Telomere shortening occurs when cells divide, both in vitro and in vivo. On the other hand, telomerase is able to maintain telomere length in cells by adding TTAGGG repeats to the ends of telomeres. However, the interrelationships existing among telomere length, telomerase activity and growth in vertebrates remain to be clarified. In the present study we measured telomere length (terminal restriction fragment length), telomerase activity and body growth of Oryzias latipes from the embryo stage until senescence. During the rapid growth stage (age 0–7 months), telomeres shortened in parallel with decreasing telomerase activity. Then, during adolescence (age 7 months – 1 year), telomeres lengthened quickly as growth slowed and telomerase activity increased. In the adult stage (age 1–4 years) characterized by little growth, telomerase activity decreased gradually and telomeres shortened. Our data indicate that telomere attrition and restoration are linked to growth and telomerase activity, and suggest that critical loss of telomere homeostasis is associated with mortality in this animal.

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The human ␤-globin locus is comprised of embryonic, fetal, and adult globin genes, each of which is expressed at distinct stages of pre-and postnatal development. Functional defects in globin proteins or expression results in mild to severe anemia, such as in sickle-cell disease or ␤-thalassemia, but the clinical symptoms of both disorders are ameliorated by persistent expression of the fetal globin genes. Recent genome-wide association studies (GWAS) identified the intergenic region between the HBS1L and MYB loci as a candidate modifier of fetal hemoglobin expression in adults. However, it remains to be clarified whether the enhancer activity within the HBS1L-MYB regulatory domain contributes to the production of fetal hemoglobin in adults. Here we report a new mouse model of hereditary persistence of fetal hemoglobin (HPFH) in which a transgene was randomly inserted into the orthologous murine Hbs1l-Myb locus. This mutant mouse exhibited typically elevated expression of embryonic globins and hematopoietic parameters similar to those observed in human HPFH. These results support the contention that mutation of the HBS1L-MYB genomic domain is responsible for elevated expression of the fetal globin genes, and this model serves as an important means for the analysis of networks that regulate fetal globin gene expression. The human ␤-type globin locus consists of embryonic, fetal, and adult globin genes. The embryonic and fetal globin genes are typically expressed in the yolk sac and fetal liver, respectively (1). In the adult spleen and bone marrow, the adult globin gene is activated, while the embryonic and fetal globin genes are silenced (1). Two mechanisms have been proposed to regulate silencing of the embryonic and fetal globin genes in the adult: autonomous active silencing of the embryonic and fetal globin genes by gene autonomous recruitment of repressors and passive silencing due to competitive sequestration of locus control region (LCR) enhancer activity by the adult ␤-globin gene (1). Reactivation of the embryonic and/or fetal globin genes could be a critically useful ploy for establishing therapies for hereditary anemias and the associated pathophysiology caused by adult globin gene mutations, such as sickle-cell disease and ␤-thalassemia (2-5).A couple of genome-wide association study (GWAS) experiments independently identified two candidate regions that might influence the expression of fetal hemoglobin in adults (6, 7). One is the BCL11A locus. BCL11A encodes a well-characterized hematopoietic transcription factor (8), and persistent expression of ␥-globin was observed in BCL11A-deficient human and murine erythroid cells, demonstrating a contribution of BCL11A to hereditary persistence of fetal hemoglobin (HPFH) (9, 10). The other is the intergenic region between the human HBS1L and MYB genes. A 24-kbp linkage disequilibrium (LD) block located 33 kbp 5= to HBS1L and 65 kbp 5= to MYB was found to exhibit strong association with elevated levels of fetal hemoglobin (7), and the LD block was designated ...

The use of glucocorticoids for treatment of sepsis has waxed and waned during the past several decades, and recent randomized controlled trials have evoked a reassessment of this therapy. Most glucocorticoid actions are mediated by its specific intracellular receptors (GRs). Thus we initially evaluated whether sepsis and high-dose corticosteroid therapy can regulate guinea pig pulmonary expression of GRs: active receptor, GRalpha, and dominant negative receptor, GRbeta. Sepsis induction by LPS injection (300 mug/kg ip) decreased mRNA and protein levels of GRalpha and increased protein expression of GRbeta in lungs. High-dose methylprednisolone (40 mg/kg ip), administered simultaneously with LPS, markedly potentiated the decrease in GRalpha expression but slightly affected the increase in GRbeta expression. Consequently, this led to a significant reduction in GRalpha nuclear translocation. Nevertheless, methylprednisolone treatment strongly eliminated LPS induction of NF-kappaB activity, as determined by NF-kappaB nuclear translocation and by gel mobility shift assays. Furthermore, the LPS-induced increase in inflammatory cells in bronchoalveolar lavage fluid was blunted by administration of the corticosteroid. On the other hand, immunofluorescent staining for cleaved caspase-3 showed a marked increase in this proapoptotic marker in lung sections, and terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling (TUNEL) represented an enhanced appearance of cell apoptosis in lungs and spleen when methylprednisolone was given together with LPS. Cell apoptosis is now considered to play a role in the pathogenesis of septic syndrome. We thus suggest that the action of glucocorticoids at high doses to accelerate sepsis-induced cell apoptosis may overwhelm their therapeutic advantages in septic shock.

Photoactive molecules with the frameworks of chlorin and/or porphyrin possessing four perfluorinated aromatic rings were conjugated with maltotriose (Mal3) via the nucleophilic aromatic substitution reaction and subsequent deprotection reaction of the oligosaccharide moieties. The resulting oligosaccharide-conjugated molecules are ultimately improved as compared to the previously reported monosaccharide-counterparts in terms of water-solubility. In particular, a water-soluble chlorin derivative surrounded by four Mal3 molecules showed an excellent biocompatibility, strong photoabsorption in the longer wavelength regions, and a very high photocytotoxicity. Thus, the present synthetic route combined with the use of an oligosaccharide was shown to be a straightforward strategy to develop a third generation photosensitizer for photodynamic therapy (PDT).