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We examined the expression and functions of Pax1 and Pax9 in a teleost fish, the medaka Oryzias latipes. While Pax1 and Pax9 show distinct expression in the sclerotome in amniotes, we could not detect the differential expression of Pax1 and Pax9 in the developing sclerotome of the medaka. Furthermore, unlike the mouse, in which Pax1 is essential for development of the vertebral body, and where the neural arch is formed independent of either Pax1 or Pax9, our morpholino knockdown experiments revealed that both Pax1 and Pax9 are indispensable for the development of the vertebral body and neural arch. Therefore, we conclude that after gene duplication, Pax1 and Pax9 subfunctionalize their roles in the sclerotome independently in teleosts and amniotes. In Stage-30 embryo, Pax9 was strongly expressed in the posterior mesoderm, as was also observed for mouse Pax9. Since this expression was not detected for Pax1 in the mouse or fish, this new expression in the posterior mesoderm likely evolved in Pax9 of ancestral vertebrates after gene duplication. Two-month-old fish injected with Pax9 morpholino oligonucleotide showed abnormal morphology in the tail hypural skeletal element, which may have been related to this expression. 相似文献
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Fabio Moda Chiara Vimercati Ilaria Campagnani Margherita Ruggerone Giorgio Giaccone Michela Morbin Lorena Zentilin Mauro Giacca Ileana Zucca Giuseppe Legname Fabrizio Tagliavini 《朊病毒》2012,6(4):383-390
Prion diseases are caused by a conformational modification of the cellular prion protein (PrPC) into disease-specific forms, termed PrPSc, that have the ability to interact with PrPC promoting its conversion to PrPSc. In vitro studies demonstrated that anti-PrP antibodies inhibit this process. In particular, the single chain variable fragment D18 antibody (scFvD18) showed high efficiency in curing chronically prion-infected cells. This molecule binds the PrPC region involved in the interaction with PrPSc thus halting further prion formation. These findings prompted us to test the efficiency of scFvD18 in vivo. A recombinant Adeno-Associated Viral vector serotype 9 was used to deliver scFvD18 to the brain of mice that were subsequently infected by intraperitoneal route with the mouse-adapted scrapie strain RML. We found that the treatment was safe, prolonged the incubation time of scrapie-infected animals and decreased the burden of total proteinase-resistant PrPSc in the brain, suggesting that scFvD18 interferes with prion replication in vivo. This approach is relevant for designing new therapeutic strategies for prion diseases and other disorders characterized by protein misfolding. 相似文献
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Effect of three chlorinated pesticides on hsromega stress gene in transgenic Drosophila melanogaster
Expression of hsromega stress gene in the third-instar larvae of 951-lacZ2 (hsromega-lacZ having-844pb sequence) and 498-lacZ1 (hrsomega-lacZ having -498bp sequence) strains of Drosophila melanogaster at LC(50) and lower dietary concentrations of hexachlorocyclohexane (HCH) pentachlorophenol (PCP), and endosulfan was examined in relation to larval mortality by beta galactosidase activity, vital dye staining, and salivary gland polytene chromosome puffing. Our results showed that both HCH and PCP at lower concentrations evoked strong hsromega stress gene expression in the larval tissues while endosulfan did not. On the other hand, puffing data revealed that endosulfan at lower doses, induced well-developed puff at the resident site (93D) of the hsromega gene but the transgenic sites (30B in 951-lacZ2 and 44B in 498-lacZ1 strain) did not show any well-developed puff. Regression in hsromega stress gene expression in 951-lacZ2 strain at LC(50) concentrations of HCH and PCP after 48 h was concurrent with extensive tissue damage as evident by trypan blue staining. Similarly, strong hsromega expression was accompanied by insignificant trypan blue staining in the larval tissues of this strain after shorter duration of exposure (2-12 h) to these toxicants. Although endosulfan under similar experimental condition did not induce hsromega, strong trypan blue staining indicated extensive tissue damage after 48 h of exposure. The present study suggests that all the three toxicants pose cytotoxic potential to Drosophila. While protective role of this stress gene was evident at the initial stages of exposure, extensive tissue damage in the later stages of intoxication accompanied by autorepression of hsromega led to larval mortality. The study further suggests that -844bp upstream sequence of the gene is adequate for hsromega inducibility against HCH and PCP but not for endosulfan for which responsive elements may be searched further upstream. 相似文献
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Lisa A. Ridnour Sneha Dhanapal Michael Hoos Joan Wilson Jennifer Lee Robert Y. S. Cheng Ernst E. Brueggemann Harry B. Hines Donna M. Wilcock Michael P. Vitek David A. Wink Carol A. Colton 《Journal of neurochemistry》2012,123(5):736-749
Fibrillar amyloid plaques are largely composed of amyloid‐beta (Aβ) peptides that are metabolized into products, including Aβ1‐16, by proteases including matrix metalloproteinase 9 (MMP‐9). The balance between production and degradation of Aβ proteins is critical to amyloid accumulation and resulting disease. Regulation of MMP‐9 and its endogenous inhibitor tissue inhibitor of metalloproteinase (TIMP)‐1 by nitric oxide (NO) has been shown. We hypothesize that nitric oxide synthase (NOS2) protects against Alzheimer's disease pathology by increasing amyloid clearance through NO regulation of MMP‐9/TIMP‐1 balance. We show NO‐mediated increased MMP‐9/TIMP‐1 ratios enhanced the degradation of fibrillar Aβ in vitro, which was abolished when silenced for MMP‐9 protein translation. The in vivo relationship between MMP‐9, NO and Aβ degradation was examined by comparing an Alzheimer's disease mouse model that expresses NOS2 with a model lacking NOS2. To quantitate MMP‐9 mediated changes, we generated an antibody recognizing the Aβ1‐16 fragment, and used mass spectrometry multi‐reaction monitoring assay for detection of immunoprecipitated Aβ1‐16 peptides. Aβ1‐16 levels decreased in brain lysates lacking NOS2 when compared with strains that express human amyloid precursor protein on the NOS2 background. TIMP‐1 increased in the APPSwDI/NOS2?/? mice with decreased MMP activity and increased amyloid burden, thereby supporting roles for NO in the regulation of MMP/TIMP balance and plaque clearance. 相似文献
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Naoki Nishizawa Yoko Kanematsu-Yamaki Masaaki Funata Hiroaki Nagai Ayako Shimizu Hisashi Fujita Junichi Sakamoto Shiro Takekawa Taiji Asami 《Bioorganic & medicinal chemistry letters》2017,27(20):4626-4629
Neuromedin U (NMU) mediates various physiological functions via NMUR1 and NMUR2 receptors. NMUR2 has been considered a promising treatment option for diabetes and obesity. Although NMU-8, a shorter peptide, has potent agonist activity for both receptors, it is metabolically unstable. Therefore, NMU-8 analogs modified with long-chain alkyl moieties via a linker were synthesized. An octadecanoyl analog (17) with amino acid substitutions [αMePhe19, Nle21, and Arg(Me)24] and a linker [Tra-γGlu-PEG(2)] dramatically increased NMUR2 selectivity, with retention of high agonist activity. Subcutaneous administration of 17 induced anorectic activity in C57BL/6J mice. Owing to its high metabolic stability, 17 would be useful in clarifying the physiological role and therapeutic application of NMU. 相似文献
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