groups: The homozygous group is patient with homozygous genotype of UGT1A1*28/*28 or UGT1A1*6/*6, with combined heterozygous genotypes of UGT1A1*28 and UGT1A1*6. The heterozygous group is patient with heterozygous genotype of either UGT1A1*28 or UGT1A1*6. The wild group is patients with no UGT1A1*28 and UGT1A1*6 mutation.
Primary outcome(s): Maximum tolerated dose for the heterozygous group and the homozygous group, respectively. Incidence rate of dose limiting toxicities for the wild group.
Study Design: Single arm Non-randomized
Project description:Interventions: Patients receive FOLFIRI with bevacizumab fixed 5mg/kg. (Treatment will be continued unless the disease progression, unacceptable toxicity, or consent withdrawal.) Definision of UGT1A1 polymorphisms groups: The homozygous group is patient with homozygous genotype of UGT1A1*28/*28 or UGT1A1*6/*6, with combined heterozygous genotypes of UGT1A1*28 and UGT1A1*6. The heterozygous group is patient with heterozygous genotype of either UGT1A1*28 or UGT1A1*6. The wild group is patients with no UGT1A1*28 and UGT1A1*6 mutation. CPT-11 dosage is wild and heterozygous:CPT-11 150mg/m2 homozygous:CPT-11 100mg/m2
Primary outcome(s): 1)incidence of adverse events 2)frequency of severe toxicity
Study Design: Single arm Non-randomized
Project description:ChIP-Seq Analysis of H3K9Ac in pairs of mouse and human samples carrying either the Gfi136S or the GFi136N variants. The objective of the study was to identify the changes in H3K9 acetylation at gene promoters that occur in samples expressing the 36N variant of the Gfi1 gene. 3 pairs of bone-marrow AML samples were obtained from mice where 1 mouse in each pair was homozygous for Gfi136S and 1 heterozygous for Gfi136N, or homozygous for 36N in one case. 2 pairs of AML samples were obtained from human patients were 1 patient was homozygous for Gfi1 36S and one was heterozygous for Gfi1 36N. H3 and H3K9Ac ChIP-Seq was carried out on each sample.
Project description:We used Nimblegen HD aCGH to detect copy-number variants between tumor and ear control-DNA samples from heterozygous and homozygous Tp53C273X knockout rats