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Steven P. Govek Celine Bonnefous Jackaline D. Julien Johnny Y. Nagasawa Mehmet Kahraman Andiliy G. Lai Karensa L. Douglas Anna M. Aparicio Beatrice D. Darimont Katherine L. Grillot James D. Joseph Joshua A. Kaufman Kyoung-Jin Lee Nhin Lu Michael J. Moon Rene Y. Prudente John Sensintaffar Peter J. Rix Nicholas D. Smith 《Bioorganic & medicinal chemistry letters》2019,29(3):367-372
Potent estrogen receptor ligands typically contain a phenolic hydrogen-bond donor. The indazole of the selective estrogen receptor degrader (SERD) ARN-810 is believed to mimic this. Disclosed herein is the discovery of ARN-810 analogs which lack this hydrogen-bond donor. These SERDs induced tumor regression in a tamoxifen-resistant breast cancer xenograft, demonstrating that the indazole NH is not necessary for robust ER-modulation and anti-tumor activity. 相似文献
43.
Anuran (frog) tadpoles and urodeles (newts and salamanders) are the only vertebrates capable of fully regenerating amputated limbs. During the early stages of regeneration these amphibians form a "blastema", a group of mesenchymal progenitor cells that specifically directs the regrowth of the limb. We report that wnt-3a is expressed in the apical epithelium of regenerating Xenopus laevis limb buds, at the appropriate time and place to play a role during blastema formation. To test whether Wnt/beta-catenin signaling is required for limb regeneration, we created transgenic X. laevis tadpoles that express Dickkopf-1 (Dkk1), a specific inhibitor of Wnt/beta-catenin signaling, under the control of a heat-shock promoter. Heat-shock immediately before limb amputation or during early blastema formation blocked limb regeneration but did not affect the development of contralateral, un-amputated limb buds. When the transgenic tadpoles were heat-shocked following the formation of a blastema, however, they retained the ability to regenerate partial hindlimb structures. Furthermore, heat-shock induced Dkk1 blocked fgf-8 but not fgf-10 expression in the blastema. We conclude that Wnt/beta-catenin signaling has an essential role during the early stages of limb regeneration, but is not absolutely required after blastema formation. 相似文献
44.
Plant cells have two endosymbiotic organelles, chloroplasts, and mitochondria. These organelles perform specific functions that depend on organelle-specific proteins. The majority of chloroplast and mitochondrial proteins are specifically imported by the transit peptide and presequence, respectively. However, a significant number of proteins are also dually targeted to these two organelles. Currently, it is not fully understood how proteins are dually targeted to both chloroplasts and mitochondria. In this study, the mechanism underlying mitochondrial targeting of dual targeting AtSufE1 in Arabidopsis was elucidated. The N-terminal fragment containing 80 residues of AtSufE1 (AtSufE1N80) was sufficient to confer dual targeting of reporter protein, AtSufE1N80:GFP, in protoplasts. Two sequence motifs, two arginine residues at 15th and 21st positions, and amino acid (aa) sequence motif AKTLLLRPLK from the 31st to 40th aa position, were responsible for targeting to mitochondria a portion of reporter proteins amid the chloroplast targeting. The sequence motif PSEVPFRRT from the 41st to 50th aa position constitutes a common motif for targeting to both chloroplasts and mitochondria. For mitochondrial import of AtSufE1:N80, Metaxin played a critical role. In addition, BiFC and protein pull-down experiments showed that AtSufE1N80 specifically interacts with import receptors, Metaxin and Tom20. The interaction of AtSufE1N80 with Metaxin was required for the interaction with Tom20. Based on these results, we propose that mitochondrial targeting of dual-targeting AtSufE1 is mediated by both mitochondria-specific and common sequence motifs in the signal sequence through the interaction with import receptors, Metaxin and Tom20, in a successive manner. 相似文献
45.
Antonio Ballell Benjamin C. Moon Laura B. Porro Michael J. Benton Emily J. Rayfield 《Palaeontology》2019,62(6):867-887
During the Mesozoic, Crocodylomorpha had a much higher taxonomic and morphological diversity than today. Members of one particularly successful clade, Thalattosuchia, are well‐known for being longirostrine: having long, slender snouts. It has generally been assumed that Thalattosuchia owed their success in part to the evolution of longirostry, leading to a feeding ecology similar to that of the living Indian gharial, Gavialis. Here, we compare form and function of the skulls of the thalattosuchian Pelagosaurus and Gavialis using digital reconstructions of the skull musculoskeletal anatomy and finite element models to show that they had different jaw muscle arrangements and biomechanical behaviour. Additionally, the relevance of feeding‐related mandibular traits linked to longirostry in the radiation of crocodylomorph clades was investigated by conducting an evolutionary rates analysis under the variable rates model. We find that, even though Pelagosaurus and Gavialis share similar patterns of stress distribution in their skulls, the former had lower mechanical resistance. This suggests that compared to Gavialis, Pelagosaurus was unable to process large, mechanically less tractable prey, instead operating as a specialized piscivore that fed on softer and smaller prey. Secondly, innovation of feeding strategies was achieved by rate acceleration of functional characters of the mandible, a key mechanism for the diversification of certain clades like thalattosuchians and eusuchians. Different rates of functional evolution suggest divergent diversification dynamics between teleosaurids and metriorhynchids in the Jurassic. 相似文献
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Min-Jeong Kim Fu-Shi Quan Hyun-Hee Kong Jong-Hyun Kim Eun-Kyung Moon 《The Korean journal of parasitology》2022,60(2):143
Acanthamoeba keratitis (AK) is a rare ocular disease, but it is a painful and sight-threatening infectious disease. Early diagnosis and adequate treatment are necessary to prevent serious complications. While AK is frequently diagnosis via several PCR assays or Acanthamoeba-specific antibodies, a more specific and effective diagnostic method is required. This study described the production of a polyclonal peptide antibody against the periplasmic binding protein (PBP) of A. castellanii and investigated its diagnostic potential. Western blot analysis showed that the PBP antibody specifically reacted with the cell lysates of A. castellanii. However, the PBP antibody did not interact with human corneal epithelial (HCE) cells and the other 3 major causative agents of keratitis. Immunocytochemistry (ICC) results revealed the specific detection of A. castellanii trophozoites and cysts by PBP antibodies when A. castellanii were co-cultured with HCE cells. PBP antibody specificity was further confirmed by co-culture of A. castellanii trophozoites with F. solani, S. aureus, and P. aeruginosa via ICC. The PBP antibody specifically reacted with the trophozoites and cysts of A. polyphaga, A. hatchetti, A. culbertsoni, A. royreba, and A. healyi, thus demonstrated its genus-specific nature. These results showed that the PBP polyclonal peptide antibody of A. castellanii could specifically detect several species of Acanthamoeba, contributing to the development of an effective antibody-based AK diagnostics. 相似文献
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Lee CK Lee CU Kim JH Son BC Kim DH Lee CH Kim HD Kim JW Yoon YD Kang SG Moon DH 《Molecules and cells》2003,15(1):114-121
This study was performed to investigate the effects of Aroclor 1254 (A1254), a commercial polychlorinated biphenyl mixture, on the expression of rat placental prolactin (PRL) family genes and reproductive activity. Placental lactogen-Iv and -II, and prolactin-like protein-A and -C mRNA levels were significantly decreased in the placentas of A1254-treated rats in a dose-dependent manner. The mRNA levels of Pit-1alpha and beta isotypes, which are involved in the regulation of PRL family gene expression, were also decreased in the A1254-treated rat placenta. In the rat placental junctional zone, high-dose A1254 (25 mg/kg B.W.) treatment reduced the number of spongiotrophoblasts, cells in which the PRL family genes are expressed. Finally, maternal exposure to A1254 was shown to have significant toxic effects on reproductive activity, including embryonic and placental growth retardation, delay of parturition, and reduction of the number of pups per litter. The results of the present study indicated that A1254 has an inhibitory effect on PRL family, Pit-1alpha, and beta gene expression in the rat placenta, leading to significant toxic effects on reproductive activity in rats. 相似文献