Mechanistic Studies of Autophagy Initiation in Mammalian Cells

Macroautophagy (herein referred to as autophagy) is an evolutionarily conserved self-digestive process cells use to adapt to starvation and other stresses. During autophagy, portions of cytoplasmic materials are engulfed into specialized double-membrane structures to form autophagosomes, which then fuse with lysosomes to degrade their cargos and regenerate nutrients. Initiation of autophagy has been extensively studied in budding yeast Saccharomyces cerevisiae. However, various significant differences exist between yeast and mammals. To pinpoint how mammalian autophagy is initiated, I first adopted proteomic approaches to identify associating partners of Unc-51-like kinase 1 (Ulk1), key initiator for mammalian autophagy. Two novel proteins, mAtg13 and Atg101, were found to interact with Ulk1 stoichiometrically. Knockdown of either mAtg13 or Atg101 led to decreased autophagy, and autophagy could be rescued with exogenous expression, suggesting the two proteins were critical for mammalian autophagy initiation. I then observed Ulk1 undergoes dramatic dephosphorylation upon starvation, particularly at serine 638 and serine 758. I found phosphorylations of Ulk1 are mediated by mammalian target-of-rapamycin (mTOR) kinase and AMP-activated protein kinase (AMPK). AMPK interacts with Ulk1 in a nutrient-dependent manner, and proper phosphorylations on Ulk1 are crucial for Ulk1/AMPK association, as a single serine-to-alanine mutation (S758A) at Ulk1 impairs this interaction. Compared to its wild-type counterpart, this Ulk1-S758A mutant initiates starvation-induced autophagy faster at early time points, but does not alter the maximum capacity of autophagy when starvation prolongs. With this layer of regulation, mammalian autophagy is capable of responding to environmental changes more promptly than previously considered

Decision-Making of Cross-Border E-Commerce Platform Supply Chains Considering Information Sharing and Free Shipping

For cross-border e-commerce companies with high shipping costs, the existing retailer and the new entrant retailer on the platform are usually concerned with information sharing and free shipping due to the uncertainty of market demand. For this, by establishing a Stackelberg game model between two competing retailers, we analyze the strategy of retailers and explore the business strategies of the cross-border e-commerce platform. The study shows that regarding information-sharing strategies, retailer A’s willingness to share information is positively related to initial market potential and negatively related to market competition intensity. Moreover, retailer B is willing to spend higher information costs to purchase information when the necessity of the product is more elevated. As for a free shipping strategy, if the existing retailer offers free shipping, the new entrant retailer should also offer free shipping service to consumers when the initial market potential is larger. Conversely, when the initial market potential is smaller, the retailer’s willingness to offer free shipping decreases when the intensity of competition in the market increases. When the market tends to be perfectly competitive, the new entrant retailer will not choose a free shipping strategy, and the platform is most profitable when information sharing and free shipping occur simultaneously. However, when the carrier charges a higher shipping fee to customers, the existing retailer is more profitable when the new entrant does not offer free shipping. Therefore, in order to achieve a win-win situation for all parties, the platform needs to develop appropriate operational strategies to influence the decisions of retailers and carriers. Some numerical experiments are made to test the validity of the model and the effect of the parameters involved in the model

Squamous differentiation in patients with superficial bladder urothelial carcinoma is associated with high risk of recurrence and poor survival

Abstract Background The independent prognostic role of squamous differentiation in pT1 bladder urothelial carcinoma has not been reported in previous studies. This article describes the impact of squamous differentiation on tumor recurrence and survival, and whether this histologic variant could indeed alter definitive treatment, based on single center-based retrospective data. Methods Totally, we retrieved (1)1449 histologically confirmed pT1 bladder urothelial carcinoma patients without histologic variants; (2)227 pT1 bladder urothelial carcinoma patients with squamous differentiation in our institution, from May 2004 to Oct 2015. The total amount of high/low grade urothelial carcinoma patients was 991/685 respectively. Transurethral resection of bladder tumor (TURBT) and intravesical chemotherapy were performed as initial treatments for all the patients. The clinical and pathological characteristics, treatment and survival outcomes were compared between squamous differentiation-positive and squamous differentiation-negative patients. Results In our study, 14% urothelial carcinoma patients were detected with squamous differentiation. The mean age of all the patients examined was 66.4, of whom 82% were males. The 5-year cancer specific survival rates were 69% for squamous differentiation-positive patients and 91% for squamous differentiation-negative patients (p < 0.001). Recurrence proved to be more common in squamous differentiation-positive patients than in negative patients. In the results of the univariate and multivariate Cox proportional hazard analysis, tumor size, lymphovascular invasion, recurrence and squamous differentiation were confirmed to be the prognostic factors associated with patients’ survival. Conclusions Squamous differentiation in pT1 bladder urothelial carcinoma is correlated to high risk of recurrence and poor prognosis as an independent prognostic factor. Radical cystectomy is essential for recurred high grade pT1 bladder urothelial carcinoma with squamous differentiation accompanied by lymphovascular invasion

A New Strategy for Disc Cutter Wear Status Perception Using Vibration Detection and Machine Learning

Carrying out status monitoring and fault-diagnosis research on cutter-wear status is of great significance for real-time understanding of the health status of Tunnel Boring Machine (TBM) equipment and reducing downtime losses. In this work, we proposed a new method to diagnose the abnormal wear state of the disc cutter by using brain-like artificial intelligence to process and analyze the vibration signal in the dynamic contact between the disc cutter and the rock. This method is mainly aimed at realizing the diagnosis and identification of the abnormal wear state of the cutter, and is not aimed at the accurate measurement of the wear amount. The author believes that when the TBM is operating at full power, the cutting forces are very high and the rock is successively broken, resulting in a complex circumstance, which is inconvenient to vibration signal acquisition and transmission. If only a small thrust is applied, to make the cutters just contact with the rock (less penetration), then the cutters will run more smoothly and suffer less environmental interference, which would be beneficial to apply the method proposed in this paper to detect the state of the cutters. A specific example was to use the frequency-domain characteristics of the periodic vibration waveform during the contact between the cutter and the granite to identify the wear status (including normal wear state, wear failure state, angled wear failure state) of the disc cutter through the artificial neural network, and the diagnosis accuracy rate is 90%

Fiber-optic vector vibroscope

A directional vibration sensor based on polarization-controlled cladding-to-core recoupling is demonstrated. A compact structure in which a short section of multi-mode fiber (MMF) stub containing a weakly tilted fiber Bragg grating (TFBG) is spliced to another single-mode fiber without any lateral offset. Multiple core modes of theMMFare coupled at the junction and appear as well defined resonances in reflection from the TFBG. Some of those resonances exhibit a strong polarization and bending dependence. Both the orientation and the amplitude of the vibrations can be determined unambiguously via dual-path power detection of the orthogonal-polarimetric lowest order LP1n modes. Meanwhile, the unwanted power fluctuations and temperature perturbations can be referenced out by monitoring the fundamental LP01 mode resonance

Orientation-recognized rotation measurement using single polarimetric multi-mode tilted fiber grating

The polarimetric sensing characteristics of multi-mode-fiber based tilted fiber Bragg grating (MMF-TFBG) have been analyzed and expe

Polarization-maintaining fiber-optic-grating vector vibroscope

A fiber-optic vector vibroscope based on orthogonal polarization cladding-to-core recoupling is demonstrated. A compact structure in which a short section of polarization-maintained (PM) fiber stub containing a straight fiber Bragg grating (FBG) is spliced to another single-mode fiber. Two well-defined orthogonally polarized cladding modes reflected by the PM-FBG are recoupled at the junction and the coupling intensity shows an extremely high sensitivity to bending in the corresponding orthogonal directions. Both the orientation and amplitude of the vibrations can be determined unambiguously via dual-path power detection of these recoupled orthogonal-polarimetric cladding modes (LP1;12 and LP1;13). Since spectral information is not required, temperature changes do not affect the sensor response, and power fluctuations can be referenced out by monitoring the power in the core mode (LP0;1) resonance