Adaptation to Endoplasmic Reticulum Stress Enhances Resistance of Oral Cancer Cells to Cisplatin by Up-Regulating Polymerase η and Increasing DNA Repair Efficiency

Endoplasmic reticulum (ER) stress response is an adaptive program to cope with cellular stress that disturbs the function and homeostasis of ER, which commonly occurs during cancer progression to late stage. Late-stage cancers, mostly requiring chemotherapy, often develop treatment resistance. Chemoresistance has been linked to ER stress response; however, most of the evidence has come from studies that correlate the expression of stress markers with poor prognosis or demonstrate proapoptosis by the knockdown of stress-responsive genes. Since ER stress in cancers usually persists and is essentially not induced by genetic manipulations, we used low doses of ER stress inducers at levels that allowed cell adaptation to occur in order to investigate the effect of stress response on chemoresistance. We found that prolonged tolerable ER stress promotes mesenchymal–epithelial transition, slows cell-cycle progression, and delays the S-phase exit. Consequently, cisplatin-induced apoptosis was significantly decreased in stress-adapted cells, implying their acquisition of cisplatin resistance. Molecularly, we found that proliferating cell nuclear antigen (PCNA) ubiquitination and the expression of polymerase η, the main polymerase responsible for translesion synthesis across cisplatin-DNA damage, were up-regulated in ER stress-adaptive cells, and their enhanced cisplatin resistance was abrogated by the knockout of polymerase η. We also found that a fraction of p53 in stress-adapted cells was translocated to the nucleus, and that these cells exhibited a significant decline in the level of cisplatin-DNA damage. Consistently, we showed that the nuclear p53 coincided with strong positivity of glucose-related protein 78 (GRP78) on immunostaining of clinical biopsies, and the cisplatin-based chemotherapy was less effective for patients with high levels of ER stress. Taken together, this study uncovers that adaptation to ER stress enhances DNA repair and damage tolerance, with which stressed cells gain resistance to chemotherapeutics.     

Automatic design for shop scheduling strategies based on hyper-heuristics: A systematic review

Against the background of smart manufacturing and Industry 4.0, how to achieve real-time scheduling has become a problem to be solved. In this regard, automatic design for shop scheduling based on hyper-heuristics has been widely studied, and a number of reviews and scheduling algorithms have been presented. Few studies, however, have specifically discussed the technical points involved in algorithm development. This study, therefore, constructs a general framework for automatic design for shop scheduling strategies based on hyper-heuristics, and various state-of-the-art technical points in the development process are summarized. First, we summarize the existing types of shop scheduling strategies and classify them using a new classification method. Second, we summarize an automatic design algorithm for shop scheduling. Then, we investigate surrogate-assisted methods that are popular in the current algorithm field. Finally, current problems and challenges are discussed, and potential directions for future research are proposed.     

A Novel LRRK2 Variant p.G2294R in the WD40 Domain Identified in Familial Parkinson’s Disease Affects LRRK2 Protein Levels

Leucine-rich repeat kinase 2 (LRRK2) is a major causative gene of late-onset familial Parkinson’s disease (PD). The suppression of kinase activity is believed to confer neuroprotection, as most pathogenic variants of LRRK2 associated with PD exhibit increased kinase activity. We herein report a novel LRRK2 variant—p.G2294R—located in the WD40 domain, detected through targeted gene-panel screening in a patient with familial PD. The proband showed late-onset Parkinsonism with dysautonomia and a good response to levodopa, without cognitive decline or psychosis. Cultured cell experiments revealed that p.G2294R is highly destabilized at the protein level. The LRRK2 p.G2294R protein expression was upregulated in the patient’s peripheral blood lymphocytes. However, macrophages differentiated from the same peripheral blood showed decreased LRRK2 protein levels. Moreover, our experiment indicated reduced phagocytic activity in the pathogenic yeasts and α-synuclein fibrils. This PD case presents an example wherein the decrease in LRRK2 activity did not act in a neuroprotective manner. Further investigations are needed in order to elucidate the relationship between LRRK2 expression in the central nervous system and the pathogenesis caused by altered LRRK2 activity.     

An economic investigation of the wind-hydrogen projects: A case study

Hydrogen as an energy carrier can play a significant role in reducing environmental emissions if it is produced from renewable energy resources. This research aims to assess hydrogen production from wind energy considering environmental, economic, and technical aspect for the East Azerbaijan province of Iran. The economic assessment is performed by calculation of payback period, levelized cost of hydrogen, and levelized cost of electricity. Since uncertainty in the power output of wind turbines may affect the payback period, all calculations are performed for four different turbine degradation rates. While it is common in the literature to choose the wind turbine based on a single criterion, this study implements Multi-Criteria Decision-Making (MCDM) techniques for this purpose. The results of Step-wise Weight Assessment Ratio Analysis illustrates that economic issue is the most important criterion for this research. The results of Weighted Aggregated Sum Product Assessment shows that Vestas V52 is the most suitable wind turbine for Ahar and Sarab cities, while Eovent EVA120 H-Darrieus is a better choice for other stations. The most suitable location for wind power generation is found to be Ahar, where it is estimated to annually generate 2914.8 kWh of electricity at the price of 0.045 $/kWh, and 47.2 tons of hydrogen at the price of 1.38 $/kg, which result in 583 tons of CO₂ emission reduction.     

MicroRNAs,Parkinson’s Disease,and Diabetes Mellitus

Parkinson’s disease (PD) is a neurodegenerative disorder that affects 1% of the population over the age of 60. Diabetes Mellitus (DM) is a metabolic disorder that affects approximately 25% of adults over the age of 60. Recent studies showed that DM increases the risk of developing PD. The link between DM and PD has been discussed in the literature in relation to different mechanisms including mitochondrial dysfunction, oxidative stress, and protein aggregation. In this paper, we review the common microRNA (miRNA) biomarkers of both diseases. miRNAs play an important role in cell differentiation, development, the regulation of the cell cycle, and apoptosis. They are also involved in the pathology of many diseases. miRNAs can mediate the insulin pathway and glucose absorption. miRNAs can also regulate PD-related genes. Therefore, exploring the common miRNA biomarkers of both PD and DM can shed a light on how these two diseases are correlated, and targeting miRNAs is a potential therapeutic opportunity for both diseases.     

Preparation and Evaluation of a Self-Nanoemulsifying Drug Delivery System Loaded with Heparin Phospholipid Complex

A self-nanoemulsifying drug delivery system (SNEDDS) was developed to enhance the absorption of heparin after oral administration, in which heparin was compounded with phospholipids to achieve better fat solubility in the form of heparin-phospholipid (HEP-Pc) complex. HEP-Pc complex was prepared using the solvent evaporation method, which increased the solubility of heparin in n-octanol. The successful preparation of HEP-Pc complex was confirmed by differential scanning calorimetry (DSC), Fourier-transform infrared (FT-IR) spectroscopy, NMR, and SEM. A heparin lipid microemulsion (HEP-LM) was prepared by high-pressure homogenization and characterized. HEP-LM can enhance the absorption of heparin after oral administration, significantly prolong activated partial thromboplastin time (APTT) and thrombin time (TT) in mice, and reduce fibrinogen (FIB) content. All these outcomes indicate that HEP-LM has great potential as an oral heparin formulation.     

An active balancer with rapid bidirectional charge shuttling and adaptive equalization current control for lithium-ion battery strings

This article proposes an active balancer, which features bidirectional charge shuttling and adaptive equalization current control, to fast counterbalance the state of charge (SOC) of cells in a lithium-ion battery (LIB) string. The power circuit consists of certain bidirectional buck-boost converters to transfer energy among the different cells back and forth. Owing to the characterization of the open-circuit voltage (OCV) vs SOC in LIB being relatively smooth near the SOC middle range, the SOC-inspected balance strategy can achieve more precise and efficient equilibrium than the voltage-based control. Accordingly, a compensated OCV-based SOC estimation is put forward to take into account the discrepancy of SOC estimation. Besides, the varied-duty-cycle (VDC) and curve-fitting modulation (CFM) methods are devised herein to tackle the problems of slow equalization rate and low balance efficacy, which arise from the diminution in balancing current as the SOC difference between the cells decreases in the later duration of equalization especially. The proposed strategies have taken the battery nonlinear characteristic and circuit parameter nonideality into account and can adaptively modulate the duty cycle with the SOC difference to keep balancing current constant throughout the balancing cycle. Simulated and experimental results are given to demonstrate the feasibility and effectiveness of the same prototype constructed. Compared with the fixed duty cycle and the VDC methods, the proposed CFM has the best balancing efficiency of 81.4%, and the balance time is shortened by 27.1% and 18.6%, respectively.     

Effects of spinosad and spinetoram on larval mortality,adult emergence,progeny production and mating in Cadra cautella (Walk.) (Lepidoptera: Pyralidae)

The bacterial formulations, spinosad and spinetoram, were evaluated for their efficacy in suppressing development and mating success in Cadra cautella (Walk.) (Lepidoptera: Pyralidae), the almond moth. A dilution series of spinosad and spinetoram was sprayed on rice flour. Rice flour samples sprayed with water served as the control. Late instar C. cautella larvae were introduced onto spinosad-, spinetoram-, or water-treated rice flour. The first experiment tested the effects of spinosad and spinetoram on larval mortality, as well as emergence of adults and progeny at different insecticide concentrations. In the second experiment, the mating success of C. cautella adults that had emerged from larvae exposed to spinosad was tested inside a cubicle. Both spinosad and spinetoram increased larval mortality, whereas both compounds reduced adult emergence and progeny production. Natural mating was reduced in the presence of the synthetic sex pheromone (Z,E)-9,12-tetradecadienyl acetate. However, exposure of C. cautella larvae to spinosad did not alter mating in adult progeny. Spinosad was more effective than spinetoram at suppressing C. cautella development. The study concludes that both spinosad and spinetoram suppress the development of immatures of C. cautella to the adult stage as well as mating. Thus, the both compounds can be used to protect stored grains from infestation by C. cautella.