Regulation of autophagy by AMP-activated protein kinase/ sirtuin 1 pathway reduces spinal cord neurons damage

Objective(s): AMP-activated protein kinase/sirtuin 1 (AMPK/SIRT1) signaling pathway has been proved to be involved in the regulation of autophagy in various models. The aim of this study was to evaluate the effect of AMPK/SIRT1 pathway on autophagy after spinal cord injury (SCI). Materials and Methods:The SCI model was established in rats in vivo and the primary spinal cord neurons were subjected to mechanical injury (MI) in vitro. The apoptosis in spinal cord tissue and neurons was assessed by TUNEL staining and Hoechst 33342 staining, respectively. The autophagy-related proteins levels were detected by Western blot. The activation of AMPK/SIRT1 pathway was determined by Western blot and immunohistochemical staining. Results: We found that the apoptosis of spinal cord tissue and cell damage of spinal cord neurons was obvious after the trauma. The ratio of LC3II/LC3I and level of p62 were first increased significantly and then decreased after the trauma in vivo and in vitro, indicating the defect in autophagy. The levels of p-AMPK and SIRT1 were increased obviously after the trauma in vivo and in vitro. Further activation of the AMPK/SIRT1 pathway by pretreatment with resveratrol, a confirmed activator of the AMPK/SIRT1 pathway, alleviated the cell damage and promoted the autophagy flux via downregulation of p62 in spinal cord neurons at 24 hr after MI. Conclusion: Our results demonstrate that regulation of autophagy by AMPK/SIRT1 pathway can restrain spinal cord neurons damage, which may be a potential intervention of SCI

Origin and Characteristics of the Crude Oils and Condensates in the Callovian-Oxfordian Carbonate Reservoirs of the Amu Darya Right Bank Block, Turkmenistan

AbstractThe Amu Darya Right Bank Block is located northeast of the Amu Darya basin, a large petroliferous sedimentary basin, with abundant natural gas resources in carbonate rocks under the ultra-thick gypsum-salt layer. Oil fields producing crude oils have recently been found around large gas fields. Unraveling the origins of the crude oils is crucial for effective petroleum exploration and exploitation. The origin of gas condensates and crude oils was unraveled through the use of comprehensively analytical and interpretative geochemical approaches. Based on oil-source correlation, the reservoir forming process has been restored. The bulk geochemical parameters of the local source rocks of the ADRBB indicated that the local sources have hydrocarbon generation and accumulation potential. The middle-lower Jurassic coal-bearing mudstone is gas prone, while the mudstone of the Callovian-Oxfordian gap layer is oil prone, and the organic matter type of Callovian-Oxfordian carbonate rocks is the mixed type between the two previous source rocks. The interpretation schemes for compositions of n-alkanes, pristane and phytane, C27–C28–C29 sterane distributions, C19+C20–C21–C23 tricyclic terpane distributions, extended tricyclic terpane ratio, and δ13C indicated that crude oil is likely from marine organic matter, while condensates mainly originate from terrestrial organic matter. However, from the perspective of the 18α-trisnorneohopane/17α-trisnorhopane and isomerization ratio of C29 sterane, condensates are too mature to have originated in the local source rocks of the ADRBB, whose maturity is well comparable with that of crude oils. The geochemical, geologic, and tectonic evolutions collectively indicate that the crude oils were most likely generated and migrated from the relatively shallow, lowly mature gap layer and Callovian-Oxfordian carbonate rocks of the ADRBB, while the condensates mostly originated from the relatively deep and highly mature middle-lower coal-bearing mudstone and Callovian-Oxfordian carbonate rocks in the Murgab depression in the southeast of the basin. Basement faults are the key factors affecting the types of oil and gas reservoirs. During the periods of oil and gas migration, traps with basement faults mainly captured natural gas and condensates and traps without basement faults were enriched with crude oils generated from local source rocks

Redefining cardiac biomarkers in predicting mortality and adverse outcomes of inpatients with COVID-19

The prognostic power of circulating cardiac biomarkers, their utility and pattern of release in coronavirus disease 2019 (COVID-19) patients have not been clearly defined. In this multi-centered retrospective study, we enrolled 3,219 patients with diagnosed COVID-19 admitted to 9 hospitals from December 31, 2019 to March 4, 2020, to estimate the associations and prognostic power of circulating cardiac injury markers with the poor outcomes of COVID-19. In the mixed-effect Cox model, after adjusting for age, gender and comorbidities, the adjusted hazard ratios of 28-day mortality for high-sensitivity cardiac troponin I (hs-cTnI) was 7.12 (95%CI, 4.60-11.03; P<0.001), NT-proB-type natriuretic peptide (NT-proBNP) was 5.11 (95%CI, 3.50-7.47; P<0.001), CK-MB was 4.86 (95%CI, 3.33-7.09; P<0.001), myoglobin was 4.50 (95%CI, 3.18-6.36; P < 0.001), and CK was 3.56 (95%CI, 2.53-5.02; P < 0.001). The cutoffs of those cardiac biomarkers for effective prognosis of 28-day mortality of COVID-19 were found to be much lower than for regular heart disease at about 49% of the currently recommended thresholds. Patients with elevated cardiac injury markers above the newly established cutoffs were associated with significantly increased risk of COVID-19 death. In conclusion, cardiac biomarker elevations are significantly associated with 28-day death in patients with COVID-19. The prognostic cutoffs for of these values might be much lower than the current reference standards. These findings can assist better management of COVID-19 patients to improve outcomes. Importantly, the newly established cutoff levels of COVID-19 associated cardiac biomarkers may serve as useful criteria for the future prospective studies and clinical trials

Redefining Cardiac Biomarkers in Predicting Mortality of Inpatients With COVID-19

The prognostic power of circulating cardiac biomarkers, their utility, and pattern of release in coronavirus disease 2019 (COVID-19) patients have not been clearly defined. In this multicentered retrospective study, we enrolled 3219 patients with diagnosed COVID-19 admitted to 9 hospitals from December 31, 2019 to March 4, 2020, to estimate the associations and prognostic power of circulating cardiac injury markers with the poor outcomes of COVID-19. In the mixed-effects Cox model, after adjusting for age, sex, and comorbidities, the adjusted hazard ratio of 28-day mortality for hs-cTnI (high-sensitivity cardiac troponin I) was 7.12 ([95% CI, 4.60-11.03] P\u3c0.001), (NT-pro)BNP (N-terminal pro-B-type natriuretic peptide or brain natriuretic peptide) was 5.11 ([95% CI, 3.50-7.47] P\u3c0.001), CK (creatine phosphokinase)-MB was 4.86 ([95% CI, 3.33-7.09] P\u3c0.001), MYO (myoglobin) was 4.50 ([95% CI, 3.18-6.36] P\u3c0.001), and CK was 3.56 ([95% CI, 2.53-5.02] P\u3c0.001). The cutoffs of those cardiac biomarkers for effective prognosis of 28-day mortality of COVID-19 were found to be much lower than for regular heart disease at about 19%-50% of the currently recommended thresholds. Patients with elevated cardiac injury markers above the newly established cutoffs were associated with significantly increased risk of COVID-19 death. In conclusion, cardiac biomarker elevations are significantly associated with 28-day death in patients with COVID-19. The prognostic cutoff values of these biomarkers might be much lower than the current reference standards. These findings can assist in better management of COVID-19 patients to improve outcomes. Importantly, the newly established cutoff levels of COVID-19-associated cardiac biomarkers may serve as useful criteria for the future prospective studies and clinical trials

Sustainable Trade Credit and Replenishment Policies under the Cap-And-Trade and Carbon Tax Regulations

The paper considers the sustainable trade credit and inventory policies with demand related to credit period and the environmental sensitivity of consumers under the carbon cap-and-trade and carbon tax regulations. First, the decision models are constructed under three cases: without regulation, carbon cap-and-trade regulation, and carbon tax regulation. The optimal solutions of the retailer in the three cases are then discussed under the exogenous and endogenous credit periods. Finally, numerical analysis is conducted to obtain conclusions. The retailer shortens the trade credit period as the environmental sensitivity of the consumer is enhanced. The cap has no effects on the credit period decisions under the carbon cap-and-trade regulation. Carbon trade price and carbon tax have negative effects on the credit period. The retailer under carbon cap-and-trade regulation is more motivated to obey regulations than that under carbon tax regulation when carbon trade price equals carbon tax. Carbon regulations have better effects on carbon emission reduction than with exogenous credit term when the retailer has the power to decide with regards credit policies

Improved Active Disturbance Rejection Double Closed-Loop Control of a Rotary-Type VCM in a Moving Mirror Control System

Aiming to address the problem of moving mirror speed fluctuations in moving mirror control systems, an improved active disturbance rejection double closed-loop controller (IADR-DCLC) is proposed and verified by simulation to realize the high-performance control of a moving mirror control system. First, the mathematical model of a rotary-type voice coil motor (RT VCM) is established, and the relationship between the angular velocity of the RT VCM and the optical path scanning velocity is analyzed. Second, in order to suppress the model uncertainty and external disturbance of the system, an improved active disturbance rejection controller (IADRC) is proposed. Compared with a conventional ADRC, the tracking differentiator of the proposed IADRC is replaced with desired signal optimization (DSO), and the actual speed is introduced to the extended state observer (ESO). The IADRC is used in the position–speed double closed-loop control model. Finally, the simulation results show that the IADR-DCLC has not only a good tracking effect but also a good anti-interference ability and can meet the requirements of the moving mirror control system for the uniformity of optical-path scanning speed and accurate control of the position of the moving mirror

A Hardware-Friendly Low-Bit Power-of-Two Quantization Method for CNNs and Its FPGA Implementation

To address the problems of convolutional neural networks (CNNs) consuming more hardware resources (such as DSPs and RAMs on FPGAs) and their accuracy, efficiency, and resources being difficult to balance, meaning they cannot meet the requirements of industrial applications, we proposed an innovative low-bit power-of-two quantization method: the global sign-based network quantization (GSNQ). This method involves designing different quantization ranges according to the sign of the weights, which can provide a larger quantization-value range. Combined with the fine-grained and multi-scale global retraining method proposed in this paper, the accuracy loss of low-bit quantization can be effectively reduced. We also proposed a novel convolutional algorithm using shift operations to replace multiplication to help to deploy the GSNQ quantized models on FPGAs. Quantization comparison experiments performed on LeNet-5, AlexNet, VGG-Net, ResNet, and GoogLeNet showed that GSNQ has higher accuracy than most existing methods and achieves “lossless” quantization (i.e., the accuracy of the quantized CNN model is higher than the baseline) at low-bit quantization in most cases. FPGA comparison experiments showed that our convolutional algorithm does not occupy on-chip DSPs, and it also has a low comprehensive occupancy in terms of on-chip LUTs and FFs, which can effectively improve the computational parallelism, and this proves that GSNQ has good hardware-adaptation capability. This study provides theoretical and experimental support for the industrial application of CNNs

The Role of Netrin-1 in Improving Functional Recovery through Autophagy Stimulation Following Spinal Cord Injury in Rats

Our previous findings indicated that treatment with Netrin-1 could improve functional recovery through the stimulation of autophagy, by activating the AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) signaling pathway in rats following spinal cord injury (SCI). However, the underlying mechanisms were not elucidated. The purpose of this study was to investigate the underlying mechanisms by which Netrin-1 promotes autophagy and improves functional recovery after SCI. Following controlled SCI in Sprague-Dawley rats, we observed that the autophagic flux in neurons was impaired, as reflected by the accumulation of light chain 3-II (LC3-II)-positive and LC3-positive autophagosomes (APs), accompanied by the accumulation of the autophagic substrate, Sequestosome 1 (SQSTM1; also known as p62). Our results showed that treatment with Netrin-1 increases the levels of the lysosomal protease cathepsin D (CTSD) and lysosomal-associated membrane protein 1 (LAMP1), through the regulation of the nuclear localization of Transcription factor EB (TFEB) via the AMPK/mTOR signaling pathway. In addition, this enhancement of lysosomal biogenesis correlated strongly with the restoration of autophagic flux, inhibition of neural apoptosis and improved functional recovery. Suppression of lysosomal biogenesis via the inhibition of the nuclear translocation of TFEB by Compound C abolished this restoration of autophagic flux and the functional recovery effects of Netrin-1 following SCI. Taken together, these results indicate that Netrin-1 enhances lysosomal biogenesis by regulating the nuclear translocation of TFEB via the AMPK/mTOR signaling pathway. Furthermore, the enhancement of lysosomal biogenesis by Netrin-1 following SCI promotes autophagic flux and improves functional recovery in rats. Thus, the regulation of lysosomal biogenesis by modulating the nuclear localization of TFEB might be a novel approach for the treatment of SCI

Mdivi-1 inhibits astrocyte activation and astroglial scar formation and enhances axonal regeneration after spinal cord injury in rats

After spinal cord injury (SCI), astrocytes become hypertrophic and proliferative, forming a dense network of astroglial processes at the site of the lesion. This constitutes a physical and biochemical barrier to axonal regeneration. Mitochondrial fission regulates cell cycle progression; inhibiting the cell cycle of astrocytes can reduce expression levels of axon growth-inhibitory molecules as well as astroglial scar formation after SCI. We therefore investigated how an inhibitor of mitochondrial fission, Mdivi-1, would affect astrocyte proliferation, astroglial scar formation, and axonal regeneration following SCI in rats. Western blot and immunofluorescent double-labeling showed that Mdivi-1 markedly reduced the expression of the astrocyte marker glial fibrillary acidic protein (GFAP), and a cell proliferation marker, proliferating cell nuclear antigen, in astrocytes 3 days after SCI. Moreover, Mdivi-1 decreased the expression of GFAP and neurocan, a chondroitin sulfate proteoglycan. Notably, immunofluorescent labeling and Nissl staining showed that Mdivi-1 elevated the production of growth-associated protein-43 and increased neuronal survival at 4 weeks after SCI. Finally, hematoxylin-eosin staining and behavioral evaluation of motor function indicated that Mdivi-1 also reduced cavity formation and improved motor function 4 weeks after SCI. Our results confirm that Mdivi-1 promotes motor function after SCI, and indicate that inhibiting mitochondrial fission using Mdivi-1 can inhibit astrocyte activation and astroglial scar formation and contribute to axonal regeneration after SCI in rats