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91.
Maren Cam Hemant K. Bid Linlin Xiao Gerard P. Zambetti Peter J. Houghton Hakan Cam 《The Journal of biological chemistry》2014,289(7):4083-4094
Under conditions of DNA damage, the mammalian target of rapamycin complex 1 (mTORC1) is inhibited, preventing cell cycle progression and conserving cellular energy by suppressing translation. We show that suppression of mTORC1 signaling to 4E-BP1 requires the coordinated activity of two tumor suppressors, p53 and p63. In contrast, suppression of S6K1 and ribosomal protein S6 phosphorylation by DNA damage is Akt-dependent. We find that loss of either p53, required for the induction of Sestrin 1/2, or p63, required for the induction of REDD1 and activation of the tuberous sclerosis complex, prevents the DNA damage-induced suppression of mTORC1 signaling. These data indicate that the negative regulation of cap-dependent translation by mTORC1 inhibition subsequent to DNA damage is abrogated in most human cancers. 相似文献
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Daniel S. La Emily A. Peterson Christiane Bode Alessandro A. Boezio Howard Bregman Margaret Y. Chu-Moyer James Coats Erin F. DiMauro Thomas A. Dineen Bingfan Du Hua Gao Russell Graceffa Hakan Gunaydin Angel Guzman-Perez Robert Fremeau Xin Huang Christopher Ilch Thomas J. Kornecook Matthew M. Weiss 《Bioorganic & medicinal chemistry letters》2017,27(15):3477-3485
The voltage-gated sodium channel NaV1.7 has received much attention from the scientific community due to compelling human genetic data linking gain- and loss-of-function mutations to pain phenotypes. Despite this genetic validation of NaV1.7 as a target for pain, high quality pharmacological tools facilitate further understanding of target biology, establishment of target coverage requirements and subsequent progression into the clinic. Within the sulfonamide class of inhibitors, reduced potency on rat NaV1.7 versus human NaV1.7 was observed, rendering in vivo rat pharmacology studies challenging. Herein, we report the discovery and optimization of novel benzoxazine sulfonamide inhibitors of human, rat and mouse NaV1.7 which enabled pharmacological assessment in traditional behavioral rodent models of pain and in turn, established a connection between formalin-induced pain and histamine-induced pruritus in mice. The latter represents a simple and efficient means of measuring target engagement. 相似文献
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Ozdener MH Brand JG Spielman AI Lischka FW Teeter JH Breslin PA Rawson NE 《Chemical senses》2011,36(7):601-612
The ability to maintain human fungiform papillae cells in culture for multiple cell cycles would be of considerable utility for characterizing the molecular, regenerative, and functional properties of these unique sensory cells. Here we describe a method for enzymatically isolating human cells from fungiform papillae obtained by biopsy and maintaining them in culture for more than 7 passages (7 months) without loss of viability and while retaining many of the functional properties of acutely isolated taste cells. Cells in these cultures exhibited increases in intracellular calcium when stimulated with perceptually appropriate concentrations of several taste stimuli, indicating that at least some of the native signaling pathways were present. This system can provide a useful model for molecular studies of the proliferation, differentiation, and physiological function of human fungiform papillae cells. 相似文献
95.
Mondor’s disease is a rare, self-limiting, benign process with acute presentation characterized by subcutaneous bands in several parts of the body. Penile Mondor’s disease (PMD) is thrombophlebitis of the superficial dorsal vein of the penis. It is usually considered as thrombophlebitis or phlebitis of subcutaneous vessels. Some findings suggest that it might be of lymphatic origin. The chest, abdominal wall, penis, upper arm, and other parts of the body may also be involved by the disease. Although its physiopathology is not exactly known, transection of the vessel during surgery or any type of trauma such as external compression may trigger its possible development. This disease almost always limits itself. It may be associated with psychological distress and sexual incompatibility. The patients usually feel the superficial vein of the penis like a hard rope and present with complaint of pain around this hardness. Diagnosis is usually easy with physical examination but color Doppler ultrasound examination is important for differential diagnosis. Thus, a close collaboration is required between radiologist and urologist in order to determine the correct diagnosis and appropriate therapies. 相似文献
96.
The evolutionary payoff accruing to parents from breeding offspringcould be an incentive for prolonged investments in the offspring.Enhanced survival for offspring as a result of such a prolongedparental investment would increase the value of remaining inthe natal territory for the offspring. Here we show that first-yearsurvival in Siberian jays is higher in the company of theirparents. Two observations point to that the enhanced survivalof retained offspring is due to nepotistic parents rather thanto the quality of a shared habitat. First, winter survivalis higher only for those retained offspring whose parents havesurvived too ; this precludes the possibility that the linkbetween timing of dispersal and survival should reflect a higher
phenotypic quality of retained offspring in general. Second,there is no support for the more parsimonious explanation thatthis link between the survival of parents and retained offspringreflects habitat quality of a shared territory. We could, withhigh statistical power, reject the possibility of a correlationbetween the survival of parental birds and unrelated immigrantsto the territory. Such a correlation would have been expectedif survival reflected habitat quality and not kinship. Our data
instead suggest a direct fitness gain to retained offspringin enhanced survival through parental nepotism (parental facilitation).The behavior of parents in allowing retained offspring accessto food that is denied to immigrants is one proximate mechanismmediating a benefit of delayed dispersal. 相似文献
97.
Tang Y Akbulut H Maynard J Petersen L Fang X Zhang WW Xia X Koziol J Linton PJ Deisseroth A 《Journal of immunology (Baltimore, Md. : 1950)》2006,177(8):5697-5707
We showed that the Ad-sig-TAA/ecdCD40L vaccine induces a tumor suppressive immune response to the hMUC-1 and rH2N tumor-associated self Ags (TAA) and to the Annexin A1 tumor vascular Ag, even in mice in which anergy exists to these Ags. When the TAA/ecdCD40L protein is given s.c. as a boost following the Ad-sig-TAA/ecdCD40L vector, the levels of the TAA-specific CD8 T cells and Abs increase dramatically over that seen with vector alone, in young (2-mo-old) as well as old (18-mo-old) mice. The Abs induced against hMUC-1 react with human breast cancer. This vaccine also induces a 4-fold decrement of negative regulatory CD4CD25FOXP3-T cells in the tumor tissue of 18-mo-old mice. These results suggest that the Ad-sig-TAA/ecdCD40L vector prime-TAA/ecdCD40L protein boost vaccine platform may be valuable in reducing postsurgery recurrence in a variety of epithelial neoplasms. 相似文献
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Gürlek A Aydoğan H Aşkar I 《Plastic and reconstructive surgery》2004,114(1):263; author reply 263-263; author reply 264