MicroRNA expression profiling assays have shown that miR-34b/c and miR-449a are down-regulated in nasopharyngeal carcinoma (NPC); however, the targets and functions of miR-34b/c and miR-449a in the pathologenesis of NPC remain elusive. In this study, we verified miR-34b/c and miR-449a were significantly reduced with the advance of NPC. Overexpression of miR-34b-3 and miR-449a suppressed the growth of NPC cells in culture and mouse tumor xenografts. Using tandem mass tags for quantitative labeling and LC-MS/MS analysis to investigate protein changes after restoring expression of miR-34b-3, 251 proteins were found to be down-regulated after miR-34b-3 transfection. Through 3 replicate experiments, we found that miR-34b-3 regulated the expression of 15 potential targeted genes mainly clustered in the key enzymes of glycolysis metabolism, including lactate dehydrogenase A (LDHA). Further investigation revealed that miR-34b-3 and miR-449a negatively regulated LDHA by binding to the 3′ untranslated regions of LDHA. Furthermore, LDHA overexpression rescued the miR-34b-3 and miR-449a induced tumor inhibition effect in CNE2 cells. In addition, miR-34b-3 and miR-449a suppressed LDH activity and reduced LD content, which were directly induced by downregulation of the LDHA. Our findings suggest that miR-34b-3 and miR-449a suppress the development of NPC through regulation of glycolysis via targeting LDHA and may be potential therapeutic targets for the treatment of NPC.
Growth of the axial and appendicular skeleton depends on endochondral ossification, which is controlled by tightly regulated cell–cell interactions in the developing growth plates. Previous studies have uncovered an important role of a disintegrin and metalloprotease 17 (ADAM17) in the normal development of the mineralized zone of hypertrophic chondrocytes during endochondral ossification. ADAM17 regulates EGF-receptor signaling by cleaving EGFR-ligands such as TGFα from their membrane-anchored precursor. The activity of ADAM17 is controlled by two regulatory binding partners, the inactive Rhomboids 1 and 2 (iRhom1, 2), raising questions about their role in endochondral ossification. To address this question, we generated mice lacking iRhom2 (iR2−/−) with floxed alleles of iRhom1 that were specifically deleted in chondrocytes by Col2a1-Cre (iR1∆Ch). The resulting iR2−/−iR1∆Ch mice had retarded bone growth compared to iR2−/− mice, caused by a significantly expanded zone of hypertrophic mineralizing chondrocytes in the growth plate. Primary iR2−/−iR1∆Ch chondrocytes had strongly reduced shedding of TGFα and other ADAM17-dependent EGFR-ligands. The enlarged zone of mineralized hypertrophic chondrocytes in iR2−/−iR1∆Ch mice closely resembled the abnormal growth plate in A17∆Ch mice and was similar to growth plates in Tgfα−/− mice or mice with EGFR mutations. These data support a model in which iRhom1 and 2 regulate bone growth by controlling the ADAM17/TGFα/EGFR signaling axis during endochondral ossification.
We present a protocol for an atomic interferometer that reaches the Heisenberg Limit (HL), within a factor of ∼ √ 2, via collective state detection and critical tuning of one-axis twist spin squeezing. It generates a Schrödinger cat (SC) state, as a superposition of two extremal collective states. When this SC interferometer is used as a gyroscope, the interference occurs at an ultrahigh Compton frequency, corresponding to a mesoscopic single object with a mass of N m, where N is the number of particles in the ensemble, and m is the mass of each particle. For 87 Rb atoms, with N = 10 6 , for example, the intereference would occur at a Compton frequency of ∼ 2 × 10 31 Hz. Under this scheme, the signal is found to depend critically on the parity of N . We present two variants of the protocol. Under Protocol A, the fringes are narrowed by a factor of N for one parity, while for the other parity the signal is zero. Under Protocol B, the fringes are narrowed by a factor of N for one parity, and by a factor of √ N for the other parity. Both protocols can be modified in a manner that reverses the behavior of the signals for the two parities. Over repeated measurements under which the probability of being even or odd is equal, the averaged sensitivity is smaller than the HL by a factor of ∼ √ 2 for both versions of the protocol. We describe an experimental scheme for realizing such an atomic interferometer, and discuss potential limitations due to experimental constraints imposed by the current state of the art, for both collective state detection and oneaxis-twist squeezing. We show that when the SC interferometer is configured as an accelerometer, the effective two-photon wave vector is enhanced by a factor of N , leading to the same degree of enhancement in sensitivity. We also show that such a mesoscopic single object can be used to increase the effective base frequency of an atomic clock by a factor of N , with a sensitivity that is equivalent to the HL, within a factor of ∼ √ 2.
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