bluuebunny/crossref_metadata_2025 huggingface dataset:
Nitroethanol in Comparison with Monensin Exhibits Greater Feed Efficiency Through Inhibiting Rumen Methanogenesis More Efficiently and Persistently in Feedlotting Lambs
Authors: Zhang Zhen-Wei , Wang Yan-Lu , Chen Yong-Yan , Wang Wei-Kang , Zhang Luo-Tong , Luo Hai-Ling , Yang Hong-Jian
Published: October 2019

This study was conducted to determine the dietary supplemental effects of nitroethanol (NEOH) in comparison with monensin on growth performance and estimated methane (CH4) production in feedlotting lambs. Sixty male, small-tailed Chinese Han lambs were arranged at random into three dietary treatment groups: (1) a basal control diet (CTR), (2) the basal diet added with 40 mg/kg monensin (MON), (3) the basal diet added with 277 mg/kg nitroethanol (NEOH). During the 32-day lamb feeding, monensin and nitroethanol were added in period 1 (day 0–16) and then withdrawn in the subsequent period 2 (day 17–32) to determine their withdrawal effects. The average daily gain (ADG) and feed conversion rate in the whole period ranked: NEOH > MON > CTR (p < 0.01), suggesting that the dietary addition of NEOH in comparison with monensin presented a more lasting beneficial effect on feed efficiency. Methane emission was estimated with rumen VFA production and gross energy intake. Both monensin and NEOH addition in comparison with the control remarkably decreased CH4 emission estimate (24.0% vs. 26.4% decrease; p < 0.01) as well as CH4 emission per kg ADG (8.7% vs. 14.0% decrease; p < 0.01), but the NEOH group presented obvious lasting methanogenesis inhibition when they were withdrawn in period 2. Moreover, the in vitro methanogenic activity of rumen fluids was also decreased with monensin or NEOH addition (12.7% vs. 30.5% decrease; p < 0.01). In summary, the dietary addition of NEOH in comparison with monensin presented a greater promoting effect on growth performance in feedlotting lambs by inhibiting rumen methanogenesis more efficiently and persistently.
In Vivo Toxicity and In Vitro Solubility Assessment of Pre-Treated Struvite as a Potential Alternative Phosphorus Source in Animal Feed
Authors: Shim Soomin , Won Seunggun , Reza Arif , Kim Seungsoo , Ahn Sungil , Jung Baedong , Yoon Byungil , Ra Changsix
Published: October 2019

Apart from using as fertilizer for plants, the application of struvite may be expanded to animal feed industries through proper pre-treatment. This study aimed to investigate the safety and efficacy of using pre-treated struvite (microwave irradiated struvite (MS) and incinerated struvite (IS)) in animal feeds. For safety assessment, an in vivo toxicity experiment using thirty female Sprague Dawley rats (average body weight (BW) of 200 ± 10 g) was conducted. The rats were randomly divided into five groups, including a control. Based on the BW, MS and IS were applied daily by oral administration with 1 and 10 mg kg−1-BW (MS1 and MS10; IS1 and IS10) using dimethyl sulfoxide (DMSO) as a vehicle. A series of jar tests were conducted for four hours to check the solubility of the MS and IS at different pH (pH 2, 4, 5, 6, and 7) and compared to a commercial P source (monocalcium phosphate, MCP, control). The toxicity experiment results showed no significant differences among the treatments in BW and organ (liver, kidney, heart, and lung) weight of rats (p > 0.05). There were no adverse effects on blood parameters and the histopathological examination showed no inflammation in the organ tissues in MS and IS treated groups compared to the control. In an in vitro solubility test, no significant difference was observed in ortho-phosphate (O-P) solubility from the MCP and MS at pH 2 and 4 (p > 0.05), while O-P solubility from MS at pH 5 to 7 was higher than MCP and found to be significantly different (p < 0.05). O-P solubility from IS was the lowest among the treatments and significantly different from MCP and MS in all the experiments (p < 0.05). The results of this study not only suggest that the struvite pre-treated as MS could be a potential alternative source of P in animal feed but also motivate further studies with more stringent designs to better examine the potential of struvite application in diverse fields.
NR4A Expression by Human Marginal Zone B-Cells
Authors: Doyon-Laliberté Kim , Chagnon-Choquet Josiane , Byrns Michelle , Aranguren Matheus , Memmi Meriam , Chrobak Pavel , Stagg John , Poudrier Johanne , Roger Michel
Published: October 2019

We have previously characterized a human blood CD19+CD1c+IgM+CD27+CD21loCD10+ innate-like B-cell population, which presents features shared by both transitional immature and marginal zone (MZ) B-cells, named herein “precursor-like” MZ B-cells. B-cells with similar attributes have been associated with regulatory potential (Breg). In order to clarify this issue and better characterize this population, we have proceeded to RNA-Seq transcriptome profiling of mature MZ and precursor-like MZ B-cells taken from the blood of healthy donors. We report that ex vivo mature MZ and precursor-like MZ B-cells express transcripts for the immunoregulatory marker CD83 and nuclear receptors NR4A1, 2, and 3, known to be associated with T-cell regulatory (Treg) maintenance and function. Breg associated markers such as CD39 and CD73 were also expressed by both populations. We also show that human blood and tonsillar precursor-like MZ B-cells were the main B-cell population to express elevated levels of CD83 and NR4A1-3 proteins ex vivo and without stimulation. Sorted tonsillar precursor-like MZ B-cells exerted regulatory activity on autologous activated CD4+ T-cells, and this was affected by a CD83 blocking reagent. We believe these observations shed light on the Breg potential of MZ populations, and identify NR4A1-3 as potential Breg markers, which as for Tregs, may be involved in stabilization of a regulatory status. Since expression and activity of these molecules can be modulated therapeutically, our findings may be useful in strategies aiming at modulation of Breg responses.
A Data Segmentation-Based Ensemble Classification Method for Power System Transient Stability Status Prediction with Imbalanced Data
Authors: Chen Zhen , Han Xiaoyan , Fan Chengwei , He Zirun , Su Xueneng , Mei Shengwei
Published: October 2019

In recent years, machine learning methods have shown the great potential for real-time transient stability status prediction (TSSP) application. However, most existing studies overlook the imbalanced data problem in TSSP. To address this issue, a novel data segmentation-based ensemble classification (DSEC) method for TSSP is proposed in this paper. Firstly, the effects of the imbalanced data problem on the decision boundary and classification performance of TSSP are investigated in detail. Then, a three-step DSEC method is presented. In the first step, the data segmentation strategy is utilized for dividing the stable samples into multiple non-overlapping stable subsets, ensuring that the samples in each stable subset are not more than the unstable ones, then each stable subset is combined with the unstable set into a training subset. For the second step, an AdaBoost classifier is built based on each training subset. In the final step, decision values from each AdaBoost classifier are aggregated for determining the transient stability status. The experiments are conducted on the Northeast Power Coordinating Council 140-bus system and the simulation results indicate that the proposed approach can significantly improve the classification performance of TSSP with imbalanced data.
Optimal Operational Scheduling of Distribution Network with Microgrid via Bi-Level Optimization Model with Energy Band
Authors: Kim Ho-Young , Kim Mun-Kyeom , Kim Hyung-Joon
Published: October 2019

An optimal operation of new distributed energy resources can significantly advance the performance of power systems, including distribution network (DN). However, increased penetration of renewable energy may negatively affect the system performance under certain conditions. From a system operator perspective, the tie-line control strategy may aid in overcoming various problems regarding increased renewable penetration. We propose a bi-level optimization model incorporating an energy band operation scheme to ensure cooperation between DN and microgrid (MG). The bi-level formulation for the cooperation problem consists of the cost minimization of the DN and profit maximization of the MG. The goal of the upper-level is to minimize the operating costs of the DN by accounting for feedback information, including the operating costs of the MG and energy band. The lower-level aims to maximize the MG profit, simultaneously satisfying the reliability and economic targets imposed in the scheduling requirements by the DN system operator. The bi-level optimization model is solved using an advanced method based on the modified non-dominated sorting genetic algorithm II. Based on simulation results using a typical MG and an actual power system, we demonstrate the applicability, effectiveness, and validity of the proposed bi-level optimization model.
An Accurate Probabilistic Model for TVWS Identification
Authors: Corral-De-Witt Danilo , Ahmed Sabbir , Awin Faroq , Rojo-Álvarez José Luis , Tepe Kemal
Published: October 2019

Television White Spaces (TVWS)-based cognitive radio systems can improve spectrum efficiency by facilitating opportunistic usage of television broadcasting spectrum by secondary users without interfering with primary users. Previously applied models introduce missed detection errors, giving a limited estimation of the spectrum occupancy, which does not correspond to the reality of its usage, hence resulting in a partial waste of this resource. Considering jointly parameters like false alarm probability and detection probability, this article proposes a probabilistic model that can identify TVWS with improved accuracy. The proposed model considers energy detection criteria, combined with simultaneous sensing of the noise and of the signal from primary users. In order to demonstrate the model effectiveness, a low-cost Mobile Spectrum Sensing Station prototype was designed, implemented, and subsequently mounted on a vehicle. More than eight million spatio-temporally variant data samples were collected by scanning the UHF-TV spectrum of 500–698 MHz in the city of Windsor, ON, Canada. Analysis of the collected data showed that the proposed model achieves an accuracy improvement of about 9.6% compared to existing models, demonstrating that TVWS vary with spatial displacement and increasing significantly in the rural areas. Even in the most crowded spectrum zone, about 28% of the channels are identified as TVWS, and this number increases to a maximum of 60% in less crowded regions in urban areas. We conclude that the proposed model improves the TVWS detection compared with other used models, and also that the elements considered in this research contribute to reduce the complexity of the mathematical calculations while maintaining the accuracy. A low-cost open-source sensing station has been designed and tested, which represents an operative and useful data source in this setting.
Stressing State Analysis of CFST Arch Supports in Deep Roadway Based on NSF Method
Authors: Shen Jiyang , Huang Wen , Yang Xiaocong , Shi Jun , Zheng Kaikai
Published: October 2019

This paper experimentally analyzes the working behavior characteristics of five concrete-filled steel tube (CFST) arch supports in deep roadway based on the numerical shape function (NSF) method and structural stressing state theory. First, the measured strain data are expanded by the NSF method and modeled as generalized strain energy density (GSED) to characterize the stressing state of the supports. Then, one of the supports is taken as an example and the Mann-Kendall (M-K) criterion is adopted to detect the mutation characteristics of the support, which derives the new definition of structural failure load. Correspondingly, the stressing state modes as well as strain and stress fields for the support are proposed to verify their mutation characteristics. Finally, the common and different characteristics of stressing state, damage development and internal forces for different supports are also summarized. The analytical results of the supports explore a new analysis method for underground structures and the unseen knowledge provides a reference to more rational future design.
Thematic Accuracy Quality Control by Means of a Set of Multinomials
Authors: Ariza-López Francisco J. , Rodríguez-Avi José , Alba-Fernández María V. , García-Balboa José L.
Published: October 2019

The error matrix has been adopted as both the “de facto” and the “de jure” standard way to report on the thematic accuracy assessment of any remotely sensed data product. This perspective assumes that the error matrix can be considered as a set of values following a unique multinomial distribution. However, the assumption of the underlying statistical model falls down when true reference data are available for quality control. To overcome this problem, a new method for thematic accuracy quality control is proposed, which uses a multinomial approach for each category and is called QCCS (quality control column set). The main advantage is that it allows us to state a set of quality specifications for each class and to test if they are fulfilled. These requirements can be related to the percentage of correctness in the classification for a particular class but also to the percentage of possible misclassifications or confusions between classes. In order to test whether such specifications are achieved or not, an exact multinomial test is proposed for each category. Furthermore, if a global hypothesis test is desired, the Bonferroni correction is proposed. All these new approaches allow a more flexible way of understanding and testing thematic accuracy quality control compared with the classical methods based on the confusion matrix. For a better understanding, a practical example of an application is included for classification with four categories.
Labeling Confidence Values for Wafer-Handling Robot Arm Performance Using a Feature-Based General Regression Neural Network and Genetic Algorithm
Authors: Huang Yi-Cheng , Yang Zi-Sheng , Liao Hsien-Shu
Published: October 2019

The prognosis and management of machine health statuses are emerging research topics. In this study, the performance degradation of a wafer-handling robot arm (WHRA) was predicted using the proposed machine-learning approach. This method considers the eccentric vertical and planar position deviations from a wafer mark using a charge-coupled device (CCD) camera. Synthesized position signals were defined using the square root of x- and y-axes deviations in the horizontal view and the square of the wafer mark diameter in the vertical view. A feature extraction method was used to determine the position status on the basis of these displacements and the area of a wafer mark in a CCD image. The root mean square error and mean, maximum, and minimum of the synthesized position signals were extracted through feature extraction and used for data mining by a general regression neural network (GRNN) and logistic regression (LR) models. The lifetime assessment by confidence value of the WHRA’s remaining useful life (RUL) by the genetic algorithm/GRNN exhibited nearly the same trend as that predicted through a run-to-failure LR model. The experimental results indicated that the proposed methodology can be used for proactive assessments of the RUL of WHRAs.
Bioelectricity Generation by Corynebacterium glutamicum with Redox-Hydrogel-Modified Carbon Electrode
Authors: Lee Soo Youn , Min Jiho , Lee Sangmin , Fitriana Hana Nur , Kim Min-Sik , Park Gwon Woo , Lee Jin-Suk
Published: October 2019

This work studied Gram-positive and weak electricigen Corynebacterium glutamicum for its ability to transfer electrons and to produce bioelectricity in microbial fuel cells (MFCs). The electrochemical and liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) results revealed that C. glutamicum had the potential to mediate electron transfer to an electrode by emitting its own extracellular electron shuttles such as flavins. To enhance the current collection from C. glutamicum, a carbon cloth anode was modified with ferrocene-branched chitosan hydrogel (redox-hydrogel). The maximum current density of the ferrocene-branched chitosan redox hydrogel anode with C. glutamicum was drastically increased to 120 µA cm−2 relative to a bare carbon cloth electrode with C. glutamicum (261 nA cm−2). The power density and polarization curves for the MFC operation with the redox-hydrogel-modified anode showed that C. glutamicum effectively generated bioelectricity by means of the redox-hydrogel anode. The results suggest that, in such an electro-fermentation process, ferrocene-branched chitosan hydrogel grafted onto an anode surface would also facilitate both electron transfer from C. glutamicum to the anode and bioelectricity generation.
Combining Dispersion Modeling and Monitoring Data for Community-Scale Air Quality Characterization
Authors: Isakov Vlad , Arunachalam Saravanan , Baldauf Richard , Breen Michael , Deshmukh Parikshit , Hawkins Andy , Kimbrough Sue , Krabbe Stephen , Naess Brian , Serre Marc , Valencia Alejandro
Published: October 2019

Spatially and temporally resolved air quality characterization is critical for community-scale exposure studies and for developing future air quality mitigation strategies. Monitoring-based assessments can characterize local air quality when enough monitors are deployed. However, modeling plays a vital role in furthering the understanding of the relative contributions of emissions sources impacting the community. In this study, we combine dispersion modeling and measurements from the Kansas City TRansportation local-scale Air Quality Study (KC-TRAQS) and use data fusion methods to characterize air quality. The KC-TRAQS study produced a rich dataset using both traditional and emerging measurement technologies. We used dispersion modeling to support field study design and analysis. In the study design phase, the presumptive placement of fixed monitoring sites and mobile monitoring routes have been corroborated using a research screening tool C-PORT to assess the spatial and temporal coverage relative to the entire study area extent. In the analysis phase, dispersion modeling was used in combination with observations to help interpret the KC-TRAQS data. We extended this work to use data fusion methods to combine observations from stationary, mobile measurements, and dispersion model estimates.
Scaling Properties of Atmospheric Wind Speed in Mesoscale Range
Authors: Carbone Francesco , Telloni Daniele , Bruno Antonio G. , Hedgecock Ian M. , De Simone Francesco , Sprovieri Francesca , Sorriso-Valvo Luca , Pirrone Nicola
Published: October 2019

The scaling properties of turbulent flows are well established in the inertial sub-range. However, those of the synoptic-scale motions are less known, also because of the difficult analysis of data presenting nonstationary and periodic features. Extensive analysis of experimental wind speed data, collected at the Mauna Loa Observatory of Hawaii, is performed using different methods. Empirical Mode Decomposition, interoccurrence times statistics, and arbitrary-order Hilbert spectral analysis allow to eliminate effects of large-scale modulations, and provide scaling properties of the field fluctuations (Hurst exponent, interoccurrence distribution, and intermittency correction). The obtained results suggest that the mesoscale wind dynamics owns features which are typical of the inertial sub-range turbulence, thus extending the validity of the turbulent cascade phenomenology to scales larger than observed before.
Spatial and Temporal Variation of Wind Erosion Climatic Erosivity and Its Response to ENSO in the Otindag Desert, China
Authors: Lou Junpeng , Wang Xunming , Cai Diwen
Published: October 2019

Wind erosion is a major cause of soil losses in China’s drylands which is further stimulated by climate variability and fragile ecological conditions. Climatic erosivity is an important index of wind erosion, therefore, evaluation of its spatiotemporal variations and relationship with the El Niño–Southern Oscillation (ENSO) will provide a theoretical basis for the comprehensive management and prevention of soil erosion. In this study, by using the climatic erosivity equation, geographic information system (GIS) and geostatistical analysis, we quantified the climatic erosivity, explored its spatiotemporal variations, and detected the effects of the Multivariate ENSO Index (MEI) on climatic erosivity in the Otindag Desert during the period of 1980–2016. The results indicated that the climatic erosivity (C-factor value) ranged from 82–445, and it decreased from the western margin to the eastern margin of the desert. The climatic erosivity showed a significant downward trend at seasonal and annual scales (p < 0.05). As far as spring, autumn and annual climatic erosivity, the whole region showed a downward trend, however, the summer and winter climatic erosivity varied spatially, in which the central and western regions showed a downward trend, but the eastern region showed an upward trend. The results showed that the average climatic erosivity is weaker during La Niña events than during El Niño events. The climatic erosivity recorded by 14 of the 20 meteorological stations, all located in central and west regions, exhibited a significant correlation with MEI (p < 0.05). The ENSO has a significant impact on climatic erosivity.
A Preliminary Impact Study of Wind on Assimilation and Forecast Systems into the One-Dimensional Fog Forecasting Model COBEL-ISBA over Morocco
Authors: Bari Driss
Published: October 2019

The assimilation impact of wind data from aircraft measurements (AMDAR), surface synoptic observations (SYNOP) and 3D numerical weather prediction (NWP) mesoscale model, on short-range numerical weather forecasting (up to 12 h) and on the assimilation system, using the one-dimensional fog forecasting model COBEL-ISBA (Code de Brouillard à l’Échelle Locale-Interactions Soil Biosphere Atmosphere), is studied in the present work. The wind data are extracted at Nouasseur airport, Casablanca, Morocco, over a winter period from the national meteorological database. It is the first time that wind profiles (up to 1300 m) are assimilated in the framework of a single-column model. The impact is assessed by performing NWP experiments with data denial tests, configured to be close to the operational settings. The assimilation system estimates the flow-dependent background covariances for each run of the model and takes the cross-correlations between temperature, humidity and wind components into account. When assimilated into COBEL-ISBA with an hourly update cycle, the wind field has a positive impact on temperature and specific humidity analysis and forecasts accuracy. Thus, a superior fit of the analysis background fields to observations is found when assimilating AMDAR without NWP wind data. The latter has shown a detrimental impact in all experiments. Besides, wind assimilation gave a clear improvement to short-range forecasts of near-surface thermodynamical parameters. Although, assimilation of SYNOP and AMDAR wind measurements slightly improves the probability of detection of fog but also increases the false alarms ratio by a lower magnitude.
The 10–20 d Low-Frequency Oscillation Characteristics of Summer Precipitation in Eastern China in the Decaying Year of CP ENSO
Authors: Cai Cong , Wang Lijuan , Wang Junyu , Wang Zhiqiang
Published: October 2019

Using National Centers for Atmospheric Prediction/National Center for Atmospheric Research (NCEP/NCAR) reanalysis data and observational data, the low-frequency oscillation characteristics of precipitation in eastern China during the decaying summer of central Pacific El Niño–Southern Oscillation (CP ENSO) and the corresponding low-frequency atmospheric oscillation characteristic were investigated. The results showed that summer precipitation in eastern China during the decaying year of CP El Niño (La Niña) was more (less) than the climatological mean and that 10–20 d was its dominant period. Low-frequency oscillations at different tropospheric levels had different effects on low-frequency precipitation. In the upper troposphere, Eastern China was dominated by low-frequency divergence and positive (negative) anomaly of low-frequency height during the decaying year of CP El Niño (La Niña), and there was strong (weak) northwest–southeast wave-active flux transport. In the middle troposphere, the range and intensity of the subtropical western Pacific High (SWPH) of CP El Niño was larger and stronger than that of CP La Niña, which may be related to the low-frequency height fields. Meanwhile, the correspnding low-frequency wind field, water vapor circulation systems and moisture transport channels in the lower troposphere, along with the low-frequency vertical movement were significantly different, causing the low-frequency precipitation of CP El Niño to be stronger than CP La Niña.
P-N Junction-Based Si Biochips with Ring Electrodes for Novel Biosensing Applications
Authors: Kiani Mahdi , Du Nan , Vogel Manja , Raff Johannes , Hübner Uwe , Skorupa Ilona , Bürger Danilo , Schulz Stefan , Schmidt Oliver , Schmidt Heidemarie
Published: October 2019

In this work, we report on the impedance of p-n junction-based Si biochips with gold ring top electrodes and unstructured platinum bottom electrodes which allows for counting target biomaterial in a liquid-filled ring top electrode region. The systematic experiments on p-n junction-based Si biochips fabricated by two different sets of implantation parameters (i.e. biochips PS5 and BS5) are studied, and the comparable significant change of impedance characteristics in the biochips in dependence on the number of bacteria suspension, i.e., Lysinibacillus sphaericus JG-A12, in Deionized water with an optical density at 600 nm from OD600 = 4–16 in the electrode ring region is demonstrated. Furthermore, with the help of the newly developed two-phase electrode structure, the modeled capacitance and resistance parameters of the electrical equivalent circuit describing the p-n junction-based biochips depend linearly on the number of bacteria in the ring top electrode region, which successfully proves the potential performance of p-n junction-based Si biochips in observing the bacterial suspension. The proposed p-n junction-based biochips reveal perspective applications in medicine and biology for diagnosis, monitoring, management, and treatment of diseases.
Efficacy of Cell-Based Therapies for Traumatic Brain Injuries
Authors: Chrostek Matthew R. , Fellows Emily G. , Guo Winston L. , Swanson William J. , Crane Andrew T. , Cheeran Maxim C. , Low Walter C. , Grande Andrew W.
Published: October 2019

Traumatic brain injuries (TBIs) are a leading cause of death and disability. Additionally, growing evidence suggests a link between TBI-induced neuroinflammation and neurodegenerative disorders. Treatments for TBI patients are limited, largely focused on rehabilitation therapy, and ultimately, fail to provide long-term neuroprotective or neurorestorative benefits. Because of the prevalence of TBI and lack of viable treatments, new therapies are needed which can promote neurological recovery. Cell-based treatments are a promising avenue because of their potential to provide multiple therapeutic benefits. Cell-based therapies can promote neuroprotection via modulation of inflammation and promote neurorestoration via induction of angiogenesis and neurogenesis. Neural stem/progenitor cell transplantations have been investigated in preclinical TBI models for their ability to directly contribute to neuroregeneration, form neural-like cells, and improve recovery. Mesenchymal stem cells (MSCs) have been investigated in clinical trials through multiple different routes of administration. Intravenous administration of MSCs appears most promising, demonstrating a robust safety profile, correlation with neurological improvements, and reductions in systemic inflammation following TBI. While still preliminary, evidence suggests cell-based therapies may become a viable treatment for TBI based on their ability to promote neuroregeneration and reduce inflammation.
Mid-Frontal Theta Modulates Response Inhibition and Decision Making Processes in Emotional Contexts
Authors: Nayak Siddharth , Kuo ChiiShyang , Tsai Arthur Chih-Hsin
Published: October 2019

Inhibitory control is an integral part of executive functions. In this study, we report event-related spectral perturbation (ERSP) results from 15 healthy adults performing an emotional stop-signal task with the use of happy, disgusted, and neutral emotional faces. Our ERSP results at the group level suggest that changes in low frequency oscillatory power for emotional and neutral conditions start at as early as 200 ms after stimulus onset and 300 ms before button press for successful go trials. To quantify the dynamics of trial-by-trial theta power, we applied the hierarchical drift diffusion model to single-trial ERSP at the mid-frontal electrode site for the go condition. Hierarchical drift diffusion modeling (HDDM) assigned higher frontal low-frequency oscillatory power for evidence accumulation in emotional contexts as compared to a neutral setting. Our results provide new evidence for dynamic modulation of sensory processing of go stimuli in inhibition and extend our knowledge for processing of response inhibition in emotional contexts.
Safinamide in Clinical Practice: A Spanish Multicenter Cohort Study
Authors: Martí-Andrés Gloria , Jiménez-Bolaños Rayco , Arbelo-González José Matias , Pagonabarraga Javier , Duran-Herrera Carmen , Valenti-Azcarate Rafael , Luquin Mª Rosario
Published: October 2019

Background: Safinamide is an approved drug for the treatment of motor fluctuations of Parkinson’s Disease (PD) patients with a potential benefit on non-motor symptoms (NMS). Methods: A retrospective multicenter cohort study was conducted, in which the clinical effect of safinamide on both motor and NMS was assessed by the Clinical Global Impression of Change scale. Furthermore, we assessed the appearance of adverse events (AEs) and its effect on dyskinesia, that were also recorded in non-fluctuating PD patients and in those previously treated with rasagiline. Results: We included 213 PD patients who received safinamide in addition to their regular levodopa therapy. Thirty-five withdrew prematurely from safinamide, mainly because of AEs. Out of 178, clinical improvement on motor and NMS was found in 76.4% and 26.2%, respectively. A total of 44 reported AEs of mild intensity. We did not find a difference concerning the clinical benefit or AEs when comparing either patients who had or had not been taking Monoamine Oxidase B Inhibitor (MAOB-I) previously or between patients with and without motor complications. Conclusions: Safinamide is an effective and safe add-on to levodopa drug for PD patients. Moreover, safinamide could elicit an additional clinical improvement in PD patients previously treated with other MAOB-I and in non- fluctuating patients with suboptimal motor control.
Childhood Trauma and Stressful Life Events Are Independently Associated with Sleep Disturbances in Adolescents
Authors: Baddam Suman K.R. , Olvera Rene L. , Canapari Craig A. , Crowley Michael J. , Williamson Douglas E.
Published: October 2019

Adolescence is a critical developmental period associated with an increase in stress, the appearance of anxiety and depressive symptoms, and changes in sleep patterns. Even though the disruption of sleep patterns in stress and anxiety and depressive disorders is well known, the independent effects of childhood trauma and stressful life events on sleep patterns are less understood. We tested the independent effects of stress (childhood trauma and stressful life events) while controlling for anxiety and depression on adolescent sleep patterns. Seven hundred fifty-two adolescents (age 12–15 years) completed self-report questionnaires about childhood trauma, stressful life events, anxiety, and depression. Four sleep factors identifying movement during sleep, sleep regularity, sleep disturbances, and sleep pressure were extracted in the principal component analysis of sleep questions. Both childhood trauma and recent stressful life events were significantly associated with sleep disturbances before and after controlling for anxiety and depression.
Transcriptional Modulation by Idelalisib Synergizes with Bendamustine in Chronic Lymphocytic Leukemia
Authors: Kost Sara E. F. , Saleh Ali , Mejia Edgard M. , Mostafizar Marina , Bouchard Eric D. J. , Banerji Versha , Marshall Aaron J. , Gibson Spencer B. , Johnston James B. , Katyal Sachin
Published: October 2019

The phosphatidyl-inositol 3 kinase (PI3K) δ inhibitor, idelalisib (IDE), is a potent inhibitor of the B-cell receptor pathway and a novel and highly effective agent for the treatment of chronic lymphocytic leukemia (CLL). We evaluated the activities of IDE in comparison to bendamusine (BEN), a commonly used alkylating agent, in primary CLL cells ex vivo. In contrast to BEN, IDE was cytotoxic to cells from extensively-treated patients, including those with a deletion (del)17p. Cross-resistance was not observed between BEN and IDE, confirming their different modes of cytotoxicity. Marked synergy was seen between BEN and IDE, even in cases that were resistant to BEN or IDE individually, and those with deletion (del) 17p. CD40L/interleukin 4 (IL4) co-treatment mimicking the CLL microenvironment increased resistance to IDE, but synergy was retained. PI3Kδ-deficient murine splenic B cells were more resistant to IDE and showed reduced synergy with BEN, thus confirming the importance of functional PI3Kδ protein. Although IDE was observed to induce γH2AX, IDE did not enhance activation of the DNA damage response nor DNA repair activity. Interestingly, IDE decreased global RNA synthesis and was antagonistic with 5,6-Dichlorobenzimidazole 1-b-D-ribofuranoside (DRB), an inhibitor of transcription. These findings add to the increasingly complex cellular effects of IDE, and B cell receptor (BCR) inhibitors in general, in CLL.
Potential and Challenges of Aptamers as Specific Carriers of Therapeutic Oligonucleotides for Precision Medicine in Cancer
Authors: Nuzzo Silvia , Roscigno Giuseppina , Affinito Alessandra , Ingenito Francesco , Quintavalle Cristina , Condorelli Gerolama
Published: October 2019

Due to the progress made in the area of precision and personalized medicine in the field of cancer therapy, strategies to selectively and specifically identify target molecules causative of the diseases are urgently needed. Efforts are being made by a number of different laboratories, companies, and researchers to develop therapeutic molecules that selectively recognize the tissues and the cells of interest, exhibit few or no off-target and side effects, are non-immunogenic, and have a strong action. Aptamers, artificially selected single-stranded DNA or RNA oligonucleotides, are promising molecules satisfying many of the requirements needed for diagnosis and precision medicine. Aptamers can also couple to their native mechanism of action the delivery of additional molecules (oligonucleotides, siRNAs, miRNAs) to target cells. In this review, we summarize recent progress in the aptamer-mediated strategy for the specific delivery of therapeutic oligonucleotides.
PARP1 Co-Regulates EP300–BRG1-Dependent Transcription of Genes Involved in Breast Cancer Cell Proliferation and DNA Repair
Authors: Sobczak Maciej , Pitt Andrew R. , Spickett Corinne M. , Robaszkiewicz Agnieszka
Published: October 2019

BRG1, an active subunit of the SWI/SNF chromatin-remodeling complex, enables the EP300-dependent transcription of proliferation and DNA repair genes from their E2F/CpG-driven promoters in breast cancer cells. In the current study, we show that BRG1–EP300 complexes are accompanied by poly-ADP-ribose polymerase 1 (PARP1), which emerges as the functional component of the promoter-bound multiprotein units that are capable of controlling gene expression. This enzyme is co-distributed with BRG1 at highly acetylated promoters of genes such as CDK4, LIG1, or NEIL3, which are responsible for cancer cell growth and the removal of DNA damage. ADP-ribosylation is necessary to maintain active transcription, since it ensures an open chromatin structure that allows high acetylation and low histone density. PARP1-mediated modification of BRG1 and EP300 does not affect the association of enzymes with gene promoters; however, it does activate EP300, which acetylates nucleosomes, leading to their eviction by BRG1, thus allowing mRNA synthesis. Although PARP1 was found at BRG1 positive/H3K27ac negative promoters of highly expressed genes in a transformed breast cancer cell line, its transcriptional activity was limited to genes simultaneously controlled by BRG1 and EP300, indicating that the ADP-ribosylation of EP300 plays a dominant role in the regulation of BRG1–EP300-driven transcription. In conclusion, PARP1 directs the transcription of some proliferation and DNA repair genes in breast cancer cells by the ADP-ribosylation of EP300, thereby causing its activation and marking nucleosomes for displacement by BRG1. PARP1 in rapidly dividing cells facilitates the expression of genes that confer a cancer cell phenotype. Our study shows a new mechanism that links PARP1 with the removal of DNA damage in breast cancer cells via the regulation of BRG1–EP300-dependent transcription of genes involved in DNA repair pathways.
Eucalyptol as a Bio-Based Solvent for Buchwald-Hartwig Reaction on O,S,N-Heterocycles
Authors: Campos Joana F. , Berteina-Raboin Sabine
Published: October 2019

We report here the use of eucalyptol as a bio-based solvent for the Buchwald–Hartwig reaction on O,S,N-heterocycles. These heterocycles containing oxygen, sulfur and nitrogen were chosen as targets or as starting materials. Once again, eucalyptol demonstrated to be a possible sustainable alternative to common solvents.
Identification of a Specific Inhibitor of Human Scp1 Phosphatase Using the Phosphorylation Mimic Phage Display Method
Authors: Yoshida Takuya , Yamazaki Kazuki , Imai Shunta , Banno Akinori , Kaneko Atsushi , Furukawa Kazuhiro , Chuman Yoshiro
Published: October 2019

Protein phosphatases are divided into tyrosine (Tyr) phosphatases and serine/threonine (Ser/Thr) phosphatases. While substrate trapping mutants are frequently used to identify substrates of Tyr phosphatases, a rapid and simple method to identify Ser/Thr phosphatase substrates is yet to be developed. The TFIIF-associating component of RNA polymerase II C-terminal domain (CTD) phosphatase/small CTD phosphatase (FCP/SCP) phosphatase family is one of the three types of Ser/Thr protein phosphatases. Defects in these phosphatases are correlated with the occurrence of various diseases such as cancer and neuropathy. Recently, we developed phosphorylation mimic phage display (PMPD) method with AlF4−, a methodology to identify substrates for FCP/SCP type Ser/Thr phosphatase Scp1. Here, we report a PMPD method using BeF3− to identify novel substrate peptides bound to Scp1. After screening peptide phages, we identified peptides that bound to Scp1 in a BeF3−-dependent manner. Synthetic phosphopeptide BeM12-1, the sequence of which was isolated at the highest frequency, directly bound to Scp1. The binding was inhibited by adding BeF3−, indicating that the peptide binds to the active center of catalytic site in Scp1. The phosphorylated BeM12-1 worked as a competitive inhibitor of Scp1. Thus, PMPD method may be applicable for the identification of novel substrates and inhibitors of the FCP/SCP phosphatase family.
Stromal Cell-Derived Factor 1 Protects Brain Vascular Endothelial Cells from Radiation-Induced Brain Damage
Authors: Heo Jong-Ik , Kim Kwang Il , Woo Sang-Keun , Kim Joong Sun , Choi Kyu Jin , Lee Hae-June , Kim Kwang Seok
Published: October 2019

Stromal cell-derived factor 1 (SDF-1) and its main receptor, CXC chemokine receptor 4 (CXCR4), play a critical role in endothelial cell function regulation during cardiogenesis, angiogenesis, and reendothelialization after injury. The expression of CXCR4 and SDF-1 in brain endothelial cells decreases due to ionizing radiation treatment and aging. SDF-1 protein treatment in the senescent and radiation-damaged cells reduced several senescence phenotypes, such as decreased cell proliferation, upregulated p53 and p21 expression, and increased senescence-associated beta-galactosidase (SA-β-gal) activity, through CXCR4-dependent signaling. By inhibiting extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription protein 3 (STAT3), we confirmed that activation of both is important in recovery by SDF-1-related mechanisms. A CXCR4 agonist, ATI2341, protected brain endothelial cells from radiation-induced damage. In irradiation-damaged tissue, ATI2341 treatment inhibited cell death in the villi of the small intestine and decreased SA-β-gal activity in arterial tissue. An ischemic injury experiment revealed no decrease in blood flow by irradiation in ATI2341-administrated mice. ATI2341 treatment specifically affected CXCR4 action in mouse brain vessels and partially restored normal cognitive ability in irradiated mice. These results demonstrate that SDF-1 and ATI2341 may offer potential therapeutic approaches to recover tissues damaged during chemotherapy or radiotherapy, particularly by protecting vascular endothelial cells.
Roles for the Endoplasmic Reticulum in Regulation of Neuronal Calcium Homeostasis
Authors: Karagas Nicholas E. , Venkatachalam Kartik
Published: October 2019

By influencing Ca2+ homeostasis in spatially and architecturally distinct neuronal compartments, the endoplasmic reticulum (ER) illustrates the notion that form and function are intimately related. The contribution of ER to neuronal Ca2+ homeostasis is attributed to the organelle being the largest reservoir of intracellular Ca2+ and having a high density of Ca2+ channels and transporters. As such, ER Ca2+ has incontrovertible roles in the regulation of axodendritic growth and morphology, synaptic vesicle release, and neural activity dependent gene expression, synaptic plasticity, and mitochondrial bioenergetics. Not surprisingly, many neurological diseases arise from ER Ca2+ dyshomeostasis, either directly due to alterations in ER resident proteins, or indirectly via processes that are coupled to the regulators of ER Ca2+ dynamics. In this review, we describe the mechanisms involved in the establishment of ER Ca2+ homeostasis in neurons. We elaborate upon how changes in the spatiotemporal dynamics of Ca2+ exchange between the ER and other organelles sculpt neuronal function and provide examples that demonstrate the involvement of ER Ca2+ dyshomeostasis in a range of neurological and neurodegenerative diseases.
IL-2 Therapy Diminishes Renal Inflammation and the Activity of Kidney-Infiltrating CD4+ T Cells in Murine Lupus Nephritis
Authors: Rose Angelika , von Spee-Mayer Caroline , Kloke Lutz , Wu Kaiyin , Kühl Anja , Enghard Philipp , Burmester Gerd-Rüdiger , Riemekasten Gabriela , Humrich Jens
Published: October 2019

An acquired deficiency of interleukin-2 (IL-2) and related disturbances in regulatory T cell (Treg) homeostasis play an important role in the pathogenesis of systemic lupus erythematosus (SLE). Low-dose IL-2 therapy was shown to restore Treg homeostasis in patients with active SLE and its clinical efficacy is currently evaluated in clinical trials. Lupus nephritis (LN), a challenging organ manifestation in SLE, is characterized by the infiltration of pathogenic CD4+ T cells into the inflamed kidney. However, the role of the Treg-IL-2 axis in the pathogenesis of LN and the mode of action of IL-2 therapy in the inflamed kidneys are still poorly understood. Using the (NZB × NZW) F1 mouse model of SLE we studied whether intrarenal Treg are affected by a shortage of IL-2 in comparison with lymphatic organs and whether and how intrarenal T cells and renal inflammation can be influenced by IL-2 therapy. We found that intrarenal Treg show phenotypic signs that are reminiscent of IL-2 deprivation in parallel to a progressive hyperactivity of intrarenal conventional CD4+ T cells (Tcon). Short-term IL-2 treatment of mice with active LN induced an expansion the intrarenal Treg population whereas long-term IL-2 treatment reduced the activity and proliferation of intrarenal Tcon, which was accompanied by a clinical and histological amelioration of LN. The association of these immune pathologies with IL-2 deficiency and their reversibility by IL-2 therapy provides important rationales for an IL-2-based immunotherapy of LN.
Lack of a Retinal Phenotype in a Syne-2/Nesprin-2 Knockout Mouse Model
Authors: Falk Nathalie , Joachimsthaler Anneka , Kessler Kristin , Lux Uwe Thorsten , Noegel Angelika Anna , Kremers Jan , Brandstätter Johann Helmut , Gießl Andreas
Published: October 2019

Syne-2 (also known as Nesprin-2) is a member of a family of proteins that are found primarily in the outer nuclear membrane, as well as other subcellular compartments. Syne-2 contains a C-terminal KASH transmembrane domain and is part of a protein network that associates the nuclear envelope to the cytoskeleton via the binding to actin filaments. Syne-2 plays a role in nuclear migration, nuclear positioning during retinal development, and in ciliogenesis. In a previous study, we showed a connection between Syne-2 and the multifunctional scaffold protein Pericentrin (Pcnt). The elimination of the interaction of Syne-2 and Pcnt showed defects in nuclear migration and the formation of outer segments during retinal development, as well as disturbances in centrosomal migration at the beginning of ciliogenesis in general. In this study, the Syne-2 KO mouse model Nesprin-2△ABD (Syne-2tm1Ngl, MGI) with special attention to Pcnt and ciliogenesis was analyzed. We show reduced expression of Syne-2 in the retina of the Syne-2 KO mouse but found no significant structural—and only a minor functional—phenotype. For the first time, detailed expression analyses showed an expression of a Syne-2 protein larger than 400 kDa (~750 kDa) in the Syne-2/Nesprin-2 KO mouse. In conclusion, the lack of an overt phenotype in Syne-2/Nesprin-2 KO mice suggests the usage of alternative translational start sites, producing Syne-2 splice variants with an intact Pcnt interaction site. Nevertheless, deletion of the actin-binding site in the Syne-2/Nesprin-2 KO mouse revealed a high variability in scotopic oscillatory potentials assuming a novel function of Syne-2 in synchronizing inner retinal processes.
Mechanisms of Collagen Crosslinking in Diabetes and Keratoconus
Authors: McKay Tina B. , Priyadarsini Shrestha , Karamichos Dimitrios
Published: October 2019

Collagen crosslinking provides the mechanical strength required for physiological maintenance of the extracellular matrix in most tissues in the human body, including the cornea. Aging and diabetes mellitus (DM) are processes that are both associated with increased collagen crosslinking that leads to increased corneal rigidity. By contrast, keratoconus (KC) is a corneal thinning disease associated with decreased mechanical stiffness leading to ectasia of the central cornea. Studies have suggested that crosslinking mediated by reactive advanced glycation end products during DM may protect the cornea from KC development. Parallel to this hypothesis, riboflavin-mediated photoreactive corneal crosslinking has been proposed as a therapeutic option to halt the progression of corneal thinning by inducing intra- and intermolecular crosslink formation within the collagen fibrils of the stroma, leading to stabilization of the disease. Here, we review the pathobiology of DM and KC in the context of corneal structure, the epidemiology behind the inverse correlation of DM and KC development, and the chemical mechanisms of lysyl oxidase-mediated crosslinking, advanced glycation end product-mediated crosslinking, and photoreactive riboflavin-mediated corneal crosslinking. The goal of this review is to define the biological and chemical pathways important in physiological and pathological processes related to collagen crosslinking in DM and KC.