bluuebunny/crossref_metadata_2025 huggingface dataset:
Oxidative Stress Increases Endogenous Complement-Dependent Inflammatory and Angiogenic Responses in Retinal Pigment Epithelial Cells Independently of Exogenous Complement Sources
Authors: Trakkides Timon-Orest , Schäfer Nicole , Reichenthaler Maria , Kühn Konstanze , Brandwijk Ricardo J. M. G. E. , Toonen Erik J. M. , Urban Florian , Wegener Joachim , Enzmann Volker , Pauly Diana
Published: November 2019

Oxidative stress-induced damage of the retinal pigment epithelium (RPE) and chronic inflammation have been suggested as major contributors to a range of retinal diseases. Here, we examined the effects of oxidative stress on endogenous complement components and proinflammatory and angiogenic responses in RPE cells. ARPE-19 cells exposed for 1–48 h to H2O2 had reduced cell–cell contact and increased markers for epithelial–mesenchymal transition but showed insignificant cell death. Stressed ARPE-19 cells increased the expression of complement receptors CR3 (subunit CD11b) and C5aR1. CD11b was colocalized with cell-derived complement protein C3, which was present in its activated form in ARPE-19 cells. C3, as well as its regulators complement factor H (CFH) and properdin, accumulated in the ARPE-19 cells after oxidative stress independently of external complement sources. This cell-associated complement accumulation was accompanied by increased nlrp3 and foxp3 expression and the subsequently enhanced secretion of proinflammatory and proangiogenic factors. The complement-associated ARPE-19 reaction to oxidative stress, which was independent of exogenous complement sources, was further augmented by the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib. Our results indicate that ARPE-19 cell-derived complement proteins and receptors are involved in ARPE-19 cell homeostasis following oxidative stress and should be considered as targets for treatment development for retinal degeneration.
Antioxidant and Anti-Inflammatory Properties of Plants Extract
Authors: Allegra Mario
Published: November 2019

Inflammation is an adaptive response triggered by noxious stimuli and conditions such as infection and tissue injury [...]
Novel Polymeric Nanocarriers Reduced Zinc and Doxycycline Toxicity in the Nematode Caenorhabditis elegans
Authors: Toledano Manuel , Toledano-Osorio Manuel , Navarro-Hortal María D. , Varela-López Alfonso , Osorio Raquel , Quiles José L.
Published: November 2019

The objective was to evaluate the toxicity of zinc- and doxycycline-loaded polymeric nanoparticles (NPs) using Caenorhabditis elegans as a model organism. These NPs are composed of ethylene glycol dimethacrylate, 2-hydroxyethyl methacrylate and methacrylic acid. NPs were loaded with doxycycline (D-NPs) and zinc (Zn-NPs) by chemical adsorption, and loading efficacy was demonstrated. Worm death rate in a concentration-response curve basis was calculated for lethality. Metabolism was evaluated through pharyngeal pumping assay. Body length measurements, brood size and egg lays were used to gauge growth, reproduction and fertility respectively. Intracellular hydrogen peroxide levels were determined to assess the reactive oxygen species production. One-way ANOVA and Bonferroni were used for comparisons (p < 0.05). Tested NPs at the highest dosage did not affect lethality or worm metabolism, expressed in terms of death rate and pharyngeal pumping per minute, respectively. Zn-NPs slightly increased worm growth. The concentration of the intracellular hydrogen peroxide levels was the lowest in the D-NPs group. The distinct NPs and concentrations employed were shown to be non-toxic for in situ administration of zinc and doxycycline, reducing the harmful effects of these compounds.
Silver Nanoparticles Induce Mitochondrial Protein Oxidation in Lung Cells Impacting Cell Cycle and Proliferation
Authors: Holmila Reetta J. , Vance Stephen A. , King Stephen Bruce , Tsang Allen W. , Singh Ravi , Furdui Cristina M.
Published: November 2019

Silver nanoparticles (AgNPs) are widely used nanomaterials in both commercial and clinical biomedical applications, due to their antibacterial properties. AgNPs are also being explored for the treatment of cancer in particular in combination with ionizing radiation. In this work, we studied the effects of AgNPs and ionizing radiation on mitochondrial redox state and function in a panel of lung cell lines (A549, BEAS-2B, Calu-1 and NCI-H358). The exposure to AgNPs caused cell cycle arrest and decreased cell proliferation in A549, BEAS-2B and Calu-1, but not in NCI-H358. The mitochondrial reactive oxygen species (ROS) and protein oxidation increased in a time- and dose-dependent manner in the more sensitive cell lines with the AgNP exposure, but not in NCI-H358. While ionizing radiation also induced changes in the mitochondrial redox profiles, in general, these were not synergistic with the effects of AgNPs with the exception of NCI-H358 and only at a higher dose of radiation.
Piperlongumine Induces Cell Cycle Arrest via Reactive Oxygen Species Accumulation and IKKβ Suppression in Human Breast Cancer Cells
Authors: Jeong Chang Hee , Ryu Haram , Kim Do Hyun , Cheng Wei Nee , Yoon Jee Eun , Kang Sukyung , Han Sung Gu
Published: November 2019

Piperlongumine (PL), a natural product derived from long pepper (Piper longum L.), is known to exhibit anticancer effects. However, the effect of PL on cell cycle-regulatory proteins in estrogen receptor (ER)-positive breast cancer cells is unclear. Therefore, we investigated whether PL can modulate the growth of ER-positive breast cancer cell line, MCF-7. We found that PL decreased MCF-7 cell proliferation and migration. Flow cytometric analysis demonstrated that PL induced G2/M phase cell cycle arrest. Moreover, PL significantly modulated the mRNA levels of cyclins B1 and D1, cyclin-dependent kinases 1, 4, and 6, and proliferating cell nuclear antigen. PL induced intracellular reactive oxygen species (hydrogen peroxide) accumulation and glutathione depletion. PL-mediated inhibition of IKKβ expression decreased nuclear translocation of NF-κB p65. Furthermore, PL significantly increased p21 mRNA levels. In conclusion, our data suggest that PL exerts anticancer effects in ER-positive breast cancer cells by inhibiting cell proliferation and migration via ROS accumulation and IKKβ suppression.
Preparation and Evaluation of Resveratrol-Loaded Composite Nanoparticles Using a Supercritical Fluid Technology for Enhanced Oral and Skin Delivery
Authors: Ha Eun-Sol , Sim Woo-Yong , Lee Seon-Kwang , Jeong Ji-Su , Kim Jeong-Soo , Baek In-hwan , Choi Du Hyung , Park Heejun , Hwang Sung-Joo , Kim Min-Soo
Published: November 2019

We created composite nanoparticles containing hydrophilic additives using a supercritical antisolvent (SAS) process to increase the solubility and dissolution properties of trans-resveratrol for application in oral and skin delivery. Physicochemical properties of trans-resveratrol-loaded composite nanoparticles were characterized. In addition, an in vitro dissolution–permeation study, an in vivo pharmacokinetic study in rats, and an ex vivo skin permeation study in rats were performed. The mean particle size of all the composite nanoparticles produced was less than 300 nm. Compared to micronized trans-resveratrol, the trans-resveratrol/hydroxylpropylmethyl cellulose (HPMC)/poloxamer 407 (1:4:1) nanoparticles with the highest flux (0.792 μg/min/cm2) exhibited rapid absorption and showed significantly higher exposure 4 h after oral administration. Good correlations were observed between in vitro flux and in vivo pharmacokinetic data. The increased solubility and flux of trans-resveratrol generated by the HPMC/surfactant nanoparticles increased the driving force on the gastrointestinal epithelial membrane and rat skin, resulting in enhanced oral and skin delivery of trans-resveratrol. HPMC/surfactant nanoparticles produced by an SAS process are, thus, a promising formulation method for trans-resveratrol for healthcare products (owing to their enhanced absorption via oral administration) and for skin application with cosmetic products.
Railway Track Monitoring Using Train Measurements: An Experimental Case Study
Authors: Malekjafarian Abdollah , OBrien Eugene , Quirke Paraic , Bowe Cathal
Published: November 2019

This paper investigates the use of drive-by train measurements for railway track monitoring. An in-service Irish Rail train was instrumented while using accelerometers and a global positioning system. The measurements were taken over two months and the train bogie accelerations from 60 passes on the Dublin-Belfast line were used for this study. A 6 km section of the line is the particular focus, where the maintenance measurements from a Track Recording Vehicle (TRV) were available. The Hilbert transform is used to obtain the instantaneous amplitudes of the acceleration signals. A new representation of the signal is proposed to show the signal energy level as a function of train location. It is shown that the forward speed of the train has a significant influence on the energy level of the signals. Therefore, a two-step speed correction is applied to the data. First, data from passes with forward speed below a certain limit are removed from the data set. Subsequently, a scaling factor is defined for the remaining signals and the energy levels of those signals are scaled while using online speed measurements. The scaled amplitudes are compared with the TRV data. It is shown that the energy levels of the signals match the TRV measurements very well.
2D Positioning Control System for the Planar Motion of a Nanopositioning Platform
Authors: Díaz-Pérez Lucía , Torralba Marta , Albajez José Antonio , Yagüe-Fabra José Antonio
Published: November 2019

A novel nanopositioning platform (referred as NanoPla) in development has been designed to achieve nanometre resolution in a large working range of 50 mm × 50 mm. Two-dimensional (2D) movement is performed by four custom-made Halbach linear motors, and a 2D laser system provides positioning feedback, while the moving part of the platform is levitating and unguided. For control hardware, this work proposes the use of a commercial generic solution, in contrast to other systems where the control hardware and software are specifically designed for that purpose. In a previous paper based on this research, the control system of one linear motor implemented in selected commercial hardware was presented. In this study, the developed control system is extended to the four motors of the nanopositioning platform to generate 2D planar movement in the whole working range of the nanopositioning platform. In addition, the positioning uncertainty of the control system is assessed. The obtained results satisfy the working requirements of the NanoPla, achieving a positioning uncertainty of ±0.5 µm along the whole working range.
Wind Load Characteristics of Wind Barriers Induced by High-Speed Trains Based on Field Measurements
Authors: Zou Yunfeng , Fu Zhengyi , He Xuhui , Cai Chenzhi , Zhou Jia , Zhou Shuai
Published: November 2019

This paper focuses on field measurements and analyses of train-generated wind loads on wind barriers (3.0 m height and porosity 0%) with respect to different running speeds of the CRH380A EMU vehicle. Multi-resolution analysis was conducted to identify the pressure distribution in different frequency bands. Results showed that the wind pressure on the wind barrier caused by train-induced wind had two significant impacts with opposite directions, which were the “head wave” and “tail wave”. The peak wind pressure on the wind barrier was approximately proportional to the square of the speed of the train, and the peak wind pressure decreased rapidly along the wind barrier height from the bottom of the wind barrier. The maximum wind pressure occurred at the rail surface height. Furthermore, results of the multi-resolution analysis illustrated that the energy of the frequency band from 0 to 2.44 Hz accounted for 94% of the total energy. This indicated that the low-frequency range component of the wind pressure dominated the design of the wind barrier. The frequency of pulse excitation of train-induced wind loads may overlap with the natural frequency of barriers, and may lead to fatigue failure due to cyclic loads generated by the repeated passage of high-speed trains. In addition, the speed of the train had a negligible effect on the energy distribution of the wind pressure in the frequency domain, while the extreme pressure increased slightly with the increase of the speed of the train.
Mechanical Analysis of Grouted Sleeve Lapping Connector
Authors: Yu Qiong , Sun Jiaqiu , Xu Zhiyuan , Li Lingzhi , Zhang Zhi , Yu Shaole
Published: November 2019

Compared to grouted splice connectors that have been widely used in constructing precast concrete structures, grouted sleeve lapping connectors have the advantages of a large sleeve interior diameter and low manufacturing cost. In this study, 16 grouted sleeve lapping connectors and three grouted splice connectors were tested under an incremental tensile load. The differences in their tensile capacities and failure modes, especially the mechanical properties of the grouted sleeve lapping connectors, were investigated. It was found that the tensile capacities of the grouted sleeve lapping connectors were up to 2.45 times that of the grouted splice connectors when the sleeve inner surfaces were smooth. All of the grouted sleeve lapping connectors failed by a bar tensile fracture or bar-grout slip, whereas the only failure mode of the grouted splice connectors was grout-sleeve failure. The bond stress distribution around the inserted bar in the grouted sleeve lapping connector was similar to the bond stress distribution around a single bar anchored in concrete. The ultimate hoop compressive strain of the sleeve and the corresponding load increase with greater lap length. In addition, an approximate mechanical model with high reliability was put forward to describe the mechanical properties of the grouted sleeve lapping connector.
Deep Learning Model Comparison for Vision-Based Classification of Full/Empty-Load Trucks in Earthmoving Operations
Authors: Liu Quan , Feng Chen , Song Zida , Louis Joseph , Zhou Jian
Published: November 2019

Earthmoving is an integral civil engineering operation of significance, and tracking its productivity requires the statistics of loads moved by dump trucks. Since current truck loads’ statistics methods are laborious, costly, and limited in application, this paper presents the framework of a novel, automated, non-contact field earthmoving quantity statistics (FEQS) for projects with large earthmoving demands that use uniform and uncovered trucks. The proposed FEQS framework utilizes field surveillance systems and adopts vision-based deep learning for full/empty-load truck classification as the core work. Since convolutional neural network (CNN) and its transfer learning (TL) forms are popular vision-based deep learning models and numerous in type, a comparison study is conducted to test the framework’s core work feasibility and evaluate the performance of different deep learning models in implementation. The comparison study involved 12 CNN or CNN-TL models in full/empty-load truck classification, and the results revealed that while several provided satisfactory performance, the VGG16-FineTune provided the optimal performance. This proved the core work feasibility of the proposed FEQS framework. Further discussion provides model choice suggestions that CNN-TL models are more feasible than CNN prototypes, and models that adopt different TL methods have advantages in either working accuracy or speed for different tasks.
Gradient-Guided Convolutional Neural Network for MRI Image Super-Resolution
Authors: Du Xiaofeng , He Yifan
Published: November 2019

Super-resolution (SR) technology is essential for improving image quality in magnetic resonance imaging (MRI). The main challenge of MRI SR is to reconstruct high-frequency (HR) details from a low-resolution (LR) image. To address this challenge, we develop a gradient-guided convolutional neural network for improving the reconstruction accuracy of high-frequency image details from the LR image. A gradient prior is fully explored to supply the information of high-frequency details during the super-resolution process, thereby leading to a more accurate reconstructed image. Experimental results of image super-resolution on public MRI databases demonstrate that the gradient-guided convolutional neural network achieves better performance over the published state-of-art approaches.
A Novel X-Ray Radiation Sensor Based on Networked SnO2 Nanowires
Authors: Kim Jae-Hun , Mirzaei Ali , Kim Hyoun Woo , Kim Hong Joo , Quoc Vuong Phan , Kim Sang Sub
Published: November 2019

X-Ray radiation sensors that work at room temperature are in demand. In this study, a novel, low-cost real-time X-ray radiation sensor based on SnO2 nanowires (NWs) was designed and tested. Networked SnO2 NWs were produced via the vapor–liquid–solid technique. X-ray diffraction (XRD), transmission electron microscopy (TEM) and field emission scanning electron microscopy (SEM) analyses were used to explore the crystallinity and morphology of synthesized SnO2 NWs. The fabricated sensor was exposed to X-rays (80 kV, 0.0–2.00 mA) and the leakage current variations were recorded at room temperature. The SnO2 NWs sensor showed a high and relatively linear response with respect to the X-ray intensity. The X-ray sensing results show the potential of networked SnO2 NWs as novel X-ray sensors.
Situated Psychological Agents: A Methodology for Educational Games
Authors: Ponticorvo Michela , Dell’Aquila Elena , Marocco Davide , Miglino Orazio
Published: November 2019

In recent years, the ever-increasing need for valid and effective training to acquire competences in multiform contexts has led to a wide diffusion of educational games (EG). In spite of their diffusion, there is still a need to reflect on the design process that should embed the games’ pedagogical potential and the instructional process in the entertainment scope. Moreover, as building EG, especially in digital environments, is an enterprise that involves specialists with different expertise, it can be useful to have a shared methodology that is easily understandable and usable by many users. In this paper, we propose to use situated psychological agents (SPA) as a methodology to design and build effective EG and show how to represent games in terms of SPA and their interactions by diagrams and describe different examples of how this approach has been applied.
Estimation of Transition Frequency during Continuous Translation Surface Perturbation
Authors: Mohd Ramli Nur Fatin Fatina , Mat Dzahir Mohd Azuwan , Yamamoto Shin-Ichiroh
Published: November 2019

Depending on task requirements, a human is able to select distinct strategies such as the use of an ankle strategy and hip strategy to maintain their balance. Postural control actions often co-occur with other movements, and such movements may bring about a change from one type of postural coordination to another. The selection of a postural control strategy has typically been investigated by the transition of the center of mass (COM), center of pressure (COP), and in between angle joint motion along with their characteristics. In this paper, we proposed a method using the logistic function of the sigmoid model based on cross-correlation coefficient (CCF) data for investigating and observing the transition of postural control strategies of COM–COP and ankle-hip angles towards anterior–posterior (AP) continuous translation perturbation. Subjects were required to stand on the motion base platform where perturbations with an increasing frequency (0.2 Hz to 0.8 Hz) and decreasing frequency (0.8 Hz to 0.2 Hz) in steps of 0.02 Hz, were induced. As the frequency increased, the COM and COP displacements were decreased, with the opposite trend observable with decreasing frequency. This pattern was also observed at the head peak-to-peak amplitude. Meanwhile, ankle and hip angular displacements were increased during increasing frequency and decreased during decreasing frequency. In this paper, the proposed sigmoid model could identify the transition frequency of COM–COP and ankle–hip transition. The mean transition frequency of COM–COP during increasing frequency was 0.44 Hz, and the ankle–hip transition frequency was 0.42 Hz. Meanwhile, for decreasing frequency, the COM–COP transition frequency was 0.55 Hz, and for the ankle–hip transition the frequency was 0.56 Hz. With frequencies, both increasing and decreasing, the COM–COP and ankle–hip transition frequencies occurred almost at the same frequency. Furthermore, the transition occurred at a lower time scale during increasing frequency compared to decreasing frequency. In conclusion, the continuous translation surface perturbation provided information on the behavior of postural control strategies. A sudden change in ‘phase angle’ was observed, where either an ankle or hip strategy was implemented to maintain balance. Besides, the transition frequency of postural control strategies could be determined to occur between 0.4 Hz and 0.6 Hz, based on the average value, for healthy young subjects in the AP plane. Furthermore, the proposed sigmoid model was believed to be able to be used in the determination of transition frequency in postural control strategies.
Dual-Polarization Radar Observations of Deep Convection over Lake Victoria Basin in East Africa
Authors: Waniha Pascal F. , Roberts Rita D. , Wilson James W. , Kijazi Agnes , Katole Benedicto
Published: November 2019

Lake Victoria in East Africa supports the livelihood of thousands of fishermen and it is estimated that 3000–5000 human deaths occur per year over the lake. It is hypothesized that most of these fatalities are due to localized, severe winds produced by intense thunderstorms over the lake during the rainy season and larger scale, intense winds over the lake during the dry season. The intense winds produce a rough state of the lake (big wave heights) that cause fishing boats to capsize. In this region, weather radars have never been a primary tool for monitoring and nowcasting high impact weather. The Tanzania Meteorological Agency operates an S-band polarimetric radar in Mwanza, Tanzania, along the south shore of Lake Victoria. This radar collects high temporal and spatial resolution data that is now being used to detect and monitor the formation of deep convection over the lake and improve scientific understanding of storm dynamics and intensification. Nocturnal thunderstorms and convection initiation over the lake are well observed by the Mwanza radar and are strongly forced by lake and land breezes and gust fronts. Unexpected is the detection of clear air echo to ranges ≥100 km over the lake that makes it possible to observe low-level winds, gust fronts, and other convergence lines near the surface of the lake. The frequent observation of extensive clear air and low-level convergence lines opens up the opportunity to nowcast strong winds, convection initiation, and subsequent thunderstorm development and incorporate this information into a regional early warning system proposed for Lake Victoria Basin (LVB). Two weather events are presented illustrating distinctly different nocturnal convection initiation over the lake that evolve into intense morning thunderstorms. The evolution of these severe weather events was possible because of the Mwanza radar observations; satellite imagery alone was insufficient to provide prediction of storm initiation, growth, movement, and decay.
Influences of the Atlantic and Pacific Oceans on Rainy Season Precipitation for the Southernmost Caribbean Small Island State, Trinidad
Authors: Mc Shine Nkese D. , Clarke Ricardo M. , Gualdi Silvio , Navarra Antonio , Chadee Xsitaaz T.
Published: November 2019

Seasonal rainfall in the Caribbean Basin is known to be modulated by sea surface temperature anomalies (SSTAs) in the Atlantic and Pacific Oceans, and particularly those in the Equatorial Pacific and Atlantic and the Tropical North Atlantic. However, little is known about how these major oceans influence the seasonal precipitation of individual small island states within the region as climate variability at the island-scale may differ from the Caribbean as a whole. Correlation and composite analyses were determined using monthly rainfall data for the southernmost island of the Caribbean, Trinidad, and an extended area of global SSTAs. In addition to the subregions that are known to modulate Caribbean rainfall, our analyses show that sea surface temperatures (SSTs) located in the subtropical South Pacific, the South Atlantic, and the Gulf of Mexico also have weak (r2 < 0.5) yet significant influences on the islands’ early rainy season (ERS) and late rainy season (LRS) precipitation. Composite maps confirm that the South Pacific, South Atlantic, and the Gulf of Mexico show significant SSTAs in December–January–February (DJF) and March–April–May (MAM) prior to the ERS and the LRS. Statistical models for seasonal forecasting of rainfall at the island scale could be improved by using the SSTAs of the Pacific and Atlantic subregions identified in this study.
Aerosol Optical Depth of the Main Aerosol Species over Italian Cities Based on the NASA/MERRA-2 Model Reanalysis
Authors: Rizza Umberto , Mancinelli Enrico , Morichetti Mauro , Passerini Giorgio , Virgili Simone
Published: November 2019

The Modern-Era Retrospective Analysis for Research and Applications, version 2 (MERRA-2) provides data at 0.5° × 0.625° resolution covering a period from 1 January 1980 to the present. Natural and anthropogenic aerosols are simulated in MERRA-2, considering the Goddard chemistry, aerosol, radiation, and transport model. This model simulates the sources, sinks, and chemistry of mixed aerosol tracers: dust, sea salt, hydrophobic and hydrophilic black carbon and organic carbon, and sulfate. MERRA-2 aerosol reanalysis is a pioneering tool for investigating air quality issues, noteworthy for its global coverage and its distinction of aerosol speciation expressed in the form of aerosol optical depth (AOD). The aim of this work was to use the MERRA-2 reanalysis to study urban air pollution at a national scale by analyzing the AOD. AOD trends were evaluated for a 30-year period (1987–2017) over five Italian cities (Milan, Rome, Cagliari, Taranto, and Palermo) in order to investigate the impacts of urbanization, industrialization, air quality regulations, and regional transport on urban aerosol load. AOD evolution predicted by the MERRA-2 model in the period 2002–2017 showed a generalized decreasing trend over the selected cities. The anthropogenic signature on total AOD was between 50% and 80%, with the largest contribution deriving from sulfate.
Transcriptional Profiling and Molecular Characterization of the yccT Mutant Link: A Novel STY1099 Protein with the Peroxide Stress Response and Cell Division of Salmonella enterica Serovar Enteritidis
Authors: Vidovic Sinisa , Liu Xiaoying , An Ran , Mendoza Kristelle M. , Abrahante Juan E. , Johny Anup K. , Reed Kent M.
Published: November 2019

Uncharacterized protein STY1099, encoded by the yccT gene, was previously identified as the most altered (i.e., upregulated) protein among the ZnO nanoparticle (NP) stimulon of Salmonella enterica serovar Enteritidis. Here we combined various stress response-related assays with functional genetics, global transcriptomic and proteomic analyses to characterize the yccT gene and its STY1099 product. Exposure of S. enterica Enteritidis to H2O2 (i.e., hydrogen peroxide) resulted in a significant (p < 0.0001) upregulation of the yccT gene, whereas exposure to paraquat (i.e., superoxide) did not alter the expression of the yccT gene. The ∆yccT mutant of S. enterica Enteritidis exposed to 0.75 mM H2O2, showed significantly reduced (p < 0.05) viability compared to the wild type strain. Further, comparative transcriptome analyses supported by Co-immunoprecipitation (Co-IP) assay revealed that STY1099 protein plays a role in redox homeostasis during the peroxide stress assault via involvement in the processes of respiratory nitrate reductase, oxidoreductase activities, cellular uptake and stress response. In addition, we found that the STY1099 protein has the monopolar subcellular location and that it interacts with key cell division proteins, MinD, and FtsH, as well as with a rod shape-determining protein MerB.
Role of Reactive Oxygen Species in Cancer Progression: Molecular Mechanisms and Recent Advancements
Authors: Aggarwal Vaishali , Tuli Hardeep , Varol Ayşegül , Thakral Falak , Yerer Mukerrem , Sak Katrin , Varol Mehmet , Jain Aklank , Khan Md. , Sethi Gautam
Published: November 2019

Reactive oxygen species (ROS) play a pivotal role in biological processes and continuous ROS production in normal cells is controlled by the appropriate regulation between the silver lining of low and high ROS concentration mediated effects. Interestingly, ROS also dynamically influences the tumor microenvironment and is known to initiate cancer angiogenesis, metastasis, and survival at different concentrations. At moderate concentration, ROS activates the cancer cell survival signaling cascade involving mitogen-activated protein kinase/extracellular signal-regulated protein kinases 1/2 (MAPK/ERK1/2), p38, c-Jun N-terminal kinase (JNK), and phosphoinositide-3-kinase/ protein kinase B (PI3K/Akt), which in turn activate the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), matrix metalloproteinases (MMPs), and vascular endothelial growth factor (VEGF). At high concentrations, ROS can cause cancer cell apoptosis. Hence, it critically depends upon the ROS levels, to either augment tumorigenesis or lead to apoptosis. The major issue is targeting the dual actions of ROS effectively with respect to the concentration bias, which needs to be monitored carefully to impede tumor angiogenesis and metastasis for ROS to serve as potential therapeutic targets exogenously/endogenously. Overall, additional research is required to comprehend the potential of ROS as an effective anti-tumor modality and therapeutic target for treating malignancies.
Exploring Biological Activity of 4-Oxo-4H-furo[2,3-h]chromene Derivatives as Potential Multi-Target-Directed Ligands Inhibiting Cholinesterases, β-Secretase, Cyclooxygenase-2, and Lipoxygenase-5/15
Authors: Mphahlele Malose J. , Agbo Emmanuel N. , Gildenhuys Samantha , Setshedi Itumeleng B.
Published: November 2019

A series of 5-oxo-5H-furo[3,2-g]chromene-6-carbaldehydes and their hydrazone derivatives were evaluated as potential multi-target-directed ligands in vitro against cholinesterases, β-secretase, cyclooxygenase-2, and lipoxygenase-15 (LOX-15), as well as for free radical-scavenging activities. The most active compounds against LOX-15 were also evaluated for activity against the human lipoxygenase-5 (LOX-5). Kinetic studies against AChE, BChE, and β-secretase (BACE-1) were performed on 2-(3-fluorophenyl)- (3b) and 2-(4-chlorophenyl)-6-[(4-trifluoromethylphenyl)hydrazonomethyl]furo[3,2-h]chromen-5-one (3e) complemented with molecular docking (in silico) to determine plausible protein-ligand interactions on a molecular level. The docking studies revealed hydrogen and/or halogen bonding interactions between the strong electron-withdrawing fluorine atoms of the trifluoromethyl group with several residues of the enzyme targets, which are probably responsible for the observed increased biological activity of these hydrazone derivatives. The two compounds were found to moderately inhibit COX-2 and lipoxygenases (LOX-5 and LOX-15). Compounds 3b and 3e were also evaluated for cytotoxicity against the breast cancer MCF-7 cell line and Hek293-T cells.
Bioelectrical Analysis of Various Cancer Cell Types Immobilized in 3D Matrix and Cultured in 3D-Printed Well
Authors: Paivana Georgia , Mavrikou Sophie , Kaltsas Grigoris , Kintzios Spyridon
Published: November 2019

Cancer cell lines are important tools for anticancer drug research and assessment. Impedance measurements can provide valuable information about cell viability in real time. This work presents the proof-of-concept development of a bioelectrical, impedance-based analysis technique applied to four adherent mammalian cancer cells lines immobilized in a three-dimensional (3D) calcium alginate hydrogel matrix, thus mimicking in vivo tissue conditions. Cells were treated with cytostatic agent5-fluoruracil (5-FU). The cell lines used in this study were SK-N-SH, HEK293, HeLa, and MCF-7. For each cell culture, three cell population densities were chosen (50,000, 100,000, and 200,000 cells/100 μL). The aim of this study was the extraction of mean impedance values at various frequencies for the assessment of the different behavior of various cancer cells when 5-FU was applied. For comparison purposes, impedance measurements were implemented on untreated immobilized cell lines. The results demonstrated not only the dependence of each cell line impedance value on the frequency, but also the relation of the impedance level to the cell population density for every individual cell line. By establishing a cell line-specific bioelectrical behavior, it is possible to obtain a unique fingerprint for each cancer cell line reaction to a selected anticancer agent.
Distinct Montages of Slow Oscillatory Transcranial Direct Current Stimulation (so-tDCS) Constitute Different Mechanisms during Quiet Wakefulness
Authors: Koo-Poeggel Ping , Böttger Verena , Marshall Lisa
Published: November 2019

Slow oscillatory- (so-) tDCS has been applied in many sleep studies aimed to modulate brain rhythms of slow wave sleep and memory consolidation. Yet, so-tDCS may also modify coupled oscillatory networks. Efficacy of weak electric brain stimulation is however variable and dependent upon the brain state at the time of stimulation (subject and/or task-related) as well as on stimulation parameters (e.g., electrode placement and applied current. Anodal so-tDCS was applied during wakefulness with eyes-closed to examine efficacy when deviating from the dominant brain rhythm. Additionally, montages of different electrodes size and applied current strength were used. During a period of quiet wakefulness bilateral frontolateral stimulation (F3, F4; return electrodes at ipsilateral mastoids) was applied to two groups: ‘Group small’ (n = 16, f:8; small electrodes: 0.50 cm2; maximal current per electrode pair: 0.26 mA) and ‘Group Large’ (n = 16, f:8; 35 cm2; 0.35 mA). Anodal so-tDCS (0.75 Hz) was applied in five blocks of 5 min epochs with 1 min stimulation-free epochs between the blocks. A finger sequence tapping task (FSTT) was used to induce comparable cortical activity across sessions and subject groups. So-tDCS resulted in a suppression of alpha power over the parietal cortex. Interestingly, in Group Small alpha suppression occurred over the standard band (8–12 Hz), whereas for Group Large power of individual alpha frequency was suppressed. Group Small also revealed a decrease in FSTT performance at retest after stimulation. It is essential to include concordant measures of behavioral and brain activity to help understand variability and poor reproducibility in oscillatory-tDCS studies.
Cystometric Measurements in Rats with an Experimentally Induced Traumatic Brain Injury and Voiding Dysfunction: A Time-Course Study
Authors: Praveen Rajneesh Chellappan , Yang Ling-Yu , Chen Shih-Ching , Hsieh Tsung-Hsun , Chin Hung-Yen , Peng Chih-Wei
Published: November 2019

Traumatic brain injuries (TBIs) are a serious public health issue worldwide with increased mortality as well as severe disabilities and injuries caused by falls and road accidents. Unfortunately, there is no approved therapy for TBIs, and bladder dysfunction is a striking symptom. Accordingly, we attempted to analyze bladder dysfunction and voiding efficiency in rats with a TBI at different time-course intervals. Time-dependent analyses were scheduled from the next day until four weeks after a TBI. Experimental animals were grouped and analyzed under the above conditions. Cystometric measurements were used for this analysis and were further elaborated as external urethral sphincter electromyographic (EUS-EMG) activity and cystometrogram (CMG) measurements. Moreover, magnetic resonance imaging (MRI) studies were conducted to investigate secondary injury progression in TBI rats, and results were compared to normal control (NC) rats. Results of EUS-EMG revealed that the burst period, active period, and silent period in TBI rats were drastically reduced compared to NC rats, but they increased later and reached a stagnant phase. Likewise, in CMG measurements, bladder function, the voided volume, and voiding efficiency decreased immediately after the TBI, and other parameters like the volume threshold, inter-contraction interval, and residual volume drastically increased. Later, those levels changed, and all observed results were compared to NC rats. MRI results revealed the prevalence of cerebral edema and the progression of secondary injury. All of the above-stated results of the experiments were extensively substantiated. Thus, these innovative findings of our study model will surely pave the way for new therapeutic interventions for TBI treatment and prominently highlight their applications in the field of neuroscience in the future.
EEG Emotion Classification Using an Improved SincNet-Based Deep Learning Model
Authors: Zeng Hong , Wu Zhenhua , Zhang Jiaming , Yang Chen , Zhang Hua , Dai Guojun , Kong Wanzeng
Published: November 2019

Deep learning (DL) methods have been used increasingly widely, such as in the fields of speech and image recognition. However, how to design an appropriate DL model to accurately and efficiently classify electroencephalogram (EEG) signals is still a challenge, mainly because EEG signals are characterized by significant differences between two different subjects or vary over time within a single subject, non-stability, strong randomness, low signal-to-noise ratio. SincNet is an efficient classifier for speaker recognition, but it has some drawbacks in dealing with EEG signals classification. In this paper, we improve and propose a SincNet-based classifier, SincNet-R, which consists of three convolutional layers, and three deep neural network (DNN) layers. We then make use of SincNet-R to test the classification accuracy and robustness by emotional EEG signals. The comparable results with original SincNet model and other traditional classifiers such as CNN, LSTM and SVM, show that our proposed SincNet-R model has higher classification accuracy and better algorithm robustness.
Is there an Exposure–Response Relationship for Nivolumab in Real-World NSCLC Patients?
Authors: Bellesoeur Audrey , Ollier Edouard , Allard Marie , Hirsch Laure , Boudou-Rouquette Pascaline , Arrondeau Jennifer , Thomas-Schoemann Audrey , Tiako Manuela , Khoudour Nihel , Chapron Jeanne , Giraud Frédérique , Wislez Marie , Damotte Diane , Lupo Audrey , Vidal Michel , Alexandre Jérôme , Goldwasser François , Tod Michel , Blanchet Benoit
Published: November 2019

Pharmacokinetic/pharmacodynamic data from real-world cohort are sparse in non small–cell lung cancer (NSCLC) patients treated with nivolumab. The aim of this prospective observational study was to explore the exposure-response relationship for effectiveness and toxicity of nivolumab in 81 outpatients with metastatic lung cancer. Nivolumab plasma trough concentrations (Cmin) were assayed at days 14, 28, and 42. Prognostic factors (including Cmin) regarding progression-free survival (PFS) and overall survival (OS) were explored using a multivariate Cox model. A Spearman’s rank test was used to investigate the relationship between Cmin and grade >2 immune-related adverse events (irAE). Mean nivolumab Cmin was 16.2 ± 6.0 µg/mL (n = 76), 25.6 ± 10.2 µg/mL (n = 64) and 33.4 ± 11.3 µg/mL (n = 53) at days 14, 28, and 42, respectively. No pharmacokinetic/pharmacodynamic (PK/PD) relationship was observed with either survival or onset of irAE. Multivariable Cox regression analysis identified Eastern Cooperative Oncology Group Performance Status (hazard ratio 1.85, 95%confidence interval 1.02–3.38, p-value = 0.043) and baseline use of corticosteroids (HR 8.08, 95%CI 1.78–36.62, p-value = 0.007) as independent risk factor for PFS and only baseline use of corticosteroids (HR 6.29, 95%CI 1.46–27.08, p-value = 0.013) for OS. No PK/PD relationship for nivolumab was observed in real-world NSCLC patients. This supports the recent use of flat dose regimens without plasma drug monitoring.
Ionizing Radiation and Complex DNA Damage: From Prediction to Detection Challenges and Biological Significance
Authors: Mavragani Ifigeneia V. , Nikitaki Zacharenia , Kalospyros Spyridon A. , Georgakilas Alexandros G.
Published: November 2019

Biological responses to ionizing radiation (IR) have been studied for many years, generally showing the dependence of these responses on the quality of radiation, i.e., the radiation particle type and energy, types of DNA damage, dose and dose rate, type of cells, etc. There is accumulating evidence on the pivotal role of complex (clustered) DNA damage towards the determination of the final biological or even clinical outcome after exposure to IR. In this review, we provide literature evidence about the significant role of damage clustering and advancements that have been made through the years in its detection and prediction using Monte Carlo (MC) simulations. We conclude that in the future, emphasis should be given to a better understanding of the mechanistic links between the induction of complex DNA damage, its processing, and systemic effects at the organism level, like genomic instability and immune responses.
Proteostasis in the Endoplasmic Reticulum: Road to Cure
Authors: Nam Su Min , Jeon Young Joo
Published: November 2019

The endoplasmic reticulum (ER) is an interconnected organelle that is responsible for the biosynthesis, folding, maturation, stabilization, and trafficking of transmembrane and secretory proteins. Therefore, cells evolve protein quality-control equipment of the ER to ensure protein homeostasis, also termed proteostasis. However, disruption in the folding capacity of the ER caused by a large variety of pathophysiological insults leads to the accumulation of unfolded or misfolded proteins in this organelle, known as ER stress. Upon ER stress, unfolded protein response (UPR) of the ER is activated, integrates ER stress signals, and transduces the integrated signals to relive ER stress, thereby leading to the re-establishment of proteostasis. Intriguingly, severe and persistent ER stress and the subsequently sustained unfolded protein response (UPR) are closely associated with tumor development, angiogenesis, aggressiveness, immunosuppression, and therapeutic response of cancer. Additionally, the UPR interconnects various processes in and around the tumor microenvironment. Therefore, it has begun to be delineated that pharmacologically and genetically manipulating strategies directed to target the UPR of the ER might exhibit positive clinical outcome in cancer. In the present review, we summarize recent advances in our understanding of the UPR of the ER and the UPR of the ER–mitochondria interconnection. We also highlight new insights into how the UPR of the ER in response to pathophysiological perturbations is implicated in the pathogenesis of cancer. We provide the concept to target the UPR of the ER, eventually discussing the potential of therapeutic interventions for targeting the UPR of the ER for cancer treatment.
HDAC Inhibitors in Acute Myeloid Leukemia
Authors: San José-Enériz Edurne , Gimenez-Camino Naroa , Agirre Xabier , Prosper Felipe
Published: November 2019

Acute myeloid leukemia (AML) is a hematological malignancy characterized by uncontrolled proliferation, differentiation arrest, and accumulation of immature myeloid progenitors. Although clinical advances in AML have been made, especially in young patients, long-term disease-free survival remains poor, making this disease an unmet therapeutic challenge. Epigenetic alterations and mutations in epigenetic regulators contribute to the pathogenesis of AML, supporting the rationale for the use of epigenetic drugs in patients with AML. While hypomethylating agents have already been approved in AML, the use of other epigenetic inhibitors, such as histone deacetylases (HDAC) inhibitors (HDACi), is under clinical development. HDACi such as Panobinostat, Vorinostat, and Tricostatin A have been shown to promote cell death, autophagy, apoptosis, or growth arrest in preclinical AML models, yet these inhibitors do not seem to be effective as monotherapies, but rather in combination with other drugs. In this review, we discuss the rationale for the use of different HDACi in patients with AML, the results of preclinical studies, and the results obtained in clinical trials. Although so far the results with HDACi in clinical trials in AML have been modest, there are some encouraging data from treatment with the HDACi Pracinostat in combination with DNA demethylating agents.
Involvement of the Chemokine Prokineticin-2 (PROK2) in Alzheimer’s Disease: From Animal Models to the Human Pathology
Authors: Lattanzi Roberta , Maftei Daniela , Petrella Carla , Pieri Massimo , Sancesario Giulia , Schirinzi Tommaso , Bernardini Sergio , Barbato Christian , Ralli Massimo , Greco Antonio , Possenti Roberta , Sancesario Giuseppe , Severini Cinzia
Published: November 2019

Among mediators of inflammation, chemokines play a pivotal role in the neuroinflammatory process related to Alzheimer’s disease (AD). The chemokine Bv8/prokineticin 2 (PROK2) is a critical player in inflammatory and neuroinflammatory diseases and has been demonstrated to be involved in Aβ toxicity. The aim of the present study was to extend the research to rats chronically intracerebroventricularly (i.c.v.) injected with Aβ, to an AD transgenic mouse model, and subsequently to AD patients, mainly with the aim of detecting a potential biomarker. Real-time PCR and immunofluorescence analysis were used to evaluate Prokineticin-2 (PROK2) mRNA and the corresponding protein levels in both animal and human AD brain extracts, and the ELISA test was used to measure the amount of PROK2 in the serum of AD patients. We demonstrated a significant upregulation of PROK2 levels in brain tissues of Aβ1–42 i.c.v. injected rats, transgenic AD mice (Tg2576), and in the hippocampus of AD patients. Additionally, through a pilot study, an approximate twofold increase of PROK2 levels has been proved in the serum of AD patients, compared to the control subjects, identifying a potential blood-based biomarker of the disease.
Hits Discovery on the Androgen Receptor: In Silico Approaches to Identify Agonist Compounds
Authors: Réau Manon , Lagarde Nathalie , Zagury Jean-François , Montes Matthieu
Published: November 2019

The androgen receptor (AR) is a transcription factor that plays a key role in sexual phenotype and neuromuscular development. AR can be modulated by exogenous compounds such as pharmaceuticals or chemicals present in the environment, and particularly by AR agonist compounds that mimic the action of endogenous agonist ligands and whether restore or alter the AR endocrine system functions. The activation of AR must be correctly balanced and identifying potent AR agonist compounds is of high interest to both propose treatments for certain diseases, or to predict the risk related to agonist chemicals exposure. The development of in silico approaches and the publication of structural, affinity and activity data provide a good framework to develop rational AR hits prediction models. Herein, we present a docking and a pharmacophore modeling strategy to help identifying AR agonist compounds. All models were trained on the NR-DBIND that provides high quality binding data on AR and tested on AR-agonist activity assays from the Tox21 initiative. Both methods display high performance on the NR-DBIND set and could serve as starting point for biologists and toxicologists. Yet, the pharmacophore models still need data feeding to be used as large scope undesired effect prediction models.