bluuebunny/crossref_metadata_2025 huggingface dataset:
Review on Energy Efficiency Progresses, Technologies and Strategies in the Ceramic Sector Focusing on Waste Heat Recovery
Authors: Castro Oliveira Miguel , Iten Muriel , Cruz Pedro L. , Monteiro Helena
Published: November 2020

Thermal processes represent a considerable part of the total energy consumption in manufacturing industry, in sectors such as steel, aluminium, cement, ceramic and glass, among others. It can even be the predominant type of energy consumption in some sectors. High thermal energy processes are mostly associated to high thermal losses, (commonly denominated as waste heat), reinforcing the need for waste heat recovery (WHR) strategies. WHR has therefore been identified as a relevant solution to increase energy efficiency in industrial thermal applications, namely in energy intensive consumers. The ceramic sector is a clear example within the manufacturing industry mainly due to the fuel consumption required for the following processes: firing, drying and spray drying. This paper reviews studies on energy efficiency improvement measures including WHR practices applied to the ceramic sector. This focuses on technologies and strategies which have significant potential to promote energy savings and carbon emissions reduction. The measures have been grouped into three main categories: (i) equipment level; (ii) plant level; and (iii) outer plant level. Some examples include: (i) high efficiency burners; (ii) hot air recycling from kilns to other processes and installation of heat exchangers; and (iii) installation of gas turbine for combined heat and power (CHP). It is observed that energy efficiency solutions allow savings up to 50–60% in the case of high efficiency burners; 15% energy savings for hot air recycling solutions and 30% in the when gas turbines are considered for CHP. Limitations to the implementation of some measures have been identified such as the high investment costs associated, for instance, with certain heat exchangers as well as the corrosive nature of certain available exhaust heat.
Real-Time Multiparameter Identification of a Salient-Pole PMSM Based on Two Steady States
Authors: Zhou Minglei , Jiang Long , Wang Chenchen
Published: November 2020

Real-time multiparameter identification has been widely investigated in relation to high-performance control and fault diagnosis of salient-pole permanent magnet synchronous motors (PMSMs). However, it is rank-deficient for simultaneously estimating flux, resistance, and dq-axis inductances based on one steady state under maximum torque per ampere (MTPA) control, which will cause the ill-convergence problem in the results. This paper proposes a new method to solve the rank deficiency problem in the multiparameter identification of salient-pole PMSMs in systems where the motor working conditions do not change frequently. For this type of system, a second steady state is constructed in order to meet the full-rank conditions for multiparameter identification and minimize the torque ripple. Furthermore, in order to reduce the influence of inductance variations, a better shift direction from the first steady state to the second is ensured based on the analysis of the theoretical error. Simulation and experimental results show that the proposed method demonstrates good identification performance.
Research on the Method of Methane Emission Prediction Using Improved Grey Radial Basis Function Neural Network Model
Authors: Yang Yongkang , Du Qiaoyi , Wang Chenlong , Bai Yu
Published: November 2020

Effectively avoiding methane accidents is vital to the security of manufacturing minerals. Coal mine methane accidents are often caused by a methane concentration overrun, and accurately predicting methane emission quantity in a coal mine is key to solving this problem. To maintain the concentration of methane in a secure range, grey theory and neural network model are increasingly used to critically forecasting methane emission quantity in coal mines. A limitation of the grey neural network model is that researchers have merely combined the conventional neural network and grey theory. To enhance the accuracy of prediction, a modified grey GM (1,1) and radial basis function (RBF) neural network model is proposed, which combines the amended grey GM (1,1) model and RBF neural network model. In this article, the proposed model is put into a simulation experiment, which is built based on Matlab software (MathWorks.Inc, Natick, Masezius, U.S). Ultimately, the conclusion of the simulation experiment verified that the modified grey GM (1,1) and RBF neural network model not only boosts the precision of prediction, but also restricts relative error in a minimum range. This shows that the modified grey GM (1,1) and RBF neural network model can make more effective and precise predict the predicts, compared to the grey GM (1,1) model and RBF neural network model.
An Investigation of Laboratory and Road Test of Common Rail Injection Vehicles Fueled with B20 Biodiesel
Authors: Reksowardojo Iman K. , Setiapraja Hari , Fajar Rizqon , Wibowo Edi , Kusdiana Dadan
Published: November 2020

In this study, biodiesel fuel with a ratio of 20% volume (B20) was used on vehicles that are used in common rail injection systems, complying with Euro2 emission regulations. Laboratory and road tests were conducted to evaluate the effects of B20 on performance, emissions and engine components. Using diesel fuel and B20 as reference fuels, tests were conducted using Euro2 vehicle technology to investigate the effects on emissions, fuel consumption, and power. Durability testing was run for travel distances covering 40,000 km under various road and environmental conditions, while vehicle performance and emissions tests were conducted using the ECE R84-03 and ECE R101 test methods, respectively. The results show that B20 has lower CO and hydrocarbon (HC) emissions for every distance travelled, with an average of around 30%. Particulate emission was a bit lower, averaging 3.4% for B20 compared to B0, while NOx was found to slightly increase at around 2% for B20. Due to its lower calorific value, for an average distance traveled, the fuel economy of B20 was around 0.5% higher compared to B0. Furthermore, the maximum power of B20 was 3% lower compared to that of B0 for the entire distance traveled. However, an evaluation of engine components after 40,000 km showed that B20 and B0 were similar. Moreover, vehicles using B20 tend to have a comparable durability of engine components when compared with B0.
A Decision-Making Framework for the Smart Charging of Electric Vehicles Considering the Priorities of the Driver
Authors: Milas Nikolaos , Mourtzis Dimitris , Tatakis Emmanuel
Published: November 2020

During the last decade, the technologies related to electric vehicles (EVs) have captured both scientific and industrial interest. Specifically, the subject of the smart charging of EVs has gained significant attention, as it facilitates the managed charging of EVs to reduce disturbances to the power grid. Despite the presence of an extended literature on the topic, the implementation of a framework that allows flexibility in the definition of the decision-making objectives, along with user-defined criteria is still a challenge. Towards addressing this challenge, a framework for the smart charging of EVs is presented in this paper. The framework consists of a heuristic algorithm that facilitates the charge scheduling within a charging station (CS), and the analytic hierarchy process (AHP) to support the driver of the EV selecting the most appropriate charging station based on their needs of transportation and personal preferences. The communications are facilitated by the Open Platform Communications–Unified Architecture (OPC–UA) standard. For the selection of the scheduling algorithm, the genetic algorithm and particle swarm optimisation have been evaluated, where the latter had better performance. The performance of the charge scheduling is evaluated, in various charging tasks, compared to the exhaustive search for small problems.
Flexible Kinetic Energy Release Controllers for a Wind Farm in an Islanding System
Authors: Chen Yi-Wei , Hsu Yuan-Yih
Published: November 2020

To improve frequency nadir following a disturbance and avoid under-frequency load shedding, two types of flexible kinetic energy release controllers for the doubly fed induction generator (DFIG) are proposed. The basic idea is to release only a small amount of kinetic energy stored at the DFIG in the initial transient period (1–3 s after the disturbance). When the frequency dip exceeds a preset threshold, the amount of kinetic energy released is increased to improve the frequency nadir. To achieve the goal of flexible kinetic energy release, a deactivation function based integral controller is first presented. To further improve the dynamic frequency response under parameter uncertainties and external disturbances, a second flexible kinetic energy release controller is designed using a proportional-integral controller, with the gains being adapted in real-time with the particle swarm optimization algorithm. Based on the MATLAB/SIMULINK simulation results for a local power system, it is concluded that the frequency nadir can be maintained around the under-frequency load shedding threshold of 59.6 Hz using the proposed controllers.
Emergy Based Decoupling Analysis of Ecosystem Services on Urbanization: A Case of Shanghai, China
Authors: Pan Hengyu , Geng Yong , Han Ji , Huang Cheng , Han Wenyi , Miao Zhuang
Published: November 2020

In order to respond to rapid urbanization, understanding the relationships between urbanization and ecosystem services (ESs) is of practical importance to move toward sustainable urban development. In this study, an emergy-GIS based method is proposed to evaluate ESs. Spatiotemporal emergy values of water retention (WR), air purification (AP), carbon sequestration (CS), soil conservation (SC), and biodiversity conservation (BC) were quantified and relationships among these ESs were analyzed by taking China’s largest city, Shanghai, as a case. The decoupling analysis was conducted to study the relationship between urbanization and ESs. Results show that the total value of regulating ESs had declined by 8.24% from 2005 to 2010. Chongming had the largest value of ESs, followed by Pudong. There is a synergetic relationship among AP, CS, and SC, while a tradeoff appears between WR and other services. Irregular “U” shape relationships between the decrease of ESs and urbanization indicators were observed. Results from decoupling analysis show that ESs experienced weak decoupling from urbanization in most districts. Finally, policy implications were raised based on the study results.
A Comparative CFD Study of Two Air Distribution Systems with Hot Aisle Containment in High-Density Data Centers
Authors: Cho Jinkyun , Woo Jesang , Park Beungyong , Lim Taesub
Published: November 2020

Removing heat from high-density information technology (IT) equipment is essential for data centers. Maintaining the proper operating environment for IT equipment can be expensive. Rising energy cost and energy consumption has prompted data centers to consider hot aisle and cold aisle containment strategies, which can improve the energy efficiency and maintain the recommended level of inlet air temperature to IT equipment. It can also resolve hot spots in traditional uncontained data centers to some degree. This study analyzes the IT environment of the hot aisle containment (HAC) system, which has been considered an essential solution for high-density data centers. The thermal performance was analyzed for an IT server room with HAC in a reference data center. Computational fluid dynamics analysis was conducted to compare the operating performances of the cooling air distribution systems applied to the raised and hard floors and to examine the difference in the IT environment between the server rooms. Regarding operating conditions, the thermal performances in a state wherein the cooling system operated normally and another wherein one unit had failed were compared. The thermal performance of each alternative was evaluated by comparing the temperature distribution, airflow distribution, inlet air temperatures of the server racks, and recirculation ratio from the outlet to the inlet. In conclusion, the HAC system with a raised floor has higher cooling efficiency than that with a hard floor. The HAC with a raised floor over a hard floor can improve the air distribution efficiency by 28%. This corresponds to 40% reduction in the recirculation ratio for more than 20% of the normal cooling conditions. The main contribution of this paper is that it realistically implements the effectiveness of the existing theoretical comparison of the HAC system by developing an accurate numerical model of a data center with a high-density fifth-generation (5G) environment and applying the operating conditions.
Pore-Structural Characteristics of Tight Fractured-Vuggy Carbonates and Its Effects on the P- and S-Wave Velocity: A Micro-CT Study on Full-Diameter Cores
Authors: Li Wei , Liu Xiangjun , Liang Lixi , Zhang Yinan , Li Xiansheng , Xiong Jian
Published: November 2020

Pore structure has been widely observed to affect the seismic wave velocity of rocks. Although taking lab measurements on 1.0-inch core plugs is popular, it is not representative of the fractured-vuggy carbonates because many fractures and vugs are on a scale up to several hundred microns (and greater) and are spatially heterogeneous. To overcome this shortage, we carried out the lab measurements on full-diameter cores (about 6.5–7.5 cm in diameter). The micro-CT (micro computed tomography) scanning technique is used to characterize the pore space of the carbonates and image processing methods are applied to filter the noise and enhance the responses of the fractures so that the constructed pore spaces are reliable. The wave velocities of P- and S-waves are determined then and the effects of the pore structure on the velocity are analyzed. The results show that the proposed image processing method is effective in constructing and quantitatively characterizing the pore space of the full-diameter fractured-vuggy carbonates. The porosity of all the collected tight carbonate samples is less than 4%. Fractures and vugs are well-developed and the spatial distributions of them are heterogeneous causing, even the samples having similar porosity, the pore structure characteristics of the samples being significantly different. The pores and vugs mainly contribute to the porosity of the samples and the fractures contribute to the change in the wave velocities more than pores and vugs.
Performance Improvement of Condensation Reduction and Removal in Heat Recovery Ventilators Using Purge Methods
Authors: Park Kwiyoung , Lee Dongchan , Chung Hyun Joon , Kim Yongchan
Published: November 2020

In this study, several purge and ventilation methods are proposed to reduce and remove condensation in a heat recovery ventilator for commercial and household buildings. The effects of the airflow rate, duration of ventilation, purge interval, and return air temperature on the quantities of condensation and condensation removal in the heat recovery ventilator are analyzed. The increase in the air flow rate and return air temperature increases the condensation removal rate owing to the enhanced evaporation of the condensate. Furthermore, the reductions in the duration of ventilation and purge interval decreased the accumulation of condensate on the heat exchanger element. Based on the experimental results, optimum ventilation and purge strategies are proposed according to the outdoor temperature. The operation of the heat recovery ventilator with the proposed ventilation and purge strategies shows at least a 33% and up to an 80% reduction in the quantity of condensate compared with a given operation method. Accordingly, the proposed operation strategies can significantly reduce the growth of microorganisms and fungi and also increase the efficiency of a heat recovery ventilator. However, further investigation on the detailed performance according to the outdoor humidity and overall energy analysis is necessary to supplement the limitations of this study.
Calciprotein Particles Cause Endothelial Dysfunction under Flow
Authors: Shishkova Daria , Markova Victoria , Sinitsky Maxim , Tsepokina Anna , Velikanova Elena , Bogdanov Leo , Glushkova Tatiana , Kutikhin Anton
Published: November 2020

Calciprotein particles (CPPs), which increasingly arise in the circulation during the disorders of mineral homeostasis, represent a double-edged sword protecting the human organism from extraskeletal calcification but potentially causing endothelial dysfunction. Existing models, however, failed to demonstrate the detrimental action of CPPs on endothelial cells (ECs) under flow. Here, we applied a flow culture system, where human arterial ECs were co-incubated with CPPs for 4 h, and a normolipidemic and normotensive rat model (10 daily intravenous injections of CPPs) to simulate the scenario occurring in vivo in the absence of confounding cardiovascular risk factors. Pathogenic effects of CPPs were investigated by RT-qPCR and Western blotting profiling of the endothelial lysate. CPPs were internalised within 1 h of circulation, inducing adhesion of peripheral blood mononuclear cells to ECs. Molecular profiling revealed that CPPs stimulated the expression of pro-inflammatory cell adhesion molecules VCAM1 and ICAM1 and upregulated transcription factors of endothelial-to-mesenchymal transition (Snail, Slug and Twist1). Furthermore, exposure to CPPs reduced the production of atheroprotective transcription factors KLF2 and KLF4 and led to YAP1 hypophosphorylation, potentially disturbing the mechanisms responsible for the proper endothelial mechanotransduction. Taken together, our results suggest the ability of CPPs to initiate endothelial dysfunction at physiological flow conditions.
New Aspects of the Kidney in the Regulation of Fibroblast Growth Factor 23 (FGF23) and Mineral Homeostasis
Authors: Mace Maria L. , Olgaard Klaus , Lewin Ewa
Published: November 2020

The bone-derived hormone fibroblast growth factor 23 (FGF23) acts in concert with parathyroid hormone (PTH) and the active vitamin D metabolite calcitriol in the regulation of calcium (Ca) and phosphate (P) homeostasis. More factors are being identified to regulate FGF23 levels and the endocrine loops between the three hormones. The present review summarizes the complex regulation of FGF23 and the disturbed FGF23/Klotho system in chronic kidney disease (CKD). In addition to the reduced ability of the injured kidney to regulate plasma levels of FGF23, several CKD-related factors have been shown to stimulate FGF23 production. The high circulating FGF23 levels have detrimental effects on erythropoiesis, the cardio-vascular system and the immune system, all contributing to the disturbed system biology in CKD. Moreover, new factors secreted by the injured kidney and the uremic calcified vasculature play a role in the mineral and bone disorder in CKD and create a vicious pathological crosstalk.
Circulating Coding and Long Non-Coding RNAs as Potential Biomarkers of Idiopathic Pulmonary Fibrosis
Authors: Di Mauro Stefania , Scamporrino Alessandra , Fruciano Mary , Filippello Agnese , Fagone Evelina , Gili Elisa , Scionti Francesca , Purrazzo Giacomo , Di Pino Antonino , Scicali Roberto , Di Martino Maria Teresa , Malaguarnera Roberta , Malatino Lorenzo , Purrello Francesco , Vancheri Carlo , Piro Salvatore
Published: November 2020

Background: Idiopathic Pulmonary Fibrosis (IPF) is a chronic degenerative disease with a median survival of 2–5 years after diagnosis. Therefore, IPF patient identification represents an important and challenging clinical issue. Current research is still searching for novel reliable non-invasive biomarkers. Therefore, we explored the potential use of long non-coding RNAs (lncRNAs) and mRNAs as biomarkers for IPF. Methods: We first performed a whole transcriptome analysis using microarray (n = 14: 7 Control, 7 IPF), followed by the validation of selected transcripts through qPCRs in an independent cohort of 95 subjects (n = 95: 45 Control, 50 IPF). Diagnostic performance and transcript correlation with functional/clinical data were also analyzed. Results: 1059 differentially expressed transcripts were identified. We confirmed the downregulation of FOXF1 adjacent non-coding developmental regulatory RNA (FENDRR) lncRNA, hsa_circ_0001924 circularRNA, utrophin (UTRN) and Y-box binding protein 3 (YBX3) mRNAs. The two analyzed non-coding RNAs correlated with Forced Vital Capacity (FVC)% and Diffusing Capacity of the Lung for carbon monoxide (DLCO)% functional data, while coding RNAs correlated with smock exposure. All analyzed transcripts showed excellent performance in IPF identification with Area Under the Curve values above 0.87; the most outstanding one was YBX3: AUROC 0.944, CI 95% = 0.895–0.992, sensitivity = 90%, specificity = 88.9%, p-value = 1.02 × 10−13. Conclusions: This study has identified specific transcript signatures in IPF suggesting that validated transcripts and microarray data could be useful for the potential future identification of RNA molecules as non-invasive biomarkers for IPF.
Inhibitory Effectiveness of Gomisin A, a Dibenzocyclooctadiene Lignan Isolated from Schizandra chinensis, on the Amplitude and Gating of Voltage-Gated Na+ Current
Authors: Chang Wei-Ting , Wu Sheng-Nan
Published: November 2020

Gomisin A (Gom A), a lignan isolated from Schisandra chinensis, has been reported produce numerous biological activities. However, its action on the ionic mechanisms remains largely unanswered. The present experiments were undertaken to investigate the possible perturbations of Gom A or other related compounds on different types of membrane ionic currents in electrically excitable cells (i.e., pituitary GH3 and pancreatic INS-1 cells). The exposure to Gom A led to the differential inhibition of peak and end-pulse components of voltage-gated Na+ current (INa) in GH3 cells with effective IC50 of 6.2 and 0.73 μM, respectively. The steady-state inactivation curve of INa in the presence of Gom A was shifted towards a more hyperpolarized potential. However, neither changes in the overall current-voltage relationship nor those for the gating charge of the current were demonstrated. The application of neither morin (10 μM) nor hesperidin (10 μM) perturbed the strength of INa, while sesamine could suppress it. However, in the continued presence of Gom A, the addition of sesamine failed to suppress INa further. Gom A also effectively suppressed the strength of persistent INa activated by long ramp voltage command, and further application of tefluthrin effectively attenuated Gom A-mediated inhibition of the current. The presence of Gom A mildly inhibited erg-mediated K+ current, while a lack of change in the amplitude of hyperpolarization-activated cation current was observed in its presence. Under cell-attached current recordings, the exposure to Gom A resulted in the decreased firing of spontaneous action currents with a minimal change in AC amplitude. In pancreatic INS-1 cells, the presence of Gom A was also noticed to inhibit peak and end-pulse components of INa differentially with the IC50 of 5.9 and 0.84 μM, respectively. Taken together, the emerging results presented herein provide the evidence that Gom A can differentially inhibit peak and sustained INa in endocrine cells (e.g., GH3 and INS-1 cells).
The 14-3-3 Proteins as Important Allosteric Regulators of Protein Kinases
Authors: Obsilova Veronika , Obsil Tomas
Published: November 2020

Phosphorylation by kinases governs many key cellular and extracellular processes, such as transcription, cell cycle progression, differentiation, secretion and apoptosis. Unsurprisingly, tight and precise kinase regulation is a prerequisite for normal cell functioning, whereas kinase dysregulation often leads to disease. Moreover, the functions of many kinases are regulated through protein–protein interactions, which in turn are mediated by phosphorylated motifs and often involve associations with the scaffolding and chaperon protein 14-3-3. Therefore, the aim of this review article is to provide an overview of the state of the art on 14-3-3-mediated kinase regulation, focusing on the most recent mechanistic insights into these important protein–protein interactions and discussing in detail both their structural aspects and functional consequences.
Early Signs of Atherogenic Features in the HDL Lipidomes of Normolipidemic Patients Newly Diagnosed with Type 2 Diabetes
Authors: Kostara Christina E. , Ferrannini Eleuterio , Bairaktari Eleni T. , Papathanasiou Athanasios , Elisaf Moses , Tsimihodimos Vasilis
Published: November 2020

Cardiovascular disease (CVD) is the major cause of death in patients with type-2 diabetes mellitus (T2DM), although the factors that accelerate atherosclerosis in these patients are poorly understood. The identification of the altered quantity and quality of lipoproteins, closely related to atherogenesis, is limited in routine to a pattern of high triglycerides and low HDL-cholesterol (HDL-C) and in research as dysfunctional HDLs. We used the emerging NMR-based lipidomic technology to investigate compositional features of the HDLs of healthy individuals with normal coronary arteries, drug-naïve; recently diagnosed T2DM patients with normal coronary arteries; and patients with recent acute coronary syndrome. Patients with T2DM and normal serum lipid profiles even at diagnosis presented significant lipid alterations in HDL, characterized by higher triglycerides, lysophosphatidylcholine and saturated fatty acids; and lower cholesterol, phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, plasmalogens and polyunsaturated fatty acids, an atherogenic pattern that may be involved in the pathogenesis of atherosclerosis. These changes are qualitatively similar to those found, more profoundly, in normolipidemic patients with established Coronary Heart Disease (CHD). We also conclude that NMR-based lipidomics offer a novel holistic exploratory approach for identifying and quantifying lipid species in biological matrixes in physiological processes and disease states or in disease biomarker discovery.
Interplay between Oxidative Stress and Metabolic Derangements in Non-Alcoholic Fatty Liver Disease: The Role of Selenoprotein P
Authors: Caviglia Gian Paolo , Rosso Chiara , Armandi Angelo , Gaggini Melania , Carli Fabrizia , Abate Maria Lorena , Olivero Antonella , Ribaldone Davide Giuseppe , Saracco Giorgio Maria , Gastaldelli Amalia , Bugianesi Elisabetta
Published: November 2020

Background: Pathogenetic mechanisms involved in the progression of non-alcoholic fatty liver disease (NAFLD) are complex and multifactorial. We investigated oxidative stress through the measurement of selenoprotein P (SeP) in serum and we explored its relation to metabolic derangements and liver damage in a group of non-diabetic NAFLD subjects. Methods: 57 NAFLD patients underwent a double-tracer oral glucose tolerance test (OGTT). Insulin resistance (IR) components were calculated at baseline as follows: hepatic-IR = (endogenous glucose production*insulin); peripheral-IR = (glucose rate of disappearance(Rd)); adipose-tissue(AT)-IR as Lipo-IR = (glycerol rate of appearance (Ra)*insulin) or AT-IR = (free fatty acids (FFAs)*insulin). The lipid and amino acid (AA) profiles were assessed by gas chromatography–mass spectrometry. SeP levels were measured by enzyme immunosorbent assay. Results: Circulating SeP correlated with insulin (rS = 0.28), FFAs (rS = 0.42), glucose Rd (rS = −0.33) and glycerol Ra (rS = −0.34); consistently, SeP levels correlated with Lipo-IR and AT-IR (rS > 0.4). Among the AA and lipid profiles, SeP inversely correlated with serine (rS = −0.31), glycine (rS = −0.44) and branched chain AA (rS = −0.32), and directly correlated with saturated (rS = 0.41) and monounsaturated FFAs (rS = 0.40). Hepatic steatosis and fibrosis increased in subjects with higher levels of SeP. In multivariable regression analysis, SeP was associated with the degree of hepatic fibrosis (t = 2.4, p = 0.022). Conclusions: SeP levels were associated with an altered metabolic profile and to the degree of hepatic fibrosis, suggesting a role in the pathogenesis of NAFLD.
Dehydroxyhispolon Methyl Ether, A Hispolon Derivative, Inhibits WNT/β-Catenin Signaling to Elicit Human Colorectal Carcinoma Cell Apoptosis
Authors: Fan Hueng-Chuen , Hsieh Ya-Chu , Li Li-Hsuan , Chang Ching-Chin , Janoušková Karolína , Ramani Modukuri V. , Subbaraju Gottumukkala V. , Cheng Kur-Ta , Chang Chia-Che
Published: November 2020

Colorectal cancer (CRC) is the fourth leading cause of cancer mortality worldwide. Aberrant activation of WNT/β-catenin signaling present in the vast majority of CRC cases is indispensable for CRC initiation and progression, and thus is a promising target for CRC therapeutics. Hispolon is a fungal-derived polyphenol with a pronounced anticancer effect. Several hispolon derivatives, including dehydroxyhispolon methyl ether (DHME), have been chemically synthesized for developing lead molecules with stronger anticancer activity. Herein, a DHME-elicited anti-CRC effect with the underlying mechanism is reported for the first time. Specifically, DHME was found to be more cytotoxic than hispolon against a panel of human CRC cell lines, while exerting limited toxicity to normal human colon cell line CCD 841 CoN. Additionally, the cytotoxic effect of DHME appeared to rely on inducing apoptosis. This notion was evidenced by DHME-elicited upregulation of poly (ADP-ribose) polymerase (PARP) cleavage and a cell population positively stained by annexin V, alongside the downregulation of antiapoptotic B-cell lymphoma 2 (BCL-2), whereas the blockade of apoptosis by the pan-caspase inhibitor z-VAD-fmk attenuated DHME-induced cytotoxicity. Further mechanistic inquiry revealed the inhibitory action of DHME on β-catenin-mediated, T-cell factor (TCF)-dependent transcription activity, suggesting that DHME thwarted the aberrantly active WNT/β-catenin signaling in CRC cells. Notably, ectopic expression of a dominant–active β-catenin mutant (∆N90-β-catenin) abolished DHME-induced apoptosis while also restoring BCL-2 expression. Collectively, we identified DHME as a selective proapoptotic agent against CRC cells, exerting more potent cytotoxicity than hispolon, and provoking CRC cell apoptosis via suppression of the WNT/β-catenin signaling axis.
The Aging Stress Response and Its Implication for AMD Pathogenesis
Authors: Blasiak Janusz , Pawlowska Elzbieta , Sobczuk Anna , Szczepanska Joanna , Kaarniranta Kai
Published: November 2020

Aging induces several stress response pathways to counterbalance detrimental changes associated with this process. These pathways include nutrient signaling, proteostasis, mitochondrial quality control and DNA damage response. At the cellular level, these pathways are controlled by evolutionarily conserved signaling molecules, such as 5’AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), insulin/insulin-like growth factor 1 (IGF-1) and sirtuins, including SIRT1. Peroxisome proliferation-activated receptor coactivator 1 alpha (PGC-1α), encoded by the PPARGC1A gene, playing an important role in antioxidant defense and mitochondrial biogenesis, may interact with these molecules influencing lifespan and general fitness. Perturbation in the aging stress response may lead to aging-related disorders, including age-related macular degeneration (AMD), the main reason for vision loss in the elderly. This is supported by studies showing an important role of disturbances in mitochondrial metabolism, DDR and autophagy in AMD pathogenesis. In addition, disturbed expression of PGC-1α was shown to associate with AMD. Therefore, the aging stress response may be critical for AMD pathogenesis, and further studies are needed to precisely determine mechanisms underlying its role in AMD. These studies can include research on retinal cells produced from pluripotent stem cells obtained from AMD donors with the mutations, either native or engineered, in the critical genes for the aging stress response, including AMPK, IGF1, MTOR, SIRT1 and PPARGC1A.
Plasmin-Induced Activation of Human Platelets Is Modulated by Thrombospondin-1, Bona Fide Misfolded Proteins and Thiol Isomerases
Authors: Pielsticker Claudia , Brodde Martin F. , Raum Lisa , Jurk Kerstin , Kehrel Beate E.
Published: November 2020

Inflammatory processes are triggered by the fibrinolytic enzyme plasmin. Tissue-type plasminogen activator, which cleaves plasminogen to plasmin, can be activated by the cross-β-structure of misfolded proteins. Misfolded protein aggregates also represent substrates for plasmin, promoting their degradation, and are potent platelet agonists. However, the regulation of plasmin-mediated platelet activation by misfolded proteins and vice versa is incompletely understood. In this study, we hypothesize that plasmin acts as potent agonist of human platelets in vitro after short-term incubation at room temperature, and that the response to thrombospondin-1 and the bona fide misfolded proteins Eap and SCN−-denatured IgG interfere with plasmin, thereby modulating platelet activation. Plasmin dose-dependently induced CD62P surface expression on, and binding of fibrinogen to, human platelets in the absence/presence of plasma and in citrated whole blood, as analyzed by flow cytometry. Thrombospondin-1 pre-incubated with plasmin enhanced these plasmin-induced platelet responses at low concentration and diminished them at higher dose. Platelet fibrinogen binding was dose-dependently induced by the C-terminal thrombospondin-1 peptide RFYVVMWK, Eap or NaSCN-treated IgG, but diminished in the presence of plasmin. Blocking enzymatically catalyzed thiol-isomerization decreased plasmin-induced platelet responses, suggesting that plasmin activates platelets in a thiol-dependent manner. Thrombospondin-1, depending on the concentration, may act as cofactor or inhibitor of plasmin-induced platelet activation, and plasmin blocks platelet activation induced by misfolded proteins and vice versa, which might be of clinical relevance.
Transcriptional Profiling of Whisker Follicles and of the Striatum in Methamphetamine Self-Administered Rats
Authors: Jang Won-Jun , Son Taekwon , Song Sang-Hoon , Ryu In Soo , Lee Sooyeun , Jeong Chul-Ho
Published: November 2020

Methamphetamine (MA) use disorder is a chronic neuropsychiatric disease characterized by recurrent binge episodes, intervals of abstinence, and relapses to MA use. Therefore, identification of the key genes and pathways involved is important for improving the diagnosis and treatment of this disorder. In this study, high-throughput RNA sequencing was performed to find the key genes and examine the comparability of gene expression between whisker follicles and the striatum of rats following MA self-administration. A total of 253 and 87 differentially expressed genes (DEGs) were identified in whisker follicles and the striatum, respectively. Multivariate and network analyses were performed on these DEGs to find hub genes and key pathways within the constructed network. A total of 129 and 49 genes were finally selected from the DEG sets of whisker follicles and of the striatum. Statistically significant DEGs were found to belong to the classes of genes involved in nicotine addiction, cocaine addiction, and amphetamine addiction in the striatum as well as in Parkinson’s, Huntington’s, and Alzheimer’s diseases in whisker follicles. Of note, several genes and pathways including retrograde endocannabinoid signaling and the synaptic vesicle cycle pathway were common between the two tissues. Therefore, this study provides the first data on gene expression levels in whisker follicles and in the striatum in relation to MA reward and thereby may accelerate the research on the whisker follicle as an alternative source of biomarkers for the diagnosis of MA use disorder.
Transcriptome Analysis of Pyrus betulaefolia Seedling Root Responses to Short-Term Potassium Deficiency
Authors: Yang Han , Li Yan , Jin Yumeng , Kan Liping , Shen Changwei , Malladi Anish , Nambeesan Savithri , Xu Yangchun , Dong Caixia
Published: November 2020

Potassium (K) plays a crucial role in multiple physiological and developmental processes in plants. Its deficiency is a common abiotic stress that inhibits plant growth and reduces crop productivity. A better understanding of the mechanisms involved in plant responses to low K could help to improve the efficiency of K use in plants. However, such responses remain poorly characterized in fruit tree species such as pears (Pyrus sp). We analyzed the physiological and transcriptome responses of a commonly used pear rootstock, Pyrus betulaefolia, to K-deficiency stress (0 mM). Potassium deprivation resulted in apparent changes in root morphology, with short-term low-K stress resulting in rapidly enhanced root growth. Transcriptome analyses indicated that the root transcriptome was coordinately altered within 6 h after K deprivation, a process that continued until 15 d after treatment. Potassium deprivation resulted in the enhanced expression (up to 5-fold) of a putative high-affinity K+ transporter, PbHAK5 (Pbr037826.1), suggesting the up-regulation of mechanisms associated with K+ acquisition. The enhanced root growth in response to K-deficiency stress was associated with a rapid and sustained decrease in the expression of a transcription factor, PbMYB44 (Pbr015309.1), potentially involved in mediating auxin responses, and the increased expression of multiple genes associated with regulating root growth. The concentrations of several phytohormones including indoleacetic acid (IAA), ABA, ETH, gibberellin (GA3), and jasmonic acid (JA) were higher in response to K deprivation. Furthermore, genes coding for enzymes associated with carbon metabolism such as SORBITOL DEHYDROGENASE (SDH) and SUCROSE SYNTHASE (SUS) displayed greatly enhanced expression in the roots under K deprivation, presumably indicating enhanced metabolism to meet the increased energy demands for growth and K+ acquisition. Together, these data suggest that K deprivation in P. betulaefolia results in the rapid re-programming of the transcriptome to enhance root growth and K+ acquisition. These data provide key insights into the molecular basis for understanding low-K-tolerance mechanisms in pears and in other related fruit trees and identifying potential candidates that warrant further analyses.
Genetic Deletion of NOD1 Prevents Cardiac Ca2+ Mishandling Induced by Experimental Chronic Kidney Disease
Authors: Gil-Fernández Marta , Navarro-García José Alberto , Val-Blasco Almudena , González-Lafuente Laura , Martínez José Carlos , Rueda Angélica , Tamayo Maria , Morgado José Luis , Zaragoza Carlos , Ruilope Luis Miguel , Delgado Carmen , Ruiz-Hurtado Gema , Fernández-Velasco María
Published: November 2020

Risk of cardiovascular disease (CVD) increases considerably as renal function declines in chronic kidney disease (CKD). Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) has emerged as a novel innate immune receptor involved in both CVD and CKD. Following activation, NOD1 undergoes a conformational change that allows the activation of the receptor-interacting serine/threonine protein kinase 2 (RIP2), promoting an inflammatory response. We evaluated whether the genetic deficiency of Nod1 or Rip2 in mice could prevent cardiac Ca2+ mishandling induced by sixth nephrectomy (Nx), a model of CKD. We examined intracellular Ca2+ dynamics in cardiomyocytes from Wild-type (Wt), Nod1−/− and Rip2−/− sham-operated or nephrectomized mice. Compared with Wt cardiomyocytes, Wt-Nx cells showed an impairment in the properties and kinetics of the intracellular Ca2+ transients, a reduction in both cell shortening and sarcoplasmic reticulum Ca2+ load, together with an increase in diastolic Ca2+ leak. Cardiomyocytes from Nod1−/−-Nx and Rip2−/−-Nx mice showed a significant amelioration in Ca2+ mishandling without modifying the kidney impairment induced by Nx. In conclusion, Nod1 and Rip2 deficiency prevents the intracellular Ca2+ mishandling induced by experimental CKD, unveiling new innate immune targets for the development of innovative therapeutic strategies to reduce cardiac complications in patients with CKD.
Combination Therapy to Treat Fungal Biofilm-Based Infections
Authors: Tits Jana , Cammue Bruno P. A. , Thevissen Karin
Published: November 2020

An increasing number of people is affected by fungal biofilm-based infections, which are resistant to the majority of currently-used antifungal drugs. Such infections are often caused by species from the genera Candida, Aspergillus or Cryptococcus. Only a few antifungal drugs, including echinocandins and liposomal formulations of amphotericin B, are available to treat such biofilm-based fungal infections. This review discusses combination therapy as a novel antibiofilm strategy. More specifically, in vitro methods to discover new antibiofilm combinations will be discussed. Furthermore, an overview of the main modes of action of promising antibiofilm combination treatments will be provided as this knowledge may facilitate the optimization of existing antibiofilm combinations or the development of new ones with a similar mode of action.
Administration of Human MSC-Derived Extracellular Vesicles for the Treatment of Primary Sclerosing Cholangitis: Preclinical Data in MDR2 Knockout Mice
Authors: Angioni Roberta , Calì Bianca , Vigneswara Vasanthy , Crescenzi Marika , Merino Ana , Sánchez-Rodríguez Ricardo , Liboni Cristina , Hoogduijn Martin J. , Newsome Philip Noel , Muraca Maurizio , Russo Francesco Paolo , Viola Antonella
Published: November 2020

Primary Sclerosing Cholangitis (PSC) is a progressive liver disease for which there is no effective medical therapy. PSC belongs to the family of immune-mediated biliary disorders and it is characterized by persistent biliary inflammation and fibrosis. Here, we explored the possibility of using extracellular vesicles (EVs) derived from human, bone marrow mesenchymal stromal cells (MSCs) to target liver inflammation and reduce fibrosis in a mouse model of PSC. Five-week-old male FVB.129P2-Abcb4tm1Bor mice were intraperitoneally injected with either 100 µL of EVs (± 9.1 × 109 particles/mL) or PBS, once a week, for three consecutive weeks. One week after the last injection, mice were sacrificed and liver and blood collected for flow cytometry analysis and transaminase quantification. In FVB.129P2-Abcb4tm1Bor mice, EV administration resulted in reduced serum levels of alkaline phosphatase (ALP), bile acid (BA), and alanine aminotransferase (ALT), as well as in decreased liver fibrosis. Mechanistically, we observed that EVs reduce liver accumulation of both granulocytes and T cells and dampen VCAM-1 expression. Further analysis revealed that the therapeutic effect of EVs is accompanied by the inhibition of NFkB activation in proximity of the portal triad. Our pre-clinical experiments suggest that EVs isolated from MSCs may represent an effective therapeutic strategy to treat patients suffering from PSC.
The Impact of Radiation-Induced DNA Damage on cGAS-STING-Mediated Immune Responses to Cancer
Authors: Storozynsky Quinn , Hitt Mary M.
Published: November 2020

Radiotherapy is a major modality used to combat a wide range of cancers. Classical radiobiology principles categorize ionizing radiation (IR) as a direct cytocidal therapeutic agent against cancer; however, there is an emerging appreciation for additional antitumor immune responses generated by this modality. A more nuanced understanding of the immunological pathways induced by radiation could inform optimal therapeutic combinations to harness radiation-induced antitumor immunity and improve treatment outcomes of cancers refractory to current radiotherapy regimens. Here, we summarize how radiation-induced DNA damage leads to the activation of a cytosolic DNA sensing pathway mediated by cyclic GMP-AMP (cGAMP) synthase (cGAS) and stimulator of interferon genes (STING). The activation of cGAS–STING initiates innate immune signaling that facilitates adaptive immune responses to destroy cancer. In this way, cGAS–STING signaling bridges the DNA damaging capacity of IR with the activation of CD8+ cytotoxic T cell-mediated destruction of cancer—highlighting a molecular pathway radiotherapy can exploit to induce antitumor immune responses. In the context of radiotherapy, we further report on factors that enhance or inhibit cGAS–STING signaling, deleterious effects associated with cGAS–STING activation, and promising therapeutic candidates being investigated in combination with IR to bolster immune activation through engaging STING-signaling. A clearer understanding of how IR activates cGAS–STING signaling will inform immune-based treatment strategies to maximize the antitumor efficacy of radiotherapy, improving therapeutic outcomes.
GOLPH3 Regulates EGFR in T98G Glioblastoma Cells by Modulating Its Glycosylation and Ubiquitylation
Authors: Arriagada Cecilia , Cavieres Viviana A. , Luchsinger Charlotte , González Alexis E. , Muñoz Vanessa C. , Cancino Jorge , Burgos Patricia V. , Mardones Gonzalo A.
Published: November 2020

Protein trafficking is altered when normal cells acquire a tumor phenotype. A key subcellular compartment in regulating protein trafficking is the Golgi apparatus, but its role in carcinogenesis is still not well defined. Golgi phosphoprotein 3 (GOLPH3), a peripheral membrane protein mostly localized at the trans-Golgi network, is overexpressed in several tumor types including glioblastoma multiforme (GBM), the most lethal primary brain tumor. Moreover, GOLPH3 is currently considered an oncoprotein, however its precise function in GBM is not fully understood. Here, we analyzed in T98G cells of GBM, which express high levels of epidermal growth factor receptor (EGFR), the effect of stable RNAi-mediated knockdown of GOLPH3. We found that silencing GOLPH3 caused a significant reduction in the proliferation of T98G cells and an unexpected increase in total EGFR levels, even at the cell surface, which was however less prone to ligand-induced autophosphorylation. Furthermore, silencing GOLPH3 decreased EGFR sialylation and fucosylation, which correlated with delayed ligand-induced EGFR downregulation and its accumulation at endo-lysosomal compartments. Finally, we found that EGF failed at promoting EGFR ubiquitylation when the levels of GOLPH3 were reduced. Altogether, our results show that GOLPH3 in T98G cells regulates the endocytic trafficking and activation of EGFR likely by affecting its extent of glycosylation and ubiquitylation.
Structural Similarities between Some Common Fluorophores Used in Biology, Marketed Drugs, Endogenous Metabolites, and Natural Products
Authors: O’Hagan Steve , Kell Douglas B.
Published: November 2020

It is known that at least some fluorophores can act as ‘surrogate’ substrates for solute carriers (SLCs) involved in pharmaceutical drug uptake, and this promiscuity is taken to reflect at least a certain structural similarity. As part of a comprehensive study seeking the ‘natural’ substrates of ‘orphan’ transporters that also serve to take up pharmaceutical drugs into cells, we have noted that many drugs bear structural similarities to natural products. A cursory inspection of common fluorophores indicates that they too are surprisingly ‘drug-like’, and they also enter at least some cells. Some are also known to be substrates of efflux transporters. Consequently, we sought to assess the structural similarity of common fluorophores to marketed drugs, endogenous mammalian metabolites, and natural products. We used a set of some 150 fluorophores along with standard fingerprinting methods and the Tanimoto similarity metric. Results: The great majority of fluorophores tested exhibited significant similarity (Tanimoto similarity > 0.75) to at least one drug, as judged via descriptor properties (especially their aromaticity, for identifiable reasons that we explain), by molecular fingerprints, by visual inspection, and via the “quantitative estimate of drug likeness” technique. It is concluded that this set of fluorophores does overlap with a significant part of both the drug space and natural products space. Consequently, fluorophores do indeed offer a much wider opportunity than had possibly been realised to be used as surrogate uptake molecules in the competitive or trans-stimulation assay of membrane transporter activities.