ERK Phosphorylates p66shcA on Ser36 and Subsequently Regulates p27^kip1 Expression via the Akt-FOXO3a Pathway: Implication of p27^kip1 in Cell Response to Oxidative Stress

Mice deficient for p66shcA represent an animal model to link oxidative stress and aging. p66shcA is implicated in oxidative stress response and mitogenic signaling. Phosphorylation of p66shcA on Ser36 is critical for its function in oxidative stress response. Here we report the identification of ERK as the kinase phosphorylating p66shcA on Ser36. Activation of ERKs was necessary and sufficient for Ser36 phosphorylation. p66shcA interacted with ERK and was demonstrated to be a substrate for ERK, with Ser36 being the major phosphorylation site. Furthermore, in response to H2O2, inhibition of ERK activation repressed p66shcA-dependent phosphorylation of FOXO3a and the down-regulation of its target gene p27kip1. Down-regulation of p27 might promote cell survival, as p27 played a proapoptotic role in oxidative stress response. As a feedback regulation, Ser36 phosphorylated p66shcA attenuated H2O2-induced ERK activation, whereas p52/46shcA facilitated ERK activation, which required tyrosine phosphorylation of CH1 domain. p66shcA formed a complex with p52/46ShcA, which may provide a platform for efficient signal propagation. Taken together, the data suggest there exists an interplay between ERK and ShcA proteins, which modulates the expression of p27 and cell response to oxidative stress

p53 functions as a negative regulator of osteoblastogenesis, osteoblast-dependent osteoclastogenesis, and bone remodeling

p53 is a well known tumor suppressor. We show that p53 also regulates osteoblast differentiation, bone formation, and osteoblast-dependent osteoclast differentiation. Indeed, p53−/− mice display a high bone mass phenotype, and p53−/− osteoblasts show accelerated differentiation, secondary to an increase in expression of the osteoblast differentiation factor osterix, as a result. Reporter assays indicate that p53 represses osterix transcription by the minimal promoter in a DNA-binding–independent manner. In addition, p53−/− osteoblasts have an enhanced ability to favor osteoclast differentiation, in association with an increase in expression of macrophage-colony stimulating factor, which is under the control of osterix. Furthermore, inactivating p53 is sufficient to rescue the osteoblast differentiation defects observed in mice lacking c-Abl, a p53-interacting protein. Thus, these results identify p53 as a novel regulator of osteoblast differentiation, osteoblast-dependent osteoclastogenesis, and bone remodeling

The roles of ShcA proteins in response to oxidative stress

Ph.DDOCTOR OF PHILOSOPH

Short-Term Prediction of Electronic Transformer Error Based on Intelligent Algorithms

As the key metering equipment in the smart grid, the measurement accuracy and stability of electronic transformer are important for the normal operation of power system. In order to solve the problem that there is no effective way to predict the error developing trend of electronic transformer, this paper proposed two kinds of short-term prediction methods for electronic transformer error based on the backpropagation neural network and the Prophet model, respectively. First, preprocessing and visualization operation are performed on the original error data. Then, the data fitting and short-term prediction of electronic transformer error are made on the basis of the backpropagation neural network and the Prophet model, and the fitting and prediction results of the two methods are compared and analysed in combination with four evaluation indexes. Finally, the Prophet model is adopted to simulate the development trend and periodic fluctuation of error, and the reason for fluctuation is analysed. The simulation results show that the Prophet model is more suitable for the prediction of electronic transformer measurement error than the backpropagation neural network

Learning Curve and Clinical Outcomes of Ultrasonic Osteotome‐based En Bloc Laminectomy for Thoracic Ossification of the Ligamentum Flavum

Objective Despite rapid advances in minimally invasive surgery, en bloc laminectomy remains the most common surgical approach for treating thoracic ossification of the ligamentum flavum (TOLF). However, the learning curve of this risky operation is rarely reported. Therefore, we aimed to describe and analyze the learning curve of ultrasonic osteotome‐based en bloc laminectomy for TOLF. Methods Among 151 consecutive patients with TOLF who underwent en bloc laminectomy performed by one surgeon between January 2012 and December 2017, we retrospectively analyzed their demographic data, surgical parameters, and neurological function. Neurological outcome was evaluated with the modified Japanese Orthopaedic Association (mJOA) scale, and the Hirabayashi method was used to calculate the neurological recovery rate. The learning curve was assessed with logarithmic curve‐fitting regression analysis. Univariate analysis methods were used for statistical analysis, including t‐test, rank sum test, and chi‐square test. Results A total of 50% of learning milestones could be reached in approximately 14 cases, and the asymptote in 76 cases. Therefore, 76 of the 151 enrolled patients were defined as the “early group,” and the remaining 75 were delimitated as the “late group” for comparison. There was a significant intergroup difference in the corrected operative time (94.80 ± 27.77 vs 65.93 ± 15.67 min, P < 0.001) and the estimated blood loss (median 240 vs 400 mL, P < 0.001). The overall follow‐up was 83.1 ± 18.5 months. The mJOA significantly increased from a median of 5 (IQR: 4–5) before the surgery to 10 (IQR: 9–10) at the last follow‐up (P < 0.001). The overall complication rate was 37.1%, and no significant intergroup difference was found, except for the incidence of dural tears (31.6% vs 17.3%, p = 0.042). Conclusion Initially, mastering the en bloc laminectomy technique using ultrasonic osteotome for TOLF treatment can be challenging, but the surgeon's experience improves as the operative time and blood loss decrease. Improved surgical experience reduced the risk of dural tears but was not associated with the overall complication rate or long‐term neurological function. Despite the relatively long learning curve, en bloc laminectomy is a secure and valid technique for TOLF treatment

Therapeutic siRNA: state of the art

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