bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevention of Doxorubicin-Induced Autophagy Attenuates Oxidative Stress and Skeletal Muscle Dysfunction
Authors: Doerr Vivian , Montalvo Ryan N. , Kwon Oh Sung , Talbert Erin E. , Hain Brian A. , Houston Fraser E. , Smuder Ashley J.
Published: March 2020

Clinical use of the chemotherapeutic doxorubicin (DOX) promotes skeletal muscle atrophy and weakness, adversely affecting patient mobility and strength. Although the mechanisms responsible for DOX-induced skeletal muscle dysfunction remain unclear, studies implicate the significant production of reactive oxygen species (ROS) in this pathology. Supraphysiological ROS levels can enhance protein degradation via autophagy, and it is established that DOX upregulates autophagic signaling in skeletal muscle. To determine the precise contribution of accelerated autophagy to DOX-induced skeletal muscle dysfunction, we inhibited autophagy in the soleus via transduction of a dominant negative mutation of the autophagy related 5 (ATG5) protein. Targeted inhibition of autophagy prevented soleus muscle atrophy and contractile dysfunction acutely following DOX administration, which was associated with a reduction in mitochondrial ROS and maintenance of mitochondrial respiratory capacity. These beneficial modifications were potentially the result of enhanced transcription of antioxidant response element-related genes and increased antioxidant capacity. Specifically, our results showed significant upregulation of peroxisome proliferator-activated receptor gamma co-activator 1-alpha, nuclear respiratory factor-1, nuclear factor erythroid-2-related factor-2, nicotinamide-adenine dinucleotide phosphate quinone dehydrogenase-1, and catalase in the soleus with DOX treatment when autophagy was inhibited. These findings establish a significant role of autophagy in the development of oxidative stress and skeletal muscle weakness following DOX administration.
The Benefits and Risks of Certain Dietary Carotenoids that Exhibit both Anti- and Pro-Oxidative Mechanisms—A Comprehensive Review
Authors: Black Homer S. , Boehm Fritz , Edge Ruth , Truscott T. George
Published: March 2020

Carotenoid pigments, particularly β-carotene and lycopene, are consumed in human foodstuffs and play a vital role in maintaining health. β-carotene is known to quench singlet oxygen and can have strong antioxidant activity. As such, it was proposed that β-carotene might reduce the risk of cancer. Epidemiological studies found inverse relationships between cancer risk and β-carotene intake or blood levels. However, clinical trials failed to support those findings and β-carotene supplementation actually increased lung cancer incidence in male smokers. Early experimental animal studies found dietary β-carotene inhibited UV-induced skin cancers. Later studies found that β-carotene supplementation exacerbated UV-carcinogenic expression. The discrepancies of these results were related to the type of diet the animals consumed. Lycopene has been associated with reduced risk of lethal stage prostate cancer. Other carotenoids, e.g., lutein and zeaxanthin, play a vital role in visual health. Numerous studies of molecular mechanisms to explain the carotenoids’ mode of action have centered on singlet oxygen, as well as radical reactions. In cellular systems, singlet oxygen quenching by carotenoids has been reported but is more complex than in organic solvents. In dietary β-carotene supplement studies, damaging pro-oxidant reactivity can also arise. Reasons for this switch are likely due to the properties of the carotenoid radicals themselves. Understanding singlet oxygen reactions and the anti-/pro-oxidant roles of carotenoids are of importance to photosynthesis, vision and cancer.
Green-Sustainable Recovery of Phenolic and Antioxidant Compounds from Industrial Chestnut Shells Using Ultrasound-Assisted Extraction: Optimization and Evaluation of Biological Activities In Vitro
Authors: Lameirão Fátima , Pinto Diana , F. Vieira Elsa , F. Peixoto Andreia , Freire Cristina , Sut Stefania , Dall’Acqua Stefano , Costa Paulo , Delerue-Matos Cristina , Rodrigues Francisca
Published: March 2020

Chestnut processing industry generates large amounts of by-products, including leaves, burs and shells that are a source of bioactive compounds. The purpose of this study was to establish an ultrasound-assisted extraction (UAE) of phenolic and antioxidant compounds from industrial chestnut shells. A central composite design (CCD) was conducted to analyze the effects of time (4–46 min) and temperature (34–76 °C) in the antioxidant activity (2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and ferric reducing antioxidant power (FRAP)) and total phenolic compounds (TPC) of chestnut shells extracts. The optimal extraction conditions were obtained at 70 °C for 40 min. The optimal extract was characterized regarding phenolic profile, radical scavenging capacity, and effects on intestinal and dermal cell lines. The optimal extract revealed high amounts of ellagic acid (40.4 µg/mg dw), followed by caffeic acid derivative (15.4 µg/mg dw) and epigallocatechin (15.3 µg/mg dw). Indeed, the extract exhibited the highest scavenging efficiencies against NO● (IC50 = 0.1 µg/mL) and HOCl (IC50 = 0.7 µg/mL) and did not conducted to a decrease on HaCaT and HFF-1 viability up to 100 μg/mL. Oppositely, a decrease on Caco-2 and HT29-MTX viability was observed. This study suggests that UAE could be a sustainable option to valorize chestnut shells as raw material for different industries.
Dynamics of the Global Stock Market Networks Generated by DCCA Methodology
Authors: Shin Ki-Hong , Lim Gyuchang , Min Seungsik
Published: March 2020

A group of stock markets can be treated as a complex system. We tried to find the financial market crisis by constructing a global 24 stock market network while using detrended cross-correlation analysis. The community structures by the Girvan-Newman method are observed and other network properties, such as the average degree, clustering coefficient, efficiency, and modularity, are quantified. The criterion of correlation between any two markets on the detrended cross-correlation analysis was considered to be 0.7. We used the return (rt) and volatility (|rt|) time series for the periods of 1, 4, 10, and 20-year of composite stock price indices during 1997–2016. Europe (France, Germany, Netherland, UK), USA (USA1, USA2, USA3, USA4) and Oceania (Australia1, Australia2) have been confirmed to make a solid community. This approach also detected the signal of financial crisis, such as Asian liquidity crisis in 1997, world-wide dot-com bubble collapse in 2001, the global financial crisis triggered by the USA in 2008, European sovereign debt crisis in 2010, and the Chinese stock price plunge in 2015 by capturing the local maxima of average degree and efficiency.
Reliable OFDM Data Transmission with Pilot Tones and Error-Correction Coding in Shallow Underwater Acoustic Channel
Authors: Kochanska Iwona
Published: March 2020

The performance of Underwater Acoustic Communication (UAC) systems are strongly related to the specific propagation conditions of the underwater channel. Horizontal, shallow-water channels are characterised by extremely disadvantageous transmission properties, due to strong multipath propagation and refraction phenomena. The paper presents the results of communication tests performed during a shallow, inland-water experiment with the use of a laboratory model of a UAC system implementing the Orthogonal Frequency-Division Multiplexing (OFDM) technique. The physical layer of data transmission is partially configurable, enabling adaptation of the modulation and channel coding parameters to the specific propagation conditions. The communication tests were preceded by measurement of the UAC channel transmission properties. Based on the estimated transmission parameters, four configurations of OFDM modulation parameters were selected, and for each of them, communication tests were performed with the use of two Error-Correction Coding (ECC) techniques. In each case, the minimum coding rate was determined for which reliable data transmission with a Bit Error Rate (BER) of less than 10 − 4 is possible.
Multifocus Image Fusion Using a Sparse and Low-Rank Matrix Decomposition for Aviator’s Night Vision Goggle
Authors: Jian Bo-Lin , Chu Wen-Lin , Li Yu-Chung , Yau Her-Terng
Published: March 2020

This study proposed the concept of sparse and low-rank matrix decomposition to address the need for aviator’s night vision goggles (NVG) automated inspection processes when inspecting equipment availability. First, the automation requirements include machinery and motor-driven focus knob of NVGs and image capture using cameras to achieve autofocus. Traditionally, passive autofocus involves first computing of sharpness of each frame and then use of a search algorithm to quickly find the sharpest focus. In this study, the concept of sparse and low-rank matrix decomposition was adopted to achieve autofocus calculation and image fusion. Image fusion can solve the multifocus problem caused by mechanism errors. Experimental results showed that the sharpest image frame and its nearby frame can be image-fused to resolve minor errors possibly arising from the image-capture mechanism. In this study, seven samples and 12 image-fusing indicators were employed to verify the image fusion based on variance calculated in a discrete cosine transform domain without consistency verification, with consistency verification, structure-aware image fusion, and the proposed image fusion method. Experimental results showed that the proposed method was superior to other methods and compared the autofocus put forth in this paper and the normalized gray-level variance sharpness results in the documents to verify accuracy.
Droplet Size Distribution Characteristics of Aerial Nozzles by Bell206L4 Helicopter under Medium and Low Airflow Velocity Wind Tunnel Conditions and Field Verification Test
Authors: Yao Weixiang , Lan Yubin , Hoffmann W. Clint , Li Jiyu , Guo Shuang , Zhang Huihui , Wang Juan
Published: March 2020

To investigate the spray atomization characteristics of aerial nozzles adapted to manned agricultural helicopters under medium-low airflow velocity (0 to 27.8 m/s) conditions, the droplet size test was carried out in both wind tunnel and field tests. In the wind tunnel test, the laser diffraction device (LDD) was used to test the spray droplet size of CP02, CP03, and CP04 aerial nozzles. A Bell206L4 helicopter was used in the field test. The results in the wind tunnel test showed that due to the nozzles had been used for a long time and the cause of wear, the spray stability of individual nozzles was affected during the test. The limitation of droplet size measurement by using LDD was also found. The field test results showed that the main distribution range of the droplet size measured in the field test was consistent with the results of the wind tunnel test, but the droplet size value was significantly higher and the uniformity of droplet size distribution was poorer than the wind tunnel test value due to the influence of the actual environment. However, the results of field test and wind tunnel test can still be used as a reference for each other.
Web Objects Based Contextual Data Quality Assessment Model for Semantic Data Application
Authors: Jarwar Muhammad Aslam , Chong Ilyoung
Published: March 2020

Due to the convergence of advanced technologies such as the Internet of Things, Artificial Intelligence, and Big Data, a healthcare platform accumulates data in a huge quantity from several heterogeneous sources. The adequate usage of this data may increase the impact of and improve the healthcare service quality; however, the quality of the data may be questionable. Assessing the quality of the data for the task in hand may reduce the associated risks, and increase the confidence of the data usability. To overcome the aforementioned challenges, this paper presents the web objects based contextual data quality assessment model with enhanced classification metric parameters. A semantic ontology of virtual objects, composite virtual objects, and services is also proposed for the parameterization of contextual data quality assessment of web objects data. The novelty of this article is the provision of contextual data quality assessment mechanisms at the data acquisition, assessment, and service level for the web objects enabled semantic data applications. To evaluate the proposed data quality assessment mechanism, web objects enabled affective stress and teens’ mood care semantic data applications are designed, and a deep data quality learning model is developed. The findings of the proposed approach reveal that, once a data quality assessment model is trained on web objects enabled healthcare semantic data, it could be used to classify the incoming data quality in various contextual data quality metric parameters. Moreover, the data quality assessment mechanism presented in this paper can be used to other application domains by incorporating data quality analysis requirements ontology.
A Broadband Active Microwave Monolithically Integrated Circuit Balun in Graphene Technology
Authors: Fadil Dalal , Passi Vikram , Wei Wei , Ben Salk Soukaina , Zhou Di , Strupinski Wlodek , Lemme Max C. , Zimmer Thomas , Pallecchi Emiliano , Happy Henri , Fregonese Sebastien
Published: March 2020

This paper presents the first graphene radiofrequency (RF) monolithic integrated balun circuit. It is composed of four integrated graphene field effect transistors (GFETs). This innovative active balun concept takes advantage of the GFET ambipolar behavior. It is realized using an advanced silicon carbide (SiC) based bilayer graphene FET technology having RF performances of about 20 GHz. Balun circuit measurement demonstrates its high frequency capability. An upper limit of 6 GHz has been achieved when considering a phase difference lower than 10° and a magnitude of amplitude imbalance less than 0.5 dB. Hence, this circuit topology shows excellent performance with large broadband performance and a functionality of up to one-third of the transit frequency of the transistor.
Cryptanalysis of a New Color Image Encryption Using Combination of the 1D Chaotic Map
Authors: Dou Yuqiang , Li Ming
Published: March 2020

Security of image communication is more and more important in many applications such as the transmission of military and medical images. To meet the requirement, a new color image encryption algorithm using a new one-dimension (1D) chaotic map was proposed recently, which can resist various attacks because the range of the new chaotic map is larger than that of the previous ones. In our study, the security of the new original method is analyzed and a novel attack method is proposed. It is demonstrated that the scheme is not secure under chosen-plaintext attack, by which the encrypted image can be successfully converted into the corresponding plaintext image without any error.
Microseismic Signal Denoising via Empirical Mode Decomposition, Compressed Sensing, and Soft-thresholding
Authors: Li Xiang , Dong Linlu , Li Biao , Lei Yifan , Xu Nuwen
Published: March 2020

Microseismic signal denoising is of great significance for P wave, S wave first arrival picking, source localization, and focal mechanism inversion. Therefore, an Empirical Mode Decomposition (EMD), Compressed Sensing (CS), and Soft-thresholding (ST) combined EMD_CS_ST denoising method is proposed. First, through EMD decomposition of the noise signal, a series of Intrinsic Mode Functions (IMF) from high frequency to low frequency are obtained. By calculating the correlation coefficient between each IMF and the original signal, the boundary component between the signal and the noise was identified, and the boundary component and its previous components were sparsely processed in the discrete wavelet transform domain to obtain the original sparse coefficient θ. Second, θ is filtered by ST to get the reconstruction coefficient θnew after denoising. Then, CS was used to recover and reconstruct θnew to get the denoised IMFnew component and then recombined with the remaining IMF components to get the signal after denoising. In the simulation experiment, the denoising process of EMD_CS_ST method is introduced in detail, and the denoising ability of EMD_CS_ST, DWT, EEMD, and VMD_DWT under 10 different noise levels is discussed. The signal-to-noise ratio, signal standard deviation, correlation coefficient, waveform diagram, and spectrogram before and after denoising are compared and analyzed. Moreover, the signals obtained from the underground cavern of the Shuangjiangkou hydropower station were denoised by the EMD_CS_ST method, and the signals before and after denoising were analyzed by time-frequency spectrum. These results show that the proposed method has better denoising ability.
Throughput Analysis of IEEE 802.11 WLANs with Inter-Network Interference
Authors: Liu Jingwei , Aoki Takumi , Li Zhetao , Pei Tingrui , Choi Young-june , Nguyen Kien , Sekiya Hiroo
Published: March 2020

Recently, we often see the environment where many one-to-one Wireless Local Area Networks (WLANs) exist in a small area. In this environment, the network throughput of certain WLAN reduces significantly because of the interference from other networks (i.e., inter-network interference). The inter-network interference is the effect of carrier-sensing activities when there are ongoing transmissions in neighbor networks. This paper presents analytical expressions using airtime concept, which newly take into account the inter-network interference, for network throughputs of WLANs. There are existing works that similarly address the WLAN’s carrier-sensing duration. However, they either consider a simple interference model or assume the simultaneous transmission time is negligible. Different from them, we consider the significant impact of simultaneous transmission. As a result, our analytical model can precisely express each network carrier-sensing duration by subtracting the simultaneous transmission time. More specifically, we have successfully obtained each network throughput by expressing frame-existence probabilities concerning each network’s End Device (ED). We also confirm the validity of the analysis by comparison with simulation. The analytical results and the simulation results agree well.
Parallel Compact Differential Evolution for Optimization Applied to Image Segmentation
Authors: Sui Xiao , Chu Shu-Chuan , Pan Jeng-Shyang , Luo Hao
Published: March 2020

A parallel compact Differential Evolution (pcDE) algorithm is proposed in this paper. The population is separated into multiple groups and the individual is run by using the method of compact Differential Evolution. The communication is implemented after predefined iterations. Two communication strategies are proposed in this paper. The first one is to replace the local optimal solution by global optimal solution in all groups, which is called optimal elite strategy (oe); the second one is to replace the local optimal solution by mean value of the local optimal solution in all groups, which is called mean elite strategy (me). Considering that the pcDE algorithm does not need to store a large number of solutions, the algorithm can adapt to the environment with weak computing power. In order to prove the feasibility of pcDE, several groups of comparative experiments are carried out. Simulation results based on the 25 test functions demonstrate the efficacy of the proposed two communication strategies for the pcDE. Finally, the proposed pcDE is applied to image segmentation and experimental results also demonstrate the superior quality of the pcDE compared with some existing methods.
Topology and Response Surface Optimization of a Bicycle Crank Arm with Multiple Load Cases
Authors: Ismail Ahmad Yusuf , Na Gangta , Koo Bonyong
Published: March 2020

This paper presents an application of topology optimization and response surface method to optimize the geometry of a bicycle crank arm and the experimental validation of it. This is purposely to reduce the crank arm mass and create a preliminary design of a lightweight structure necessary for the high-performance bicycle development. A three-dimensional bike crank arm model was made in the SpaceClaim software followed by a static finite element analysis using ANSYS Workbench 2019 R1. A multiple cycling load was applied simultaneously in seven crank angles of 30, 45, 60, 90, 120, 135, and 150° relative to the horizontal position to create the multiple loads to the crank. From there, topology optimization was then conducted to investigate the effect of mass constraint, stress constraint, angle of cycling, and crank materials on the topological pattern result. To minimize stress concentration at corners, a shape optimization using the response surface method was conducted and obtained the final geometry. From the result, it is shown that both optimization methods not only successfully reduce the crank arm mass and provide several optimum design options but also are able to reduce the maximum stress in the crank arm up to 20% after the optimization process. The experimental validation using a newly developed wireless measurement system shows a considerable agreement to the numerical results.
Improvement of Fog Simulation by the Nudging of Meteorological Tower Data in the WRF and PAFOG Coupled Model
Authors: Kim Wonheung , Yum Seong Soo , Hong Jinkyu , Song Jae In
Published: March 2020

Improvement of fog simulation accuracy was investigated for the fogs that occurred on the south coast of the Korean Peninsula using the WRF (3D) and PAFOG (1D) coupled model. In total, 22 fog cases were simulated and accuracy of the fog simulation was examined based on Critical Success Index, Hit Rate and False Alarm Rate. The performance of the coupled WRF-PAFOG model was better than that of the single WRF model as expected. However, much more significant improvement appeared only when the data from a 300 m meteorological tower was not only used for the initial conditions but also nudged during the simulation. Moreover, a proper prescription of soil moisture was found to be important for accurate fog simulation especially for the fog cases with prior precipitation since efficient moisture supply from the precipitation-soaked soil might have been critical for fog formation. It was also demonstrated that with such optimal coupled model setting, a coastal radiation fog event with prior precipitation could be very realistically simulated: the fog onset and dissipation times matched so well with observation. In detail, radiative cooling at the surface was critical to form a surface inversion layer as the night fell. Then the vapor flux from the precipitation-soaked surface was confined within the inversion layer to form fog. It is suggested that a proper prescription of soil moisture in the model based on observations, if readily available, could be a cost-effective method for improving operational fog forecasting, considering the fact that tall meteorological towers are a rarity in the world.
Generation of Viable Bacterial and Fungal Aerosols during Biomass Combustion
Authors: Mirskaya Ekaterina , Agranovski Igor E.
Published: March 2020

Biomass combustion is known to be one of the main contributors to air pollution. However, the influence of biomass burning on the distribution of viable bacterial and fungal aerosols is uncertain. This study aimed to examine survivability of bacteria and fungi in the post-combustion products, and to investigate the aerosolization of viable cells during combustion of different types of organic materials. Laboratory experiments included a small-scale combustion of organic materials contaminated with microorganisms in order to determine the survivability of microbes in the combustion products and the potential aerosolization of viable cells during combustion. Field experiments were completed during intentional and prescribed biomass burning events in order to investigate the aerosolization mechanisms that are not available at the laboratory scale. Laboratory experiments did not demonstrate aerosolization of microorganisms during biomass combustion. However, the relatively high survival rate of bacteria in the combustion products ought to be accounted for, as the surviving microorganisms can potentially be aerosolized by high velocity natural air flows. Field investigations demonstrated significant increase in the bioaerosol concentration above natural background during and after biomass combustion.
Exploring Successful Parameter Region for Coarse-Grained Simulation of Biomolecules by Bayesian Optimization and Active Learning
Authors: Kanada Ryo , Tokuhisa Atsushi , Tsuda Koji , Okuno Yasushi , Terayama Kei
Published: March 2020

Accompanied with an increase of revealed biomolecular structures owing to advancements in structural biology, the molecular dynamics (MD) approach, especially coarse-grained (CG) MD suitable for macromolecules, is becoming increasingly important for elucidating their dynamics and behavior. In fact, CG-MD simulation has succeeded in qualitatively reproducing numerous biological processes for various biomolecules such as conformational changes and protein folding with reasonable calculation costs. However, CG-MD simulations strongly depend on various parameters, and selecting an appropriate parameter set is necessary to reproduce a particular biological process. Because exhaustive examination of all candidate parameters is inefficient, it is important to identify successful parameters. Furthermore, the successful region, in which the desired process is reproducible, is essential for describing the detailed mechanics of functional processes and environmental sensitivity and robustness. We propose an efficient search method for identifying the successful region by using two machine learning techniques, Bayesian optimization and active learning. We evaluated its performance using F1-ATPase, a biological rotary motor, with CG-MD simulations. We successfully identified the successful region with lower computational costs (12.3% in the best case) without sacrificing accuracy compared to exhaustive search. This method can accelerate not only parameter search but also biological discussion of the detailed mechanics of functional processes and environmental sensitivity based on MD simulation studies.
Interactions between Avibactam and Ceftazidime-Hydrolyzing Class D β-Lactamases
Authors: Frère Jean-Marie , Bogaerts Pierre , Huang Te-Din , Stefanic Patrick , Moray Joël , Bouillenne Fabrice , Brans Alain
Published: March 2020

Class D β-lactamases exhibit very heterogeneous hydrolysis activity spectra against the various types of clinically useful β-lactams. Similarly, and according to the available data, their sensitivities to inactivation by avibactam can vary by a factor of more than 100. In this paper, we performed a detailed kinetic study of the interactions between two ceftazidime-hydrolyzing OXA enzymes and showed that they were significantly more susceptible to avibactam than several other class D enzymes that do not hydrolyze ceftazidime. From a clinical point of view, this result is rather interesting if one considers that avibactam is often administered in combination with ceftazidime.
TGF-β Signaling
Authors: Tzavlaki Kalliopi , Moustakas Aristidis
Published: March 2020

Transforming growth factor-β (TGF-β) represents an evolutionarily conserved family of secreted polypeptide factors that regulate many aspects of physiological embryogenesis and adult tissue homeostasis. The TGF-β family members are also involved in pathophysiological mechanisms that underlie many diseases. Although the family comprises many factors, which exhibit cell type-specific and developmental stage-dependent biological actions, they all signal via conserved signaling pathways. The signaling mechanisms of the TGF-β family are controlled at the extracellular level, where ligand secretion, deposition to the extracellular matrix and activation prior to signaling play important roles. At the plasma membrane level, TGF-βs associate with receptor kinases that mediate phosphorylation-dependent signaling to downstream mediators, mainly the SMAD proteins, and mediate oligomerization-dependent signaling to ubiquitin ligases and intracellular protein kinases. The interplay between SMADs and other signaling proteins mediate regulatory signals that control expression of target genes, RNA processing at multiple levels, mRNA translation and nuclear or cytoplasmic protein regulation. This article emphasizes signaling mechanisms and the importance of biochemical control in executing biological functions by the prototype member of the family, TGF-β.
BMP-SMAD1/5 Signaling Regulates Retinal Vascular Development
Authors: Benn Andreas , Alonso Florian , Mangelschots Jo , Génot Elisabeth , Lox Marleen , Zwijsen An
Published: March 2020

Vascular development is an orchestrated process of vessel formation from pre-existing vessels via sprouting and intussusceptive angiogenesis as well as vascular remodeling to generate the mature vasculature. Bone morphogenetic protein (BMP) signaling via intracellular SMAD1 and SMAD5 effectors regulates sprouting angiogenesis in the early mouse embryo, but its role in other processes of vascular development and in other vascular beds remains incompletely understood. Here, we investigate the function of SMAD1/5 during early postnatal retinal vascular development using inducible, endothelium-specific deletion of Smad1 and Smad5. We observe the formation of arterial-venous malformations in areas with high blood flow, and fewer and less functional tip cells at the angiogenic front. The vascular plexus region is remarkably hyperdense and this is associated with reduced vessel regression and aberrant vascular loop formation. Taken together, our results highlight important functions of SMAD1/5 during vessel formation and remodeling in the early postnatal retina.
The Vitamin D Receptor Regulates Glycerolipid and Phospholipid Metabolism in Human Hepatocytes
Authors: Martínez-Sena Teresa , Soluyanova Polina , Guzmán Carla , Valdivielso José Manuel , Castell José Vicente , Jover Ramiro
Published: March 2020

The vitamin D receptor (VDR) must be relevant to liver lipid metabolism because VDR deficient mice are protected from hepatosteatosis. Therefore, our objective was to define the role of VDR on the overall lipid metabolism in human hepatocytes. We developed an adenoviral vector for human VDR and performed transcriptomic and metabolomic analyses of cultured human hepatocytes upon VDR activation by vitamin D (VitD). Twenty percent of the VDR responsive genes were related to lipid metabolism, including MOGAT1, LPGAT1, AGPAT2, and DGAT1 (glycerolipid metabolism); CDS1, PCTP, and MAT1A (phospholipid metabolism); and FATP2, SLC6A12, and AQP3 (uptake of fatty acids, betaine, and glycerol, respectively). They were rapidly induced (4–6 h) upon VDR activation by 10 nM VitD or 100 µM lithocholic acid (LCA). Most of these genes were also upregulated by VDR/VitD in mouse livers in vivo. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS) metabolomics demonstrated intracellular accumulation of triglycerides, with concomitant decreases in diglycerides and phosphatidates, at 8 and 24 h upon VDR activation. Significant alterations in phosphatidylcholines, increases in lyso-phosphatidylcholines and decreases in phosphatidylethanolamines and phosphatidylethanolamine plasmalogens were also observed. In conclusion, active VitD/VDR signaling in hepatocytes triggers an unanticipated coordinated gene response leading to triglyceride synthesis and to important perturbations in glycerolipids and phospholipids.
The Role of MECP2 and CCR5 Polymorphisms on the Development and Course of Systemic Lupus Erythematosus
Authors: Rzeszotarska Ewa , Sowinska Anna , Stypinska Barbara , Walczuk Ewa , Wajda Anna , Lutkowska Anna , Felis-Giemza Anna , Olesinska Marzena , Puszczewicz Mariusz , Majewski Dominik , Jagodzinski Pawel Piotr , Czerewaty Michal , Malinowski Damian , Pawlik Andrzej , Jaronczyk Malgorzata , Paradowska-Gorycka Agnieszka
Published: March 2020

Systemic lupus erythematosus (SLE) is a chronic and systemic autoimmune disease. SLE is described by production of autoantibodies and causes damage of many organs. T-cells play a crucial role in SLE pathogenesis. T-cells intensify inflammation through a number of processes, which leads to autoimmunization. CCR5 and MECP2 genes are linked with T-cells and pathogenesis of SLE. Polymorphisms in these genes are related with the prognostic factors of risk of disease onset and disease severity. The aim of this study was to estimate the influence of polymorphisms in MECP2 and CCR5 genes on the development and course of systemic lupus erythematosus. We examined 137 SLE patients and 604 healthy controls. We studied polymorphisms for CCR5 gene: rs333 and for MECP2: rs2075596, rs1734787, rs17435, and rs2239464. We genotyped our MECP2 samples and we performed a restriction fragment length polymorphism (RFLP) analysis for CCR5 samples. We showed a risk factor for allele T in rs17435 and for allele A in rs2075596 in MECP2. We noticed that MECP2 rs2075596 G/A, rs1734787 C/A, rs17435 A/T, and rs2239464 G/A polymorphisms are more prevalent in SLE patients than in healthy controls. We believe that above-mentioned MECP2 polymorphisms can be considered as SLE susceptibility factor.
Spectroscopic and Structural Analysis of Cu2+-Induced Fluorescence Quenching of ZsYellow
Authors: Kim In Jung , Xu Yongbin , Nam Ki Hyun
Published: March 2020

Fluorescent proteins exhibit fluorescence quenching by specific transition metals, suggesting their potential as fluorescent protein-based metal biosensors. Each fluorescent protein exhibits unique spectroscopic properties and mechanisms for fluorescence quenching by metals. Therefore, the metal-induced fluorescence quenching analysis of various new fluorescent proteins would be important step towards the development of such fluorescent protein-based metal biosensors. Here, we first report the spectroscopic and structural analysis of the yellow fluorescent protein ZsYellow, following its metal-induced quenching. Spectroscopic analysis showed that ZsYellow exhibited a high degree of fluorescence quenching by Cu2+. During Cu2+-induced ZsYellow quenching, fluorescence emission was recovered by adding EDTA. The crystal structure of ZsYellow soaked in Cu2+ solution was determined at a 2.6 Å resolution. The electron density map did not indicate the presence of Cu2+ around the chromophore or the β-barrel surface, which resulted in fluorescence quenching without Cu2+ binding to specific site in ZsYellow. Based on these results, we propose the fluorescence quenching to occur in a distance-dependent manner between the metal and the fluorescent protein, when these components get to a closer vicinity at higher metal concentrations. Our results provide useful insights for future development of fluorescent protein-based metal biosensors.
Valproic Acid-Induced Hyperammonemic Encephalopathy in a Patient with Bipolar Disorder: A Case Report
Authors: Wu Meng-Yu , Chang Fang-Yu , Ke Jian-Yu , Chen Chien-Sheng , Lin Po-Chen , Wang Tzong-Shi
Published: March 2020

Valproic acid (VPA) is widely used to control various seizure disorders and psychiatric disorders. Valproic acid-induced hyperammonemic encephalopathy (VHE) is a rare but dangerous complication of VPA-induced toxicity. For this case report, several risk factors were identified, including young age, polytherapy regimens, VPA overdose, poor liver function, and carnitine deficiency. The detailed mechanisms of VHE remained unclear. Hyperammonemia may be caused by hypocarnitinemia, leading to imbalanced VPA metabolism. VHE may initially cause gastrointestinal symptoms, followed by a decreased level of consciousness and seizure. Early diagnosis of VHE is important for physicians for the timely reversal of VHE by discontinuing administration of VPA and administering lactulose or levocarnitine. Here, we describe a patient with a bipolar disorder who presented with VHE after receiving a strict vegetarian diet in our hospital. We recommend that VHE be included in the differential diagnosis of patients with high serum VPA levels and strictly vegetarian diets, especially those presenting with acute gastrointestinal symptoms.
The Reaction Switching Produces A Greater Bias to Prepotent Response than Reaction Inhibition
Authors: Fadeev Kirill , Alikovskaia Tatyana , Tumyalis Alexey , Smirnov Alexey , Golokhvast Kirill
Published: March 2020

There is a discussion about common or various mechanisms of response inhibition and response switching. To understand these mechanisms, we used a modified Go/NoGo task with three stimulus categories. The subjects were instructed to press a button in response to frequent Go stimuli, press another button in response to rare Go stimuli and hold any motor response following the presentation of NoGo stimuli. The results showed a decrease in reaction time for frequent Go, following both categories of rare stimuli and the decrease was greater following rare Go. Also, the total number of errors did not differ between Go and NoGo, however, a greater bias of error rate towards frequent Go stimuli was found for rare Go compared to NoGo. Finally, positive correlations were found between the increase in reaction time for rare Go compared to frequent Go and the number of errors for both rare Go and rare NoGo. Together, these results indicate that both rare Go and NoGo stimuli required to inhibit the prepotent response, but rare Go in comparison to NoGo stimuli also evoked a conflict between prepotent and alternative responses, which is expressed in greater response bias toward frequent Go.
Molecular Engineering Strategies Tailoring the Apoptotic Response to a MET Therapeutic Antibody
Authors: Modica Chiara , Gallo Simona , Chiriaco Cristina , Spilinga Martina , Comoglio Paolo Maria , Crepaldi Tiziana , Basilico Cristina , Vigna Elisa
Published: March 2020

The MET oncogene encodes a tyrosine kinase receptor involved in the control of a complex network of biological responses that include protection from apoptosis and stimulation of cell growth during embryogenesis, tissue regeneration, and cancer progression. We previously developed an antagonist antibody (DN30) inducing the physical removal of the receptor from the cell surface and resulting in suppression of the biological responses to MET. In its bivalent form, the antibody displayed a residual agonist activity, due to dimerization of the lingering receptors, and partial activation of the downstream signaling cascade. The balance between the two opposing activities is variable in different biological systems and is hardly predictable. In this study, we generated and characterized two single-chain antibody fragments derived from DN30, sharing the same variable regions but including linkers different in length and composition. The two engineered molecules bind MET with high affinity but induce different biological responses. One behaves as a MET-antagonist, promoting programmed cell death in MET “addicted” cancer cells. The other acts as a hepatocyte growth factor (HGF)-mimetic, protecting normal cells from doxorubicin-induced apoptosis. Thus, by engineering the same receptor antibody, it is possible to generate molecules enhancing or inhibiting apoptosis either to kill cancer cells or to protect healthy tissues from the injuries of chemotherapy.
Gauging the Impact of Cancer Treatment Modalities on Circulating Tumor Cells (CTCs)
Authors: Mathias Trevor J. , Chang Katarina T. , Martin Stuart S. , Vitolo Michele I.
Published: March 2020

The metastatic cascade consists of multiple complex steps, but the belief that it is a linear process is diminishing. In order to metastasize, cells must enter the blood vessels or body cavities (depending on the cancer type) via active or passive mechanisms. Once in the bloodstream and/or lymphatics, these cancer cells are now termed circulating tumor cells (CTCs). CTC numbers as well as CTC clusters have been used as a prognostic marker with higher numbers of CTCs and/or CTC clusters correlating with an unfavorable prognosis. However, we have very limited knowledge about CTC biology, including which of these cells are ultimately responsible for overt metastatic growth, but due to the fact that higher numbers of CTCs correlate with a worse prognosis; it would seem appropriate to either limit CTCs and/or their dissemination. Here, we will discuss the different cancer treatments which may inadvertently promote the mobilization of CTCs and potential CTC therapies to decrease metastasis.
A Disintegrin and Metalloproteinase 9 (ADAM9) in Advanced Hepatocellular Carcinoma and Their Role as a Biomarker During Hepatocellular Carcinoma Immunotherapy
Authors: Oh Sooyeon , Park YoungJoon , Lee Hyun-Jung , Lee Jooho , Lee Soo-Hyeon , Baek Young-Seok , Chun Su-Kyung , Lee Seung-Min , Kim Mina , Chon Young-Eun , Ha Yeonjung , Cho Yuri , Kim Gi Jin , Hwang Seong-Gyu , Kwack KyuBum
Published: March 2020

The chemotherapeutics sorafenib and regorafenib inhibit shedding of MHC class I-related chain A (MICA) from hepatocellular carcinoma (HCC) cells by suppressing a disintegrin and metalloprotease 9 (ADAM9). MICA is a ligand for natural killer (NK) group 2 member D (NKG2D) and is expressed on tumor cells to elicit attack by NK cells. This study measured ADAM9 mRNA levels in blood samples of advanced HCC patients (n = 10). In newly diagnosed patients (n = 5), the plasma ADAM9 mRNA level was significantly higher than that in healthy controls (3.001 versus 1.00, p < 0.05). Among four patients treated with nivolumab therapy, two patients with clinical response to nivolumab showed significant decreases in fold changes of serum ADAM9 mRNA level from 573.98 to 262.58 and from 323.88 to 85.52 (p < 0.05); however, two patients with no response to nivolumab did not. Using the Cancer Genome Atlas database, we found that higher expression of ADAM9 in tumor tissues was associated with poorer survival of HCC patients (log-rank p = 0.00039), while ADAM10 and ADAM17 exhibited no such association. In addition, ADAM9 expression showed a positive correlation with the expression of inhibitory checkpoint molecules. This study, though small in sample size, clearly suggested that ADAM9 mRNA might serve as biomarker predicting clinical response and that the ADAM9-MICA-NKG2D system can be a good therapeutic target for HCC immunotherapy. Future studies are warranted to validate these findings.
Immune-Complexome Analysis Identifies Immunoglobulin-Bound Biomarkers That Predict the Response to Chemotherapy of Pancreatic Cancer Patients
Authors: Mandili Giorgia , Follia Laura , Ferrero Giulio , Katayama Hiroyuki , Hong Wang , Momin Amin A. , Capello Michela , Giordano Daniele , Spadi Rosella , Satolli Maria Antonietta , Evangelista Andrea , Hanash Samir M. , Cordero Francesca , Novelli Francesco
Published: March 2020

Pancreatic Ductal Adenocarcinoma (PDA) is an aggressive malignancy with a very poor outcome. Although chemotherapy (CT) treatment has poor efficacy, it can enhance tumor immunogenicity. Tumor-Associated Antigens (TAA) are self-proteins that are overexpressed in tumors that may induce antibody production and can be PDA theranostic targets. However, the prognostic value of TAA-antibody association as Circulating Immune Complexes (CIC) has not yet been elucidated, mainly due to the lack of techniques that lead to their identification. In this study, we show a novel method to separate IgG, IgM, and IgA CIC from sera to use them as prognostic biomarkers of CT response. The PDA Immune-Complexome (IC) was identified using a LTQ-Orbitrap mass spectrometer followed by computational analysis. The analysis of the IC of 37 PDA patients before and after CT revealed differential associated antigens (DAA) for each immunoglobulin class. Our method identified different PDA-specific CIC in patients that were associated with poor prognosis patients. Finally, CIC levels were significantly modified by CT suggesting that they can be used as effective prognostic biomarkers to follow CT response in PDA patients.
KLF5 Is Crucial for Androgen-AR Signaling to Transactivate Genes and Promote Cell Proliferation in Prostate Cancer Cells
Authors: Li Juan , Zhang Baotong , Liu Mingcheng , Fu Xing , Ci Xinpei , A Jun , Fu Changying , Dong Ge , Wu Rui , Zhang Zhiqian , Fu Liya , Dong Jin-Tang
Published: March 2020

Androgen/androgen receptor (AR) signaling drives both the normal prostate development and prostatic carcinogenesis, and patients with advanced prostate cancer often develop resistance to androgen deprivation therapy. The transcription factor Krüppel-like factor 5 (KLF5) also regulates both normal and cancerous development of the prostate. In this study, we tested whether and how KLF5 plays a role in the function of AR signaling in prostate cancer cells. We found that KLF5 is upregulated by androgen depending on AR in LNCaP and C4-2B cells. Silencing KLF5, in turn, reduced AR transcriptional activity and inhibited androgen-induced cell proliferation and tumor growth in vitro and in vivo. Mechanistically, KLF5 occupied the promoter of AR, and silencing KLF5 repressed AR transcription. In addition, KLF5 and AR physically interacted with each other to regulate the expression of multiple genes (e.g., MYC, CCND1 and PSA) to promote cell proliferation. These findings indicate that, while transcriptionally upregulated by AR signaling, KLF5 also regulates the expression and transcriptional activity of AR in androgen-sensitive prostate cancer cells. The KLF5-AR interaction could provide a therapeutic opportunity for the treatment of prostate cancer.
Non-Coding microRNAs as Novel Potential Tumor Markers in Testicular Cancer
Authors: Regouc Manuel , Belge Gazanfer , Lorch Anja , Dieckmann Klaus-Peter , Pichler Martin
Published: March 2020

Testicular cancer is an important disease with increasing incidence and a high burden of morbidity and mortality in young men worldwide. Histological examination of the testicular tissue after orchiectomy plays an important role alongside patient history, imaging, clinical presentation and laboratory parameters. Surgical procedures and chemotherapeutic treatment provide a high chance of cure in early stages, though some patients in advanced stages belonging to a poor risk group experience cancer-related death. Though conventional serum-based tumor markers, including α-fetoprotein (AFP), the β-subunit of human chorionic gonadotropin (β-hCG), and lactate dehydrogenase (LDH), are useful as prognostic and diagnostic biomarkers, unfortunately, these tumor markers only have a sensitivity of about 60%, and in pure seminoma even lower with about 20%. Therefore, the development of new tumor markers is an important and intensively ongoing issue. The analysis of epigenetic modification and non-coding RNA microRNAs (miRNAs) are carrying most promising potential as tumor markers in future. miRNAs are small RNAs secreted by testicular tumor cells and circulate and be measurable in body fluids. In recent years, miRNAs of the miR-371-373 cluster in particular have been identified as potentially superior tumor markers in testicular cancer patients. Studies showed that miR-371a-3p and miR-302/367 expression significantly differ between testicular tumors and healthy testicular tissue. Several studies including high prospective multi-center trials clearly demonstrated that these miRNAs significantly exceed the sensitivity and specificity of conventional tumor markers and may help to facilitate the diagnosis, follow-up, and early detection of recurrences in testicular cancer patients. In addition, other miRNAs such as miR-223-3p, miR-449, miR-383, miR-514a-3p, miR-199a-3p, and miR-214 will be discussed in this review. However, further studies are needed to identify the value of these novel markers in additional clinical scenarios, including the monitoring in active surveillance or after adjuvant chemotherapy, but also to show the limitations of these tumor markers. The aim of this review is to give an overview on the current knowledge regarding the relevance of non-coding miRNAs as biomarkers in testicular cancer.