bluuebunny/crossref_metadata_2025 huggingface dataset:
A Cohort Study on Respiratory Symptoms and Diseases Caused by Toner-Handling Work: Longitudinal Analyses from 2003 to 2013
Authors: Terunuma Niina , Ikegami Kazunori , Kitamura Hiroko , Ando Hajime , Kurosaki Shizuka , Masuda Masashi , Kochi Takeshi , Yanagi Nobuaki , Ogami Akira , Higashi Toshiaki
Published: October 2019

The purpose of this study was to examine the effects of toner-handling work on respiratory symptoms and diseases. We conducted a prospective cohort study of 1468 workers between 2003 and 2013. The cohort included 887 toner-handling workers and 581 non-toner-handling workers, employed in one toner and copier manufacturing enterprise. Toner-handling workers were subdivided into two groups based on the 8-h time-weighted average toner exposure concentration for each work category in the baseline survey. We compared the incidence of respiratory disease and longitudinal changes in the prevalence of subjective respiratory symptoms among three groups, as follows: High-concentration toner exposure group, the low-concentration toner exposure group, and a control group. The incidence of respiratory disease and changes in the prevalence of subjective respiratory symptoms were not significantly different between the non-toner-handling group and the toner-handling group. In contrast, the odds ratio for yearly changes in the prevalence of wheezing without asthmatic response was significantly lower in the high-concentration toner exposure group than in the control group. At the study site, dust scattering was well controlled and workers used respiratory protection appropriately. These findings suggest that toner-handling work had little adverse effect on respiratory function in a work environment with sufficiently controlled ventilation.
Wheat Yellow Mosaic Virus NIb Interacting with Host Light Induced Protein (LIP) Facilitates Its Infection through Perturbing the Abscisic Acid Pathway in Wheat
Authors: Zhang Tianye , Liu Peng , Zhong Kaili , Zhang Fan , Xu Miaoze , He Long , Jin Peng , Chen Jianping , Yang Jian
Published: October 2019

Positive-sense RNA viruses have a small genome with very limited coding capacity and are highly reliant on host factors to fulfill their infection. However, few host factors have been identified to participate in wheat yellow mosaic virus (WYMV) infection. Here, we demonstrate that wheat (Triticum aestivum) light-induced protein (TaLIP) interacts with the WYMV nuclear inclusion b protein (NIb). A bimolecular fluorescence complementation (BIFC) assay displayed that the subcellular distribution patterns of TaLIP were altered by NIb in Nicotiana benthamiana. Transcription of TaLIP was significantly decreased by WYMV infection and TaLIP-silencing wheat plants displayed more susceptibility to WYMV in comparison with the control plants, suggesting that knockdown of TaLIP impaired host resistance. Moreover, the transcription level of TaLIP was induced by exogenous abscisic acid (ABA) stimuli in wheat, while knockdown of TaLIP significantly repressed the expression of ABA-related genes such as wheat abscisic acid insensitive 5 (TaABI5), abscisic acid insensitive 8 (TaABI8), pyrabatin resistance 1-Llike (TaPYL1), and pyrabatin resistance 3-Llike (TaPYL3). Collectively, our results suggest that the interaction of NIb with TaLIP facilitated the virus infection possibly by disturbing the ABA signaling pathway in wheat.
Disease Associated Mutations in KIR Proteins Linked to Aberrant Inward Rectifier Channel Trafficking
Authors: Zangerl-Plessl Eva-Maria , Qile Muge , Bloothooft Meye , Stary-Weinzinger Anna , van der Heyden Marcel A. G.
Published: October 2019

The ubiquitously expressed family of inward rectifier potassium (KIR) channels, encoded by KCNJ genes, is primarily involved in cell excitability and potassium homeostasis. Channel mutations associate with a variety of severe human diseases and syndromes, affecting many organ systems including the central and peripheral neural system, heart, kidney, pancreas, and skeletal muscle. A number of mutations associate with altered ion channel expression at the plasma membrane, which might result from defective channel trafficking. Trafficking involves cellular processes that transport ion channels to and from their place of function. By alignment of all KIR channels, and depicting the trafficking associated mutations, three mutational hotspots were identified. One localized in the transmembrane-domain 1 and immediately adjacent sequences, one was found in the G-loop and Golgi-export domain, and the third one was detected at the immunoglobulin-like domain. Surprisingly, only few mutations were observed in experimentally determined Endoplasmic Reticulum (ER)exit-, export-, or ER-retention motifs. Structural mapping of the trafficking defect causing mutations provided a 3D framework, which indicates that trafficking deficient mutations form clusters. These “mutation clusters” affect trafficking by different mechanisms, including protein stability.
Transcriptome Profile Alteration with Cadmium Selenide/Zinc Sulfide Quantum Dots in Saccharomyces cerevisiae
Authors: Horstmann Cullen , Kim Daniel S , Campbell Chelsea , Kim Kyoungtae
Published: October 2019

Quantum Dots (QDs) are becoming more prevalent in products used in our daily lives, such as TVs and laptops, due to their unique and tunable optical properties. The possibility of using QDs as fluorescent probes in applications, such as medical imaging, has been a topic of interest for some time, but their potential toxicity and long-term effects on the environment are not well understood. In the present study, we investigated the effects of yellow CdSe/ZnS-QDs on Saccharomyces cerevisiae. We utilized growth assays, RNA-seq, reactive oxygen species (ROS) detection assays, and cell wall stability experiments to investigate the potential toxic effects of CdSe/ZnS-QDs. We found CdSe/ZnS-QDs had no negative effects on cell viability; however, cell wall-compromised cells showed more sensitivity in the presence of 10 µg/mL CdSe/ZnS-QDs compared to non-treated cells. In CdSe/ZnS-treated and non-treated cells, no significant change in superoxide was detected, but according to our transcriptomic analysis, thousands of genes in CdSe/ZnS-treated cells became differentially expressed. Four significantly differentiated genes found, including FAF1, SDA1, DAN1, and TIR1, were validated by consistent results with RT-qPCR assays. Our transcriptome analysis led us to conclude that exposure of CdSe/ZnS-QDs on yeast significantly affected genes implicated in multiple cellular processes.
Interactions of 7,8-Dihydroxyflavone with Serum Albumin as well as with CYP2C9, CYP2C19, CYP3A4, and Xanthine Oxidase Biotransformation Enzymes
Authors: Fliszár-Nyúl Eszter , Mohos Violetta , Bencsik Tímea , Lemli Beáta , Kunsági-Máté Sándor , Poór Miklós
Published: October 2019

7,8-dihydroxyflavone (DHF) is a flavone aglycone which has beneficial effects in several central nervous system diseases. Most of the pharmacokinetic properties of DHF have been characterized, while only limited information is available regarding its interactions with serum albumin and biotransformation enzymes. In this study, the interactions of DHF with albumin was examined employing fluorescence spectroscopy and ultrafiltration. Furthermore, the inhibitory effects of DHF on cytochrome P450 (CYP2C9, CYP2C19, and CYP3A4) and xanthine oxidase (XO) enzymes were also tested using in vitro models. Our results demonstrate that DHF forms a stable complex with albumin (K = 4.9 × 105 L/mol) and that it is able to displace both Site I and Site II ligands. Moreover, DHF proved to be a potent inhibitor of each enzyme tested, showing similar or slightly weaker effects than the positive controls used. Considering the above-listed observations, the coadministration of DHF with drugs may interfere with the drug therapy due to the development of pharmacokinetic interactions.
Effects of Methylphenidate on Cognitive Function in Adults with Traumatic Brain Injury: A Meta-Analysis
Authors: Chien Yung-Jiun , Chien Yung-Chen , Liu Chien-Ting , Wu Hsin-Chi , Chang Chun-Yu , Wu Meng-Yu
Published: October 2019

This meta-analysis evaluated the effects of methylphenidate (MPH) on cognitive outcome and adverse events in adults with traumatic brain injuries (TBI). We searched PubMed, EMBASE, and PsycINFO for randomized controlled trials (RCTs) published before July 2019. Studies that compared the effects of MPH and placebos in adults with TBI were included. The primary outcome was cognitive function, while the secondary outcome was adverse events. Meta-regression and sensitivity analysis were conducted to evaluate heterogeneity. Seventeen RCTs were included for qualitative analysis, and ten RCTs were included for quantitative analysis. MPH significantly improved processing speed, measured by Choice Reaction Time (standardized mean difference (SMD): −0.806; 95% confidence interval (CI): −429 to −0.182, p = 0.011) and Digit Symbol Coding Test (SMD: −0.653; 95% CI: −1.016 to −0.289, p < 0.001). Meta-regression showed that the reaction time was inversely associated with the duration of MPH. MPH administration significantly increased heart rate (SMD: 0.553; 95% CI: 0.337 to 0.769, p < 0.001), while systolic or diastolic blood pressure did not exhibit significant differences. Therefore, MPH elicited better processing speed in adults with TBI. However, MPH use could significantly increase heart rate. A larger study is required to evaluate the effect of dosage, age, or optimal timing on treatment of adults with TBI.
Amantadine Improves Delayed Neuropsychiatric Sequelae of Carbon Monoxide Poisoning: A Case Report
Authors: Nakano Tomosuke , Hasegawa Toshiki , Suzuki Dai , Motomura Eishi , Okada Motohiro
Published: October 2019

Carbon monoxide (CO) poisoning causes severe brain damage, including delayed neuropsychiatric sequelae (DNS), which occur after a lucid interval following recovery from the insult of acute CO poisoning. We describe a 39-year-old male who developed DNS, including gait disturbance, trunk ataxia, and fecal/urine incontinence, after remission of acute CO poisoning. Furthermore, he showed confusion, with disorientation in terms of time and space. All symptoms, including cognitive impairment, were dramatically improved by amantadine monotherapy. The present case illustrates the possibility of amantadine treatment for cognitive impairment as well as Parkinsonism induced by CO poisoning.
Theoretical and Practical Implications of Treating Cachexia in Advanced Lung Cancer Patients
Authors: Bonomi Philip , Fidler Mary Jo , Shah Palmi , Borgia Jeffrey
Published: October 2019

Lung cancer continues to be a major worldwide health issue, with more than 50% of patients having incurable metastatic disease at diagnosis. Fortunately, the advanced lung cancer treatment landscape is changing rapidly as a result of the positive impact of effective inhibitors of tumor driver mutations, and the more recent discovery that immune modulation with anti-PD-1/PD-L1 monoclonal antibodies results in tumor regression and prolonged survival. While a relatively small subset of lung cancer patients are candidates for inhibitors of driver mutations, the majority of advanced lung cancer patients are candidates for an immunotherapy regimen. Many of these patients have cachexia, which is associated with increased cancer therapy toxicity and possibly reduced responsiveness to immunotherapy. Two ongoing cachexia trials, one testing a ghrelin analogue and the other testing a multimodal strategy, have endpoints which assess clinical benefit—weight gain and relief of anorexia/cachexia symptoms. Provided that the trial objectives are achieved, these treatment strategies will provide a way to relieve suffering and distress for cachectic cancer patients. While awaiting the results of these trials, it would be reasonable to consider designing studies testing cachexia treatments combined with first-line immunotherapy and chemotherapy–immunotherapy in stage IV lung cancer patients, with enhanced overall survival being one of the endpoints.
The Pivotal Roles of the Epithelial Membrane Protein Family in Cancer Invasiveness and Metastasis
Authors: Ahmat Amin Mohammad Khusni B. , Shimizu Akio , Ogita Hisakazu
Published: October 2019

The members of the family of epithelial membrane proteins (EMPs), EMP1, EMP2, and EMP3, possess four putative transmembrane domain structures and are composed of approximately 160 amino acid residues. EMPs are encoded by the growth arrest-specific 3 (GAS3)/peripheral myelin protein 22 kDa (PMP22) gene family. The GAS3/PMP22 family members play roles in cell migration, growth, and differentiation. Evidence indicates an association of these molecules with cancer progression and metastasis. Each EMP has pro- and anti-metastatic functions that are likely involved in the complex mechanisms of cancer progression. We have recently demonstrated that the upregulation of EMP1 expression facilitates cancer cell migration and invasion through the activation of a small GTPase, Rac1. The inoculation of prostate cancer cells overexpressing EMP1 into nude mice leads to metastasis to the lymph nodes and lungs, indicating that EMP1 contributes to metastasis. Pro-metastatic properties of EMP2 and EMP3 have also been proposed. Thus, targeting EMPs may provide new insights into their clinical utility. Here, we highlight the important aspects of EMPs in cancer biology, particularly invasiveness and metastasis, and describe recent therapeutic approaches.
Are ENT1/ENT1, NOTCH3, and miR-21 Reliable Prognostic Biomarkers in Patients with Resected Pancreatic Adenocarcinoma Treated with Adjuvant Gemcitabine Monotherapy?
Authors: Jiraskova Lucie , Ryska Ales , Duintjer Tebbens Erik Jurjen , Hornychova Helena , Cecka Filip , Staud Frantisek , Cerveny Lukas
Published: October 2019

Evidence on equilibrative nucleoside transporter 1 (ENT1) and microRNA-21 (miR‑21) is not yet sufficiently convincing to consider them as prognostic biomarkers for patients with pancreatic ductal adenocarcinoma (PDAC). Here, we investigated the prognostic value of ENT1/ENT1, miR-21, and neurogenic locus homolog protein 3 gene (NOTCH3) in a well-defined cohort of resected patients treated with adjuvant gemcitabine chemotherapy (n = 69). Using a combination of gene expression quantification in microdissected tissue, immunohistochemistry, and univariate/multivariate statistical analyses we did not confirm association of ENT1/ENT1 and NOTCH3 with improved disease-specific survival (DSS). Low miR-21 was associated with longer DSS in patients with negative regional lymph nodes or primary tumor at stage 1 and 2. In addition, downregulation of ENT1 was observed in PDAC of patients with high ENT1 expression in normal pancreas, whereas NOTCH3 was upregulated in PDAC of patients with low NOTCH3 levels in normal pancreas. Tumor miR‑21 was upregulated irrespective of its expression in normal pancreas. Our data confirmed that patient stratification based on expression of ENT1/ENT1 or miR‑21 is not ready to be implemented into clinical decision-making processes. We also conclude that occurrence of ENT1 and NOTCH3 deregulation in PDAC is dependent on their expression in normal pancreas.
Understanding and Targeting Apoptotic Pathways in Ovarian Cancer
Authors: Al-Alem Linah F. , Baker Andrew T. , Pandya Unnati M. , Eisenhauer Eric L. , Rueda Bo R.
Published: October 2019

Ovarian cancer cells evade the immune system as well as chemotherapeutic and/or biologic treatments through inherent or acquired mechanisms of survival and drug resistance. Depending on the cell type and the stimuli, this threshold can range from external forces such as blunt trauma to programmed processes such as apoptosis, autophagy, or necroptosis. This review focuses on apoptosis, which is one form of programmed cell death. It highlights the multiple signaling pathways that promote or inhibit apoptosis and reviews current clinical therapies that target apoptotic pathways in ovarian cancer.
The Role of Merlin/NF2 Loss in Meningioma Biology
Authors: Lee Sungho , Karas Patrick J. , Hadley Caroline C. , Bayley V James C. , Khan A. Basit , Jalali Ali , Sweeney Alex D. , Klisch Tiemo J. , Patel Akash J.
Published: October 2019

Mutations in the neurofibromin 2 (NF2) gene were among the first genetic alterations implicated in meningioma tumorigenesis, based on analysis of neurofibromatosis type 2 (NF2) patients who not only develop vestibular schwannomas but later have a high incidence of meningiomas. The NF2 gene product, merlin, is a tumor suppressor that is thought to link the actin cytoskeleton with plasma membrane proteins and mediate contact-dependent inhibition of proliferation. However, the early recognition of the crucial role of NF2 mutations in the pathogenesis of the majority of meningiomas has not yet translated into useful clinical insights, due to the complexity of merlin’s many interacting partners and signaling pathways. Next-generation sequencing studies and increasingly sophisticated NF2-deletion-based in vitro and in vivo models have helped elucidate the consequences of merlin loss in meningioma pathogenesis. In this review, we seek to summarize recent findings and provide future directions toward potential therapeutics for this tumor.
PIK3CA Cooperates with KRAS to Promote MYC Activity and Tumorigenesis via the Bromodomain Protein BRD9
Authors: Bell Catherine M. , Raffeiner Philipp , Hart Jonathan R. , Vogt Peter K.
Published: October 2019

Tumor formation is generally linked to the acquisition of two or more driver genes that cause normal cells to progress from proliferation to abnormal expansion and malignancy. In order to understand genetic alterations involved in this process, we compared the transcriptomes of an isogenic set of breast epithelial cell lines that are non-transformed or contain a single or double knock-in (DKI) of PIK3CA (H1047R) or KRAS (G12V). Gene set enrichment analysis revealed that DKI cells were enriched over single mutant cells for genes that characterize a MYC target gene signature. This gene signature was mediated in part by the bromodomain-containing protein 9 (BRD9) that was found in the SWI-SNF chromatin-remodeling complex, bound to the MYC super-enhancer locus. Small molecule inhibition of BRD9 reduced MYC transcript levels. Critically, only DKI cells had the capacity for anchorage-independent growth in semi-solid medium, and CRISPR-Cas9 manipulations showed that PIK3CA and BRD9 expression were essential for this phenotype. In contrast, KRAS was necessary for DKI cell migration, and BRD9 overexpression induced the growth of KRAS single mutant cells in semi-solid medium. These results provide new insight into the earliest transforming events driven by oncoprotein cooperation and suggest BRD9 is an important mediator of mutant PIK3CA/KRAS-driven oncogenic transformation.
Genomic Perspective on Mouse Liver Cancer Models
Authors: Yim Sun Young , Lee Ju-Seog
Published: October 2019

Selecting the most appropriate mouse model that best recapitulates human hepatocellular carcinoma (HCC) allows translation of preclinical mouse studies into clinical studies. In the era of cancer genomics, comprehensive and integrative analysis of the human HCC genome has allowed categorization of HCC according to molecular subtypes. Despite the variety of mouse models that are available for preclinical research, there is a lack of evidence for mouse models that closely resemble human HCC. Therefore, it is necessary to identify the accurate mouse models that represent human HCC based on molecular subtype as well as histologic aggressiveness. In this review, we summarize the mouse models integrated with human HCC genomic data to provide information regarding the models that recapitulates the distinct aspect of HCC biology and prognosis based on molecular subtypes.
Identification of SERPINE1 as a Regulator of Glioblastoma Cell Dispersal with Transcriptome Profiling
Authors: Seker Fidan , Cingoz Ahmet , Sur-Erdem İlknur , Erguder Nazli , Erkent Alp , Uyulur Fırat , Esai Selvan Myvizhi , Gümüş Zeynep Hülya , Gönen Mehmet , Bayraktar Halil , Wakimoto Hiroaki , Bagci-Onder Tugba
Published: October 2019

High mortality rates of glioblastoma (GBM) patients are partly attributed to the invasive behavior of tumor cells that exhibit extensive infiltration into adjacent brain tissue, leading to rapid, inevitable, and therapy-resistant recurrence. In this study, we analyzed transcriptome of motile (dispersive) and non-motile (core) GBM cells using an in vitro spheroid dispersal model and identified SERPINE1 as a modulator of GBM cell dispersal. Genetic or pharmacological inhibition of SERPINE1 reduced spheroid dispersal and cell adhesion by regulating cell-substrate adhesion. We examined TGFβ as a potential upstream regulator of SERPINE1 expression. We also assessed the significance of SERPINE1 in GBM growth and invasion using TCGA glioma datasets and a patient-derived orthotopic GBM model. SERPINE1 expression was associated with poor prognosis and mesenchymal GBM in patients. SERPINE1 knock-down in primary GBM cells suppressed tumor growth and invasiveness in the brain. Together, our results indicate that SERPINE1 is a key player in GBM dispersal and provide insights for future anti-invasive therapy design.
A 2.5D Electrode System Constructed of Magnetic Sb–SnO2 Particles and a PbO2 Electrode and Its Electrocatalysis Application on Acid Red G Degradation
Authors: Yuan Mengmeng , Salman Nasir Muhammad , Guo Hua , Xu Zhicheng , Xu Hao , Yan Wei , Liao Zhengwei , Wang Yu
Published: October 2019

A novel electrode consisting of a Ti/PbO2 shell and Fe3O4/Sb–SnO2 particles was developed for electrochemical oxidation treatment of wastewater. Scanning electron microscope (SEM), X-ray diffraction (XRD), the current limiting method, toxicity experiments, and high-performance liquid chromatography were adopted to characterize its morphology, crystal structure, electrochemical properties, the toxicity of the wastewater, and hydroxyl radicals. Acid Red G (ARG), a typical azo dye, was additionally used to test the oxidation ability of the electrode. Results indicated that the 2.5D electrode could significantly improve the mass transfer coefficient and •OH content of the 2D electrode, thereby enhancing the decolorization, degradation, and mineralization effect of ARG, and reducing the toxicity of the wastewater. The experiments revealed that, at higher current density, lower dye concentration and higher temperature, the electrochemical oxidation of ARG favored. Under the condition of 50 mA/cm2, 25 °C, and 100 ppm, the ARG, Chemical Oxygen Demand (COD) and Total Organic Carbon (TOC) removal efficiency reached 100%, 65.89%, and 52.52%, respectively, and the energy consumption and the current efficiency were 1.06 kWh/g COD, 8.29%, and energy consumption for TOC and mineralization current efficiency were 3.81 kWh/g COD, 9.01%. Besides, the Fe3O4/Sb–SnO2 particles after electrolysis for 50 h still had remarkable stability. These results indicated that the ARG solution could be adequately removed on the 2.5D electrode, providing an effective method for wastewater treatment.
Catalyzed Synthesis of Natural Products
Authors: Diez David
Published: October 2019

Natural Products are secondary metabolites, that have been the inspiration for chemists and chemical biologists for many years and have a special relevance in the chemical space [...]
Selective Catalytic Transfer Hydrogenolysis of Glycerol to 2-Isopropoxy-Propan-1-Ol over Noble Metal Ion-Exchanged Mordenite Zeolite
Authors: Singh Bhupendra Kumar , Kim Yongseok , Kwon Seungdon , Na Kyungsu
Published: October 2019

This study investigated the selective conversion of glycerol to 2-isopropoxy-propan-1-ol over noble metal ion-exchanged mordenite zeolites (RuMOR, RhMOR, and PdMOR) as heterogeneous catalysts via catalytic transfer hydrogenolysis (CTH) using propan-2-ol as the solvent, hydrogen supplier, and reactive coupling reagent with glycerol. The catalytic reactions were performed at 140 °C under inert conditions with a 0.5 MPa initial pressure of N2. A single product, 2-isopropoxy-propan-1-ol, was catalytically generated without any appreciable by-products. The catalytic results were reproducible, and the catalysts exhibited good recyclability.
Synthesis of Diesel and Jet Fuel Range Cycloalkanes with Cyclopentanone and Furfural
Authors: Wang Wei , Sun Shaoying , Han Fengan , Li Guangyi , Shao Xianzhao , Li Ning
Published: October 2019

Diesel and jet fuel range cycloalkanes were obtained in ~84.8% overall carbon yield with cyclopentanone and furfural, which can be produced from hemicellulose. Firstly, 2,5-bis(furan-2-ylmethyl)-cyclopentanone was prepared by the aldol condensation/hydrogenation reaction of cyclopentanone and furfural under solid base and selective hydrogenation catalyst. Over the optimized catalyst (Pd/C-CaO), 98.5% carbon yield of 2,5-bis(furan-2-ylmethyl)-cyclopentanone was acquired at 423 K. Subsequently, the 2,5-bis(furan-2-ylmethyl)-cyclopentanone was further hydrodeoxygenated over the M/H-ZSM-5(Pd, Pt and Ru) catalyst. Overall, 86.1% carbon yield of diesel and jet fuel range cycloalkanes was gained over the Pd/H-ZSM-5 catalyst under solvent-free conditions. The cycloalkane mixture obtained in this work has a high density (0.82 g mL−1) and a low freezing point (241.7 K). Therefore, it can be mixed into diesel and jet fuel to increase their volumetric heat values or payloads.
Facile Fabrication of Metal Oxide Based Catalytic Electrodes by AC Plasma Deposition and Electrochemical Detection of Hydrogen Peroxide
Authors: Bui Quang-Tan , Yu In-Keun , Gopalan Anantha Iyengar , Saianand Gopalan , Kim Woonjung , Choi Seong-Ho
Published: October 2019

In this study, the fabrication of a metal oxide nanoparticles (NPs) dispersed catalytic electrode is described based on a new alternating current (AC) plasma deposition approach. The fabrication involves the treatment of AC plasma on a precursor solution comprised of metal salts such as CuCl2, FeCl2, and ZnCl2, and a monomer (acrylic acid) in the presence/absence of a cross-linker. Furthermore, the utility of such developed electrodes has been demonstrated for the electrochemical determination of hydrogen peroxide (H2O2). The electrode materials obtained through plasma treatment was characterized by Fourier transform infrared (FT-IR) spectroscopy, scanning electron microscope (SEM), contact angle measurements, energy-dispersive X-ray spectroscopy (EDS), X-ray photoelectron spectroscopy (XPS), and cyclic voltammetry. Among the metal oxide modified electrodes prepared by the AC plasma deposition method, the copper oxide (CuO) NPs catalytic electrode exhibited significant oxidation and reduction peaks for H2O2 in phosphate-buffered saline solution. The catalytic electrode with CuO NPs exhibited a combination of good H2O2 sensing characteristics such as good sensitivity (63.52 mA M−1 cm−2), good selectivity, low detection limits (0.6 µM), fast sensing response (5 s), a wide linear range (0.5–8.5 mM), and good stability over 120 cycles. Based on our results, it is well demonstrated that plasma deposition could be effectively utilized for the fabrication of the catalytic electrode for detection of H2O2 concentrations. Further, the strategy of using AC plasma for fabrication of metal oxide-based modified electrodes could also be extended for the fabrication of other kinds of nanomaterials-based sensors.
Heterogeneous Oxidation of Phenolic Compounds with Photosensitizing Catalysts Incorporated into Chitosan
Authors: Foszpańczyk Magdalena , Bilińska Lucyna , Gmurek Marta , Ledakowicz Stanisław
Published: October 2019

The increasing amount of hazardous micropollutants in the aqueous environment has recently become a concern, especially because they are not usually included in environmental monitoring programs. There is also limited knowledge regarding their behavior in the environment and their toxicity. This paper presents results regarding the heterogeneous photosensitized oxidation of 10 phenolic compounds under visible light. All of the selected compounds are classified as pollutants of emerging concern. For the first time, the application of photosensitizing catalysts incorporated into a chitosan carrier was investigated from several points of view, namely, structure characterization, singlet oxygen generation potential, photodegradation ability, biodegradability, and toxicity assessment. It was found that compounds of different origins were degraded with high effectivity. Photoactive chitosan was stable and could be reused for at least 12 cycles without losing its photocatalytic activity. The Hammett constants for all of the degraded compounds were determined. Improved biodegradability after the treatment was achieved for almost all compounds, apart from 4-hydroxybenzoic acid, and only slightly for 2-phenylphenol. The acute toxicity was assessed using bioluminescent Vibrio fischeri bacteria, indicating lower toxicity than the parent compounds.
Opposed Actions of PKA Isozymes (RI and RII) and PKC Isoforms (cPKCβI and nPKCε) in Neuromuscular Developmental Synapse Elimination
Authors: Garcia Neus , Balañà Cori , Lanuza Maria A. , Tomàs Marta , Cilleros-Mañé Víctor , Just-Borràs Laia , Tomàs Josep
Published: October 2019

Background: During neuromuscular junction (NMJ) development, synapses are produced in excess. By sensing the activity-dependent release of ACh, adenosine, and neurotrophins, presynaptic receptors prompt axonal competition and loss of the unnecessary axons. The receptor action is mediated by synergistic and antagonistic relations when they couple to downstream kinases (mainly protein kinases A and C (PKA and PKC)), which phosphorylate targets involved in axonal disconnection. Here, we directly investigated the involvement of PKA subunits and PKC isoforms in synapse elimination. Methods: Selective PKA and PKC peptide modulators were applied daily to the Levator auris longus (LAL) muscle surface of P5–P8 transgenic B6.Cg-Tg (Thy1-YFP) 16 Jrs/J (and also C57BL/6J) mice, and the number of axons and the postsynaptic receptor cluster morphology were evaluated in P9 NMJ. Results: PKA (PKA-I and PKA-II isozymes) acts at the pre- and postsynaptic sites to delay both axonal elimination and nAChR cluster differentiation, PKC activity promotes both axonal loss (a cPKCβI and nPKCε isoform action), and postsynaptic nAChR cluster maturation (a possible role for PKCθ). Moreover, PKC-induced changes in axon number indirectly influence postsynaptic maturation. Conclusions: PKC and PKA have opposed actions, which suggests that changes in the balance of these kinases may play a major role in the mechanism of developmental synapse elimination.
Off-Target Deletion of Conditional Dbc1 Allele in the Foxp3YFP-Cre Mouse Line under Specific Setting
Authors: Xie Chichu , Zhu Fangming , Wang Julie , Zhang Weizhou , Bellanti Joseph A. , Li Bin , Brand David , Olsen Nancy , Zheng Song Guo
Published: October 2019

The Cre-LoxP conditional knockout strategy has been used extensively to study gene function in a specific cell-type. In this study, the authors tried to engineer mice in which the Dbc1 gene is conditionally knocked out in Treg cells. Unexpectedly, the conditional Dbc1 allele was completely deleted with a low frequency in some Foxp3YFP-Cre mice harboring floxed Dbc1 allele under specific settings. It was found that the germline recombination of floxed Dbc1 allele, which caused Dbc1 knock out mice, occurred in the male Foxp3YFP-Cre mice harboring floxed Dbc1 allele. Even though the authors documented that Foxp3 is expressed in the testis, the germline recombination was not caused by the germline expression of Cre, which was driven by the Foxp3 promoter. The germline recombination may be caused by the unspecific expression of Cre recombinase in the fetus, in which the floxed Dbc1 allele of some stem cells with development potential to germ cells may be recombined. Additionally, this study found that the floxed Dbc1 allele was recombined in non-T cells of some Foxp3Cre Dbc1fl mice, which need to be characterized. Our results also suggest that using male mice with a low frequency of recombined gene allele can reduce the risk of having full knock out mice.
Roles of the Hepatic Endocannabinoid and Apelin Systems in the Pathogenesis of Liver Fibrosis
Authors: Melgar-Lesmes Pedro , Perramon Meritxell , Jiménez Wladimiro
Published: October 2019

Hepatic fibrosis is the consequence of an unresolved wound healing process in response to chronic liver injury and involves multiple cell types and molecular mechanisms. The hepatic endocannabinoid and apelin systems are two signalling pathways with a substantial role in the liver fibrosis pathophysiology—both are upregulated in patients with advanced liver disease. Endogenous cannabinoids are lipid-signalling molecules derived from arachidonic acid involved in the pathogenesis of cardiovascular dysfunction, portal hypertension, liver fibrosis, and other processes associated with hepatic disease through their interactions with the CB1 and CB2 receptors. Apelin is a peptide that participates in cardiovascular and renal functions, inflammation, angiogenesis, and hepatic fibrosis through its interaction with the APJ receptor. The endocannabinoid and apelin systems are two of the multiple cell-signalling pathways involved in the transformation of quiescent hepatic stellate cells into myofibroblast like cells, the main matrix-producing cells in liver fibrosis. The mechanisms underlying the control of hepatic stellate cell activity are coincident despite the marked dissimilarities between the endocannabinoid and apelin signalling pathways. This review discusses the current understanding of the molecular and cellular mechanisms by which the hepatic endocannabinoid and apelin systems play a significant role in the pathophysiology of liver fibrosis.
Promising Prognosis Marker Candidates on the Status of Epithelial–Mesenchymal Transition and Glioma Stem Cells in Glioblastoma
Authors: Takashima Yasuo , Kawaguchi Atsushi , Yamanaka Ryuya
Published: October 2019

Multivariable analyses of global expression profiling are valid indicators of the prognosis of various diseases including brain cancers. To identify the candidates for markers of prognosis of glioblastoma, we performed multivariable analyses on the status of epithelial (EPI)–mesenchymal (MES) transition (EMT), glioma (GLI) stem cells (GSCs), molecular target therapy (MTT), and potential glioma biomarkers (PGBs) using the expression data and clinical information from patients. Random forest survival and Cox proportional hazards regression analyses indicated significant variable values for DSG3, CLDN1, CDH11, FN1, HDAC3/7, PTEN, L1CAM, OLIG2, TIMP4, IGFBP2, and GFAP. The analyses also comprised prognosis prediction formulae that could distinguish between the survival curves of the glioblastoma patients. In addition to the genes mentioned above, HDAC1, FLT1, EGFR, MGMT, PGF, STAT3, SIRT1, and GADD45A constituted complex genetic interaction networks. The calculated status scores obtained by principal component analysis indicated that GLI genes covered the status of EPI, GSC, and MTT-related genes. Moreover, survival tree analyses indicated that MEShigh, MEShighGLIlow, GSChighGLIlow, MEShighMTTlow, and PGBhigh showed poor prognoses and MESmiddle, GSClow, and PGBlow showed good prognoses, suggesting that enhanced EMT and GSC are associated with poor survival and that lower expression of EPI markers and the pre-stages of EMT are relatively less malignant in glioblastoma. These results demonstrate that the assessment of EMT and GSC enables the prediction of the prognosis of glioblastoma that would help develop novel therapeutics and de novo marker candidates for the prognoses of glioblastoma.
Suppression of the Peripheral Immune System Limits the Central Immune Response Following Cuprizone-Feeding: Relevance to Modelling Multiple Sclerosis
Authors: Sen Monokesh K. , Almuslehi Mohammed S. M. , Gyengesi Erika , Myers Simon J. , Shortland Peter J. , Mahns David A. , Coorssen Jens R.
Published: October 2019

Cuprizone (CPZ) preferentially affects oligodendrocytes (OLG), resulting in demyelination. To investigate whether central oligodendrocytosis and gliosis triggered an adaptive immune response, the impact of combining a standard (0.2%) or low (0.1%) dose of ingested CPZ with disruption of the blood brain barrier (BBB), using pertussis toxin (PT), was assessed in mice. 0.2% CPZ(±PT) for 5 weeks produced oligodendrocytosis, demyelination and gliosis plus marked splenic atrophy (37%) and reduced levels of CD4 (44%) and CD8 (61%). Conversely, 0.1% CPZ(±PT) produced a similar oligodendrocytosis, demyelination and gliosis but a smaller reduction in splenic CD4 (11%) and CD8 (14%) levels and no splenic atrophy. Long-term feeding of 0.1% CPZ(±PT) for 12 weeks produced similar reductions in CD4 (27%) and CD8 (43%), as well as splenic atrophy (33%), as seen with 0.2% CPZ(±PT) for 5 weeks. Collectively, these results suggest that 0.1% CPZ for 5 weeks may be a more promising model to study the ‘inside-out’ theory of Multiple Sclerosis (MS). However, neither CD4 nor CD8 were detected in the brain in CPZ±PT groups, indicating that CPZ-mediated suppression of peripheral immune organs is a major impediment to studying the ‘inside-out’ role of the adaptive immune system in this model over long time periods. Notably, CPZ(±PT)-feeding induced changes in the brain proteome related to the suppression of immune function, cellular metabolism, synaptic function and cellular structure/organization, indicating that demyelinating conditions, such as MS, can be initiated in the absence of adaptive immune system involvement.
Intracellular Redox-Balance Involvement in Temozolomide Resistance-Related Molecular Mechanisms in Glioblastoma
Authors: Lo Dico Alessia , Salvatore Daniela , Martelli Cristina , Ronchi Dario , Diceglie Cecilia , Lucignani Giovanni , Ottobrini Luisa
Published: October 2019

Glioblastoma (GBM) is the most common astrocytic-derived brain tumor in adults, characterized by a poor prognosis mainly due to the resistance to the available therapy. The study of mitochondria-derived oxidative stress, and of the biological events that orbit around it, might help in the comprehension of the molecular mechanisms at the base of GBM responsiveness to Temozolomide (TMZ). Sensitive and resistant GBM cells were used to test the role of mitochondrial ROS release in TMZ-resistance. Chaperone-Mediated Autophagy (CMA) activation in relation to reactive oxygen species (ROS) release has been measured by monitoring the expression of specific genes. Treatments with H2O2 were used to test their potential in reverting resistance. Fluctuations of cytoplasmic ROS levels were accountable for CMA induction and cytotoxic effects observed in TMZ sensitive cells after treatment. On the other hand, in resistant cells, TMZ failed in producing an increase in cytoplasmic ROS levels and CMA activation, preventing GBM cell toxicity. By increasing oxidative stress, CMA activation was recovered, as also cell cytotoxicity, especially in combination with TMZ treatment. Herein, for the first time, it is shown the relation between mitochondrial ROS release, CMA activation and TMZ-responsiveness in GBM.
Androgens and Androgen Receptor Actions on Bone Health and Disease: From Androgen Deficiency to Androgen Therapy
Authors: Chen Jia-Feng , Lin Pei-Wen , Tsai Yi-Ru , Yang Yi-Chien , Kang Hong-Yo
Published: October 2019

Androgens are not only essential for bone development but for the maintenance of bone mass. Therefore, conditions with androgen deficiency, such as male hypogonadism, androgen-insensitive syndromes, and prostate cancer with androgen deprivation therapy are strongly associated with bone loss and increased fracture risk. Here we summarize the skeletal effects of androgens—androgen receptors (AR) actions based on in vitro and in vivo studies from animals and humans, and discuss bone loss due to androgens/AR deficiency to clarify the molecular basis for the anabolic action of androgens and AR in bone homeostasis and unravel the functions of androgen/AR signaling in healthy and disease states. Moreover, we provide evidence for the skeletal benefits of androgen therapy and elucidate why androgens are more beneficial than male sexual hormones, highlighting their therapeutic potential as osteoanabolic steroids in improving bone fracture repair. Finally, the application of selective androgen receptor modulators may provide new approaches for the treatment of osteoporosis and fractures as well as building stronger bones in diseases dependent on androgens/AR status.
Wnt Glycation Inhibits Canonical Signaling
Authors: Ye Zhennan , Mittag Sonnhild , Schmidt Martin , Simm Andreas , Horstkorte Rüdiger , Huber Otmar
Published: October 2019

Glycation occurs as a non-enzymatic reaction between amino and thiol groups of proteins, lipids, and nucleotides with reducing sugars or α-dicarbonyl metabolites. The chemical reaction underlying is the Maillard reaction leading to the formation of a heterogeneous group of compounds named advanced glycation end products (AGEs). Deleterious effects have been observed to accompany glycation such as alterations of protein structure and function resulting in crosslinking and accumulation of insoluble protein aggregates. A substantial body of evidence associates glycation with aging. Wnt signaling plays a fundamental role in stem cell biology as well as in regeneration and repair mechanisms. Emerging evidence implicates that changes in Wnt/β-catenin pathway activity contribute to the aging process. Here, we investigated the effect of glycation of Wnt3a on its signaling activity. Methods: Glycation was induced by treatment of Wnt3a-conditioned medium (CM) with glyoxal (GO). Effects on Wnt3a signaling activity were analyzed by Topflash/Fopflash reporter gene assay, co-immunoprecipitation, and quantitative RT-PCR. Results: Our data show that GO-treatment results in glycation of Wnt3a. Glycated Wnt3a suppresses β-catenin transcriptional activity in reporter gene assays, reduced binding of β-catenin to T-cell factor 4 (TCF-4) and extenuated transcription of Wnt/β-catenin target genes. Conclusions: GO-induced glycation impairs Wnt3a signaling function.
Transcriptional Regulation of Autophagy Genes via Stage-Specific Activation of CEBPB and PPARG during Adipogenesis: A Systematic Study Using Public Gene Expression and Transcription Factor Binding Datasets
Authors: Ahmed Mahmoud , Lai Trang Huyen , Hwang Jin Seok , Zada Sahib , Pham Trang Minh , Kim Deok Ryong
Published: October 2019

Autophagy is the cell self-eating mechanism to maintain cell homeostasis by removing damaged intracellular proteins or organelles. It has also been implicated in the development and differentiation of various cell types including the adipocyte. Several links between adipogenic transcription factors and key autophagy genes has been suggested. In this study, we tried to model the gene expression and their transcriptional regulation during the adipocyte differentiation using high-throughput sequencing datasets of the 3T3-L1 cell model. We applied the gene expression and co-expression analysis to all and the subset of autophagy genes to study the binding, and occupancy patterns of adipogenic factors, co-factors and histone modifications on key autophagy genes. We also analyzed the gene expression of key autophagy genes under different transcription factor knockdown adipocyte cells. We found that a significant percent of the variance in the autophagy gene expression is explained by the differentiation stage of the cell. Adipogenic master regulators, such as CEBPB and PPARG target key autophagy genes directly. In addition, the same factor may also control autophagy gene expression indirectly through autophagy transcription factors such as FOXO1, TFEB or XBP1. Finally, the binding of adipogenic factors is associated with certain patterns of co-factors binding that might modulate the functions. Some of the findings were further confirmed under the knockdown of the adipogenic factors in the differentiating adipocytes. In conclusion, autophagy genes are regulated as part of the transcriptional programs through adipogenic factors either directly or indirectly through autophagy transcription factors during adipogenesis.
Perturbation of Methionine/S-adenosylmethionine Metabolism as a Novel Vulnerability in MLL Rearranged Leukemia
Authors: Barve Aditya , Vega Alexis , Shah Parag P. , Ghare Smita , Casson Lavona , Wunderlich Mark , Siskind Leah J. , Beverly Levi J.
Published: October 2019

Leukemias bearing mixed lineage leukemia (MLL) rearrangement (MLL-R) resulting in expression of oncogenic MLL fusion proteins (MLL-FPs) represent an especially aggressive disease subtype with the worst overall prognoses and chemotherapeutic response. MLL-R leukemias are uniquely dependent on the epigenetic function of the H3K79 methyltransferase DOT1L, which is misdirected by MLL-FPs activating gene expression, driving transformation and leukemogenesis. Given the functional necessity of these leukemias to maintain adequate methylation potential allowing aberrant activating histone methylation to proceed, driving leukemic gene expression, we investigated perturbation of methionine (Met)/S-adenosylmethionine (SAM) metabolism as a novel therapeutic paradigm for MLL-R leukemia. Disruption of Met/SAM metabolism, by either methionine deprivation or pharmacologic inhibition of downstream metabolism, reduced overall cellular methylation potential, reduced relative cell numbers, and induced apoptosis selectively in established MLL-AF4 cell lines or MLL-AF6-expressing patient blasts but not in BCR-ABL-driven K562 cells. Global histone methylation dynamics were altered, with a profound loss of requisite H3K79 methylation, indicating inhibition of DOT1L function. Relative occupancy of the repressive H3K27me3 modification was increased at the DOT1L promoter in MLL-R cells, and DOT1L mRNA and protein expression was reduced. Finally, pharmacologic inhibition of Met/SAM metabolism significantly prolonged survival in an advanced, clinically relevant patient–derived MLL-R leukemia xenograft model, in combination with cytotoxic induction chemotherapy. Our findings provide support for further investigation into the development of highly specific allosteric inhibitors of enzymatic mediators of Met/SAM metabolism or dietary manipulation of methionine levels. Such inhibitors may lead to enhanced treatment outcomes for MLL-R leukemia, along with cytotoxic chemotherapy or DOT1L inhibitors.
Effects of the Prefabricated Cu-Ti Film on the Microstructure and Mechanical Properties of the Multiphase Coating by Thermo Plasma Nitriding on C17200 Cu Alloy
Authors: Zhu Yandan , Yan Mufu , Zhang Quanli , Wang Qiwen , Zhuo Hangyu
Published: October 2019

To improve the surface wear resistance, plasma nitriding of the prefabricated Cu-Ti films on the C17200 Cu alloy is performed to investigate the effects of the composition of the Cu-Ti films on the microstructure and the mechanical properties of the modified surface. The results firstly showed that obvious microstructure evolution appeared during the thermo-plasma nitriding process, where both the surface morphology of the composed phases and the cross-sectional profiles of the multiphase coatings varied for the three types of films. Small amounts of Ti-N compounds, Be3Ti2Cu, and different types of Cu-Ti intermetallics formed in the multiphase coating after plasma nitriding, which is dependent on the composition of the prefabricated Cu-Ti film. Correspondingly, the surface hardness and the wear resistance of the C17200 Cu substrates were obviously improved, with the obtained adhesive strength of the substrate reaching a satisfactory range.