bluuebunny/crossref_metadata_2025 huggingface dataset:
Natural Killer Cell Therapy: A New Treatment Paradigm for Solid Tumors
Authors: Oh Sooyeon , Lee Joo-Ho , Kwack KyuBum , Choi Sang-Woon
Published: October 2019

In treatments of solid tumors, adoptive transfer of ex vivo expanded natural killer (NK) cells has dawned as a new paradigm. Compared with cytotoxic T lymphocytes, NK cells take a unique position targeting tumor cells that evade the host immune surveillance by down-regulating self-antigen presentation. Recent findings highlighted that NK cells can even target cancer stem cells. The efficacy of allogeneic NK cells has been widely investigated in the treatment of hematologic malignancies. In solid tumors, both autologous and allogeneic NK cells have demonstrated potential efficacy. In allogeneic NK cell therapy, the mismatch between the killer cell immunoglobulin-like receptor (KIR) and human leukocyte antigen (HLA) can be harnessed to increase the antitumor activity. However, the allogeneic NK cells cause more adverse events and can be rejected by the host immune system after repeated injections. In this regard, the autologous NK cell therapy is safer. This article reviews the published results of clinical trials and discusses strategies to enhance the efficacy of the NK cell therapy. The difference in immunophenotype of the ex vivo expanded NK cells resulted from different culture methods may affect the final efficacy. Furthermore, currently available standard anticancer therapy, molecularly targeted agents, and checkpoint inhibitors may directly or indirectly enhance the efficacy of NK cell therapy. A recent study discovered that NK cell specific genetic defects are closely associated with the tumor immune microenvironment that determines clinical outcomes. This finding warrants future investigations to find the implication of NK cell specific genetic defects in cancer development and treatment, and NK cell deficiency syndrome should be revisited to enhance our understanding. Overall, it is clear that NK cell therapy is safe and promises a new paradigm for the treatment of solid tumors.
Intelligent Analysis Algorithm for Satellite Health under Time-Varying and Extremely High Thermal Loads
Authors: Li En-Hui , Li Yun-Ze , Li Tian-Tian , Li Jia-Xin , Zhai Zhuang-Zhuang , Li Tong
Published: October 2019

This paper presents a dynamic health intelligent evaluation model proposed to analyze the health deterioration of satellites under time-varying and extreme thermal loads. New definitions such as health degree and failure factor and new topological system considering the reliability relationship are proposed to characterize the dynamic performance of health deterioration. The dynamic health intelligent evaluation model used the thermal network method (TNM) and fuzzy reasoning to solve the problem of model missing and non-quantization between temperature and failure probability, and it can quickly evaluate and analyze the dynamic health of satellite through the collaborative processing of continuous event and discrete event. In addition, the temperature controller in the thermal control subsystem (TCM) is the target of thermal damage, and the effects of different heat load amplitude, duty ratio, and cycle on its health deterioration are compared and analyzed.
Entropic Divergence and Entropy Related to Nonlinear Master Equations
Authors: Biró Tamás Sándor , Néda Zoltán , Telcs András
Published: October 2019

We reverse engineer entropy formulas from entropic divergence, optimized to given classes of probability distribution function (PDF) evolution dynamical equation. For linear dynamics of the distribution function, the traditional Kullback–Leibler formula follows from using the logarithm function in the Csiszár’s f-divergence construction, while for nonlinear master equations more general formulas emerge. As applications, we review a local growth and global reset (LGGR) model for citation distributions, income distribution models and hadron number fluctuations in high energy collisions.
Energy-Neutral Operation Based on Simultaneous Wireless Information and Power Transfer for Wireless Powered Sensor Networks
Authors: Choi Hyun-Ho , Lee Jung-Ryun
Published: October 2019

For energy-neutral operation (ENO) of wireless sensor networks (WSNs), we apply a wireless powered communication network (WPCN) to a WSN with a hierarchical structure. In this hierarchical wireless powered sensor network (WPSN), sensor nodes with high harvesting energies and good link budgets have energy remaining after sending their data to the cluster head (CH), whereas the CH suffers from energy scarcity. Thus, we apply the simultaneous wireless information and power transfer (SWIPT) technique to the considered WPSN so that the sensor nodes can transfer their remaining energy to the CH while transmitting data in a cooperative manner. To maximize the achievable rate of sensing data while guaranteeing ENO, we propose a novel ENO framework, which provides a frame structure for SWIPT operation, rate improvement subject to ENO, SWIPT ratio optimization, as well as clustering and CH selection algorithm. The results of extensive simulations demonstrate that the proposed ENO based on SWIPT significantly improves the achievable rate and reduces the energy dissipated in the network while guaranteeing ENO, in comparison with the conventional schemes without SWIPT.
A Numerical Feasibility Study of Kinetic Energy Harvesting from Lower Limb Prosthetics
Authors: Jia Yu , Wei Xueyong , Pu Jie , Xie Pengheng , Wen Tao , Wang Congsi , Lian Peiyuan , Xue Song , Shi Yu
Published: October 2019

With the advancement trend of lower limb prosthetics headed towards bionics (active ankle and knee) and smart prosthetics (gait and condition monitoring), there is an increasing integration of various sensors (micro-electromechanical system (MEMS) accelerometers, gyroscopes, magnetometers, strain gauges, pressure sensors, etc.), microcontrollers and wireless systems, and power drives including motors and actuators. All of these active elements require electrical power. However, inclusion of a heavy and bulky battery risks to undo the lightweight advancements achieved by the strong and flexible composite materials in the past decades. Kinetic energy harvesting holds the promise to recharge a small on-board battery in order to sustain the active systems without sacrificing weight and size. However, careful design is required in order not to over-burden the user from parasitic effects. This paper presents a feasibility study using measured gait data and numerical simulation in order to predict the available recoverable power. The numerical simulations suggest that, depending on the axis, up to 10s mW average electrical power is recoverable for a walking gait and up to 100s mW average electrical power is achievable during a running gait. This takes into account parasitic losses and only capturing a fraction of the gait cycle to not adversely burden the user. The predicted recoverable power levels are ample to self-sustain wireless communication and smart sensing functionalities to support smart prosthetics, as well as extend the battery life for active actuators in bionic systems. The results here serve as a theoretical foundation to design and develop towards regenerative smart bionic prosthetics.
PMSM Vector Control Strategy Based on Active Disturbance Rejection Controller
Authors: Zhou Kai , Ai Min , Sun Yancheng , Wu Xiaogang , Li Ran
Published: October 2019

Based on current research into the vector control principles of the permanent magnet synchronous motor (PMSM), a control strategy founded upon an Active Disturbances Rejection Controller (ADRC) is proposed. This control strategy consists of an ADRC speed loop and current controller. By studying the factors affecting the running state of a PMSM, a mathematical model is established, and the design principle of the active disturbances rejection controller is analyzed in order to design the ADRC speed loop. The speed loop considers errors caused by uncertain factors, such as external disturbances, to be the disturbance amount, which is observed and then compensated for by the ADRC, thereby improving the dynamic and static performance as well as the anti-disturbance capability of the system. In order to achieve the strong coupling of the PMSM, the current controller was also designed to decouple the d–q axis current. Our simulation and experimental results demonstrate the feasibility and practicability of this control strategy.
Operation Optimization of Multi-District Integrated Energy System Considering Flexible Demand Response of Electric and Thermal Loads
Authors: Zhou Cheng , Zheng Jianyong , Liu Sai , Liu Yu , Mei Fei , Pan Yi , Shi Tian , Wu Jianzhang
Published: October 2019

Multi-district integrated energy system (IES) can make full use of the complementary characteristics of district power and thermal system, and loads in different districts. It can improve the flexibility and economy of system operation, which has a good development prospect. Firstly, based on the general energy transfer model of the district heating network (DHN), the DHN system is described by the basic equations of the heating network and nodes considering the characteristics of the transmission time delay and heat loss in pipelines. A coupling model of DHN and multi-district IES is established. Secondly, the flexible demand response (FDR) model of electric and thermal loads is established. The load characteristics of each district in IES are studied. A shiftable load model based on the electric quantity balance is constructed. Considering the flexibility of the heat demand, a thermal load adjustment model based on the comfort constraint is constructed to make the thermal load elastic and controllable in time and space. Finally, a mixed integer linear programming (MILP) model for operation optimization of multi-district IES with the DHN considering the FDR of electric and thermal loads is established based on the supply and demand sides. The result shows that the proposed model makes full use of the complementary characteristics of electric and thermal loads in different districts. It realizes the coordinated distribution of thermal energy among different districts and improves the efficiency of thermal energy utilization through the DHN. FDR effectively reduces the peak-valley difference of loads. It further reduces the total operating cost by the coordinated operation of the DHN and multi-district IES.
Circuit Topology and Small Signal Modeling of Variable Duty Cycle Controlled Three-Level LLC Converter
Authors: Humaira Hussain , Baek Seung-Woo , Kim Hag-Wone , Cho Kwan-Yuhl
Published: October 2019

With a view to regulate the output voltage with fixed frequency, without using any additional component or complex modulation technique, a topology of a variable duty controlled three-level LLC converter is proposed and an equivalent small signal model for Electric Vehicle (EV) charger applications is deduced in this paper. The steady state equations of each operating region are derived in time domain. Based on an Extended Describing Function (EDF) approach, a small signal equivalent circuit is modeled which includes both frequency and duty controlled terms. The equivalent circuit is further simplified to derive a transfer function of duty control to output voltage. The transfer function is verified through simulation software. Analyzing the transfer function, a voltage controller is designed and implemented with a PI compensator. The simulation results of the proposed control schemes are illustrated and discussed. The topology is compared to a conventional frequency control topology and the merits of the proposed topology are presented.
Optimal Strategy to Exploit the Flexibility of an Electric Vehicle Charging Station
Authors: Diaz-Londono Cesar , Colangelo Luigi , Ruiz Fredy , Patino Diego , Novara Carlo , Chicco Gianfranco
Published: October 2019

The increasing use of electric vehicles connected to the power grid gives rise to challenges in the vehicle charging coordination, cost management, and provision of potential services to the grid. Scheduling of the power in an electric vehicle charging station is a quite challenging task, considering time-variant prices, customers with different charging time preferences, and the impact on the grid operations. The latter aspect can be addressed by exploiting the vehicle charging flexibility. In this article, a specific definition of flexibility to be used for an electric vehicle charging station is provided. Two optimal charging strategies are then proposed and evaluated, with the purpose of determining which strategy can offer spinning reserve services to the electrical grid, reducing at the same time the operation costs of the charging station. These strategies are based on a novel formulation of an economic model predictive control algorithm, aimed at minimising the charging station operation cost, and on a novel formulation of the flexibility capacity maximisation, while reducing the operation costs. These formulations incorporate the uncertainty in the arrival time and state of charge of the electric vehicles at their arrival. Both strategies lead to a considerable reduction of the costs with respect to a simple minimum time charging strategy, taken as the benchmark. In particular, the strategy that also accounts for flexibility maximisation emerges as a new tool for maintaining the grid balance giving cost savings to the charging stations.
A Hybrid Multi-Objective Crisscross Optimization for Dynamic Economic/Emission Dispatch Considering Plug-In Electric Vehicles Penetration
Authors: Mei Panpan , Wu Lianghong , Zhang Hongqiang , Liu Zhenzu
Published: October 2019

Due to the significant uncertainty of charging time and charging power consumption, the large increase in plug-in electric vehicles (PEVs) may create a major influences on the power system: According to people’s living habits, PEVs are basically charged during peak load periods (after work). Once PEVs continue the random charging behavior, there will be a higher difference of peak-valley and bigger burden on the grid. A new strategy is put forward for dynamic economic/emission dispatch (DEED) with the consideration of PEVs for the purpose to shave the peak and fill the valley in this paper, and the influences brought from different loads of grid-to-vehicle (G2V) and vehicle-to-grid (V2G) on DEED problem are discussed. The problem to be solved is a challenging multi-objective non-linear problem. By taking advantage of the differential evolution (DE) algorithms and a newly developed crisscross optimization algorithm, a new multi-objective hybrid optimization algorithm is put forward to deal with the problem including effectively dealing with the inequality and equality constraints. A case study is presented to show the feasibility and effectiveness of the put forward method. The analysis results demonstrate that the put forward algorithm could effectively solve DEED problem, showing that the resulting approach of peak shaving and valley filling could significantly save economic costs and reduce emissions under the same load.
IGDT-Based Wind–Storage–EVs Hybrid System Robust Optimization Scheduling Model
Authors: Sun Bo , Li Simin , Xie Jingdong , Sun Xin
Published: October 2019

Wind power has features of uncertainty. When wind power producers (WPPs) bid in the day-ahead electricity market, how to deal with the deviation between forecasting output and actual output is one of the important topics in the design of electricity market with WPPs. This paper makes use of a non-probabilistic approach—Information gap decision theory (IGDT)—to model the uncertainty of wind power, and builds a robust optimization scheduling model for wind–storage–electric vehicles(EVs) hybrid system with EV participations, which can make the scheduling plan meet the requirements within the range of wind power fluctuations. The proposed IGDT robust optimization model first transforms the deterministic hybrid system optimization scheduling model into a robust optimization model that can achieve the minimum recovery requirement within the range of wind power output fluctuation, and comprehensively considers each constraint. The results show that the wind–storage–EVs hybrid system has greater operational profits and less impact on the safe and stable operation of power grids when considering the uncertainty of wind power. In addition, the proposed method can provide corresponding robust wind power fluctuation under different expected profits of the decision-maker to the wind–storage–EVs hybrid system.
Fluids in Music: The Mathematics of Pan’s Flutes
Authors: Nita Bogdan G. , Ramanathan Sajan
Published: October 2019

We discuss the mathematics behind the Pan’s flute. We analyze how the sound is created, the relationship between the notes that the pipes produce, their frequencies and the length of the pipes. We find an equation which models the curve that appears at the bottom of any Pan’s flute due to the different pipe lengths.
Quality of Work Life and Organizational Performance: Workers’ Feelings of Contributing, or Not, to the Organization’s Productivity
Authors: Leitão João , Pereira Dina , Gonçalves Ângela
Published: October 2019

This is a pioneering study on the relationship between quality of work life and the employee’s perception of their contribution to organizational performance. It unveils the importance of subjective and behavioral components of quality of work life and their influence on the formation of the collaborator’s individual desire to contribute to strengthening the organization’s productivity. The results obtained indicate that for workers: feeling their supervisors’ support through listening to their concerns and by sensing they take them on board; being integrated in a good work environment; and feeling respected both as professionals and as people; positively influence their feeling of contributing to organizational performance. The results are particularly relevant given the increased weight of services in the labor market, together with intensified automation and digitalization of collaborators’ functions. The findings also contribute to the ongoing debate about the need for more work on the subjective and behavioral components of so-called smart and learning organizations, rather than focusing exclusively on remuneration as the factor stimulating organizational productivity based on the collaborator’s contribution.
Older Adults’ Preference for Landscape Features Along Urban Park Walkways in Nanjing, China
Authors: Wang Xinxin , Rodiek Susan
Published: October 2019

Evidence shows that walking in urban parks has multiple health benefits for older adults, but little research is available on their preference for specific walkway features. This study explored a range of common landscape and hardscape features to learn which were preferred by park users over age 60. This photo comparison study hypothesized that older adults would prefer certain features of urban park walkways, with each feature represented by four different paired images (28 pairs in all). Within each pair of photos, both were identical except for the specific feature being tested in that comparison, where the image was digitally modified to depict the hypothesized feature. A total of 283 older adults (mean age 71 years) completed the survey by selecting the images they preferred. In this Chinese sample, older park users significantly favored all seven hypothesized walkway features, providing empirical support for the existing research and design-based literature on green space for older adults. This study found minor gender differences in visual preferences for walkway features and increasing preference for access to seating with advancing age. By helping to confirm which walkway features are preferred by older adults, these findings can be used to improve the future design and management of urban parks in China, which are an important source of exercise and recreation for nearby elderly residents.
Social Exclusion, Surveillance Use, and Facebook Addiction: The Moderating Role of Narcissistic Grandiosity
Authors: Lim Myungsuh
Published: October 2019

One hundred and eighty-eight participants completed the online questionnaire with items on demographics (age and gender), social exclusion, surveillance use, Facebook addiction, and narcissistic grandiosity. The findings showed that social exclusion was positively associated with Facebook addiction (B = 0.237, p < 0.001) and surveillance use was significantly positively associated with Facebook addiction (B = 0.211, p < 0.01). The surveillance use of Facebook was found to be a significant mediator between the risk of social exclusion on Facebook and Facebook addiction (B = 0.054, CI [0.20, 0.113]). Narcissistic grandiosity significantly moderated the associations between social exclusion and Facebook addiction (B = 0.079, p = 0.012). These findings suggest that the risk of social exclusion could serve as facilitator of Facebook addiction depending on narcissistic grandiosity.
Optimization of Ammonia Stripping of Piggery Biogas Slurry by Response Surface Methodology
Authors: Zou Mengyuan , Dong Hongmin , Zhu Zhiping , Zhan Yuanhang
Published: October 2019

Ammonia stripping is a pretreatment method for piggery biogas slurry, and the effectiveness of the method is affected by many factors. Based on the results of single-factor experiments, response surface methodology is adopted to establish a quadratic polynomial mathematical model relating stripping time, pH value and gas flow rate to the average removal rate of ammonia nitrogen to explore the interactions among various influencing factors, obtain optimized combined parameters for ammonia stripping, and carry out experimental verification of the parameters. The results show that when hollow polyhedral packing is adopted under operating conditions including a stripping time of 90 min, pH value of 11, gas flow rate of 28 m3/h, gas–liquid ratio of 2000 and temperature of 30 °C, the average removal rate of ammonia nitrogen in biogas slurry can reach approximately 73%. The experimental value is only 4.2% different from the predicted value, which indicates that analysis on the interaction among factors influencing ammonia stripping of biogas slurry and parameter optimization of the regression model are accurate and effective.
Landscape Pattern Changes in the Xingkai Lake Area, Northeast China
Authors: Liu Xiaohui , Zhang Yuan , Dong Guihua , Hou Guanglei , Jiang Ming
Published: October 2019

Understanding landscape change is important for ecologically sustainable development. In this paper, we assessed the spatiotemporal variations of landscape pattern in the Xingkai Lake area using remote sensing data from 1982, 1995, 2000, 2005, 2010, and 2015. Landscape patterns of marshlands, paddy fields, dry farmlands, and their combinations were analyzed at class and landscape levels. We examined the stability of landscape types through principal component analysis based on class level indices for landscape types. The results indicated that marshland areas decreased significantly by 33.87% but paddy fields increased by 1.84 times from 1982 to 2015. The largest conversion of dry farmlands to paddy fields was 90.88 km2 during the period 2010–2015. In contrast, the largest conversion of paddy fields to dry farmlands was 86.03 km2 during the period 2000–2005. The difference in relative change revealed that dry farmlands had experienced a greater relative change than paddy fields since 2000. The interspersion and juxtaposition index decreased, while the number of patches grew. This showed that landscape fragmentation was increasing and the landscape pattern was becoming dispersed. Marshlands were more stable than paddy fields and dry farmlands across all time periods, except for the year 2005.
Characterization of Airborne Particles Emitted During Application of Cosmetic Talc Products
Authors: Rasmussen Pat , Levesque Christine , Niu Jianjun , Gardner Howard , Nilsson Gregory , Macey Kristin
Published: October 2019

A pilot study was undertaken to characterize the concentration, duration and particle size distribution of the talc cloud that forms in the personal breathing zone (PBZ) during application of certain talc-containing cosmetics. Multiple direct-reading instruments were employed to simultaneously monitor PM4 concentrations (particulate matter with aerodynamic diameter < 4 µm; mg/m3) at different distances from each of three subjects while they applied talc products. Results indicated that the purpose and method of applying the talc product, combined with behavioral and physical differences amongst subjects, all strongly influenced airborne talc concentrations and the duration of the cloud. Air concentrations of talc in the PBZ averaged around 1.0 mg/m3, and the duration of exposure varied from less than one minute to more than ten minutes. The real-time monitors captured the occasional formation of secondary clouds, likely caused by resuspension of talc particles from skin or other surfaces. Measurements of aerosolized baby powder, face powder, and two adult body powders indicated that the median aerodynamic diameter of the talc cloud ranged from 1.7 to 2.0 µm. These direct-reading approaches were valuable for providing detailed characterization of short duration exposures to airborne talc particles, and will be useful to support future exposure assessments of talc and other powders in consumer products.
Effects of a Dementia Screening Program on Healthcare Utilization in South Korea: A Difference-In-Difference Analysis
Authors: Lee Su Jung , Seo Hyun-Ju , Lee Dong Young , Moon So-Hyun
Published: October 2019

To determine whether Seoul’s dementia screening program increased the rate of diagnosis and the appropriate use of healthcare services for people with dementia, a retrospective data analysis was conducted based on administrative data from the Health Insurance Review and Assessment Service. Two cohorts were constructed to represent the year before Seoul’s dementia screening program began (2007) (control group) and the year after the implementation of the program (2009) (treatment group). A difference-in-difference analysis was used to compare the diagnosis rates, number of clinic visits, and dementia-related drug prescription rates for 4 districts that implemented dementia screening programs between 2007 and 2009 and 14 areas that did not. After the introduction of the program, there was a 55.4% increase in physician-diagnosed dementia. The “average drug cost per patient” increased by 52.2% (Exp(β) = 1.522, p = 0.0264), the “average outpatient visits per patient” tended to increase by 13.5% (Exp(β) = 1.135, p = 0.1852), and the “average outpatient treatment fees per visit per patient” tended to increase by 24.4% (Exp(β) = 1.244, p = 0.0821). The implementation of dementia screening programs led to an increase in healthcare service utilization. Therefore, this program was found to be an effective strategy for reducing undiagnosed dementia cases and encouraging patients to use adequate healthcare services.
Can Between-Session Homework Be Delivered Digitally? A Pilot Randomized Clinical Trial of CBT for Adjustment Disorders
Authors: Quero Soledad , Rachyla Iryna , Molés Mar , Mor Sonia , Tur Cintia , Cuijpers Pim , López-Montoyo Alba , Botella Cristina
Published: October 2019

Adjustment disorder (AjD) is one of the most common disorders in clinical practice, and its symptoms are severe enough to cause great distress and functional impairment. The AjD CBT protocol specifically developed for this disorder has shown positive results when delivered face to face and through virtual reality. Despite existing evidence supporting the benefits of therapeutic homework as part of a psychological intervention, little is known about how to increase homework engagement in psychotherapy. This study examines the feasibility (doability, initial efficacy and acceptability) of a digital support system to deliver homework via the Internet in the treatment of AjD. Participants were randomly assigned to a traditional homework condition or a digital support system condition. Both interventions resulted in statistically significant improvements, with large effect sizes, in all the outcome measures at post-treatment, with no significant differences between groups. At 12-month follow-up, these therapeutic gains were maintained, and an improvement was even observed in both conditions, with no significant differences between groups. Additionally, treatment satisfaction predicted efficacy in both groups separately and when the whole group was considered. This is the first study to explore the feasibility an initial efficacy of delivering a therapeutic homework component for AjD through the Internet.
Comprehensive Analysis and Functional Studies of WRKY Transcription Factors in Nelumbo nucifera
Authors: Li Jing , Xiong Yacen , Li Yi , Ye Shiqi , Yin Qi , Gao Siqi , Yang Dong , Yang Mei , Palva E. Tapio , Deng Xianbao
Published: October 2019

The WRKY family is one of the largest transcription factor (TF) families in plants and plays central roles in modulating plant stress responses and developmental processes, as well as secondary metabolic regulations. Lotus (Nelumbo nucifera) is an aquatic crop that has significant food, ornamental and pharmacological values. Here, we performed an overview analysis of WRKY TF family members in lotus, and studied their functions in environmental adaptation and regulation of lotus benzylisoquinoline alkaloid (BIA) biosynthesis. A total of 65 WRKY genes were identified in the lotus genome and they were well clustered in a similar pattern with their Arabidopsis homologs in seven groups (designated I, IIa-IIe, and III), although no lotus WRKY was clustered in the group IIIa. Most lotus WRKYs were functionally paired, which was attributed to the recently occurred whole genome duplication in lotus. In addition, lotus WRKYs were regulated dramatically by salicilic acid (SA), jasmonic acid (JA), and submergence treatments, and two lotus WRKYs, NnWRKY40a and NnWRKY40b, were significantly induced by JA and promoted lotus BIA biosynthesis through activating BIA biosynthetic genes. The investigation of WRKY TFs for this basal eudicot reveals new insights into the evolution of the WRKY family, and provides fundamental information for their functional studies and lotus breeding.
Functional Characterization of the Intact Diaphragm in a Nebulin-Based Nemaline Myopathy (NM) Model-Effects of the Fast Skeletal Muscle Troponin Activator tirasemtiv
Authors: Lee Eun-Jeong , Kolb Justin , Hwee Darren T. , Malik Fady I. , Granzier Henk L.
Published: October 2019

Respiratory failure due to diaphragm dysfunction is considered a main cause of death in nemaline myopathy (NM) and we studied both isometric force and isotonic shortening of diaphragm muscle in a mouse model of nebulin-based NM (Neb cKO). A large contractile deficit was found in nebulin-deficient intact muscle that is frequency dependent, with the largest deficits at low–intermediate stimulation frequencies (e.g., a deficit of 72% at a stimulation frequency of 20 Hz). The effect of the fast skeletal muscle troponin activator (FSTA) tirasemtiv on force was examined. Tirasemtiv had a negligible effect at maximal stimulation frequencies, but greatly reduced the force deficit of the diaphragm at sub-maximal stimulation levels with an effect that was largest in Neb cKO diaphragm. As a result, the force deficit of Neb cKO diaphragm fell (from 72% to 29% at 20 Hz). Similar effects were found in in vivo experiments on the nerve-stimulated gastrocnemius muscle complex. Load-clamp experiments on diaphragm muscle showed that tirasemtiv increased the shortening velocity, and reduced the deficit in mechanical power by 33%. Thus, tirasemtiv significantly improves muscle function in a mouse model of nebulin-based nemaline myopathy.
Genome-Wide Identification of Direct Targets of the TTG1–bHLH–MYB Complex in Regulating Trichome Formation and Flavonoid Accumulation in Arabidopsis Thaliana
Authors: Wei Zelou , Cheng Yalong , Zhou Chenchen , Li Dong , Gao Xin , Zhang Shuoxin , Chen Mingxun
Published: October 2019

Extensive studies have shown that the MBW complex consisting of three kinds of regulatory proteins, MYB and basic helix–loop–helix (bHLH) transcription factors and a WD40 repeat protein, TRANSPARENT TESTA GLABRA1 (TTG1), acts in concert to promote trichome formation and flavonoid accumulation in Arabidopsis thaliana. TTG1 functions as an essential activator in these two biological processes. However, direct downstream targets of the TTG1-dependent MBW complex have not yet been obtained in the two biological processes at the genome-wide level in A. thaliana. In the present study, we found, through RNA sequencing and quantitative real-time PCR analysis, that a great number of regulatory and structural genes involved in both trichome formation and flavonoid accumulation are significantly downregulated in the young shoots and expanding true leaves of ttg1-13 plants. Post-translational activation of a TTG1-glucocorticoid receptor fusion protein and chromatin immunoprecipitation assays demonstrated that these downregulated genes are directly or indirectly targeted by the TTG1-dependent MBW complex in vivo during trichome formation and flavonoid accumulation. These findings further extend our understanding of the role of TTG1-dependent MBW complex in the regulation of trichome formation and flavonoid accumulation in A. thaliana.
B-Cell Activating Factor Enhances Hepatocyte-Driven Angiogenesis via B-Cell CLL/Lymphoma 10/Nuclear Factor-KappaB Signaling during Liver Regeneration
Authors: Chou Chia-Hung , Ho Cheng-Maw , Lai Shou-Lun , Chen Chiung-Nien , Wu Yao-Ming , Shun Chia-Tung , Wen Wen-Fen , Lai Hong-Shiee
Published: October 2019

B-cell activating factor (BAFF) is found to be associated with the histological severity of nonalcoholic steatohepatitis (NASH). BAFF was also found to have a protective role in hepatic steatosis via down regulating the expression of steatogenesis genes and enhancing steatosis in hepatocytes through BAFF-R. However, the roles of BAFF during liver regeneration are not well defined. In this study, C57/B6 mice with 70% partial hepatectomy were used as a liver regeneration model. BAFF expression was determined by enzyme immunoassay, and anti-BAFF-neutralizing antibodies were administered to confirm the effects of BAFF on liver regeneration. Western blotting, immunohistochemistry, and florescence staining determined the expression of B-cell CCL/lymphoma 10 (BCL10). The angiogenesis promoting capability was evaluated after the transfection of cells with siRNA targeting BCL10 expression, and the role of NF-κB was assessed. The results revealed that the BAFF and BCL10 levels were upregulated after partial hepatectomy. Treatment with anti-BAFF-neutralizing antibodies caused death in mice that were subjected to 70% partial hepatectomy within 72 h. In vitro, recombinant BAFF protein did not enhance hepatocyte proliferation; however, transfection with BCL10 siRNA arrested hepatocytes at the G2/M phase. Interestingly, conditioned medium from BAFF-treated hepatocytes enhanced angiogenesis and endothelial cell proliferation. Moreover, Matrix metalloproteinase-9 (MMP-9), Fibroblast growth factor 4 (FGF4), and Interleukin-8 (IL-8) proteins were upregulated by BAFF through BCL10/NF-κB signaling. In mice that were treated with anti-BAFF-neutralizing antibodies, the microvessel density (MVD) of the remaining liver tissues and liver regeneration were both reduced. Taken together, our study demonstrated that an increased expression of BAFF and activation of BCL10/NF-κB signaling were involved in hepatocyte-driven angiogenesis and survival during liver regeneration.
Probiotics Can Cure Oral Aphthous-Like Ulcers in Inflammatory Bowel Disease Patients: A Review of the Literature and a Working Hypothesis
Authors: Cappello Francesco , Rappa Francesca , Canepa Federica , Carini Francesco , Mazzola Margherita , Tomasello Giovanni , Bonaventura Giuseppe , Giuliana Giovanna , Leone Angelo , Saguto Dario , Scalia Federica , Bucchieri Fabio , Fucarino Alberto , Campisi Giuseppina
Published: October 2019

Dysbiosis has been associated with the onset of several chronic autoimmune or inflammatory pathologies (e.g., inflammatory bowel diseases—IBD), because of its primary role in the establishment of a chronic inflammatory process leading to tissue damage. Inflammatory bowel diseases can even involve areas far away from the gut, such as the extraintestinal manifestations involving the oral cavity with the onset of aphthous-like ulcers (ALU). Studies carried out on animal models have shown that intestinal dysbiosis may be related to the development of autoimmune diseases, even if the mechanisms involved are not yet well known. The aim of this paper is to verify the hypothesis that in inflammatory bowel diseases patients, aphthous-like ulcers are the result of the concomitance of intestinal dysbiosis and other events, e.g., the microtraumas, occurring in the oral mucosa, and that ex adiuvantibus therapy with probiotics can be employed to modify the natural course of the aphthous-like ulcers.
Systematic Approach to Developing Splice Modulating Antisense Oligonucleotides
Authors: Aung-Htut May , McIntosh Craig , Ham Kristin , Pitout Ianthe , Flynn Loren , Greer Kane , Fletcher Sue , Wilton Steve
Published: October 2019

The process of pre-mRNA splicing is a common and fundamental step in the expression of most human genes. Alternative splicing, whereby different splice motifs and sites are recognised in a developmental and/or tissue-specific manner, contributes to genetic plasticity and diversity of gene expression. Redirecting pre-mRNA processing of various genes has now been validated as a viable clinical therapeutic strategy, providing treatments for Duchenne muscular dystrophy (inducing specific exon skipping) and spinal muscular atrophy (promoting exon retention). We have designed and evaluated over 5000 different antisense oligonucleotides to alter splicing of a variety of pre-mRNAs, from the longest known human pre-mRNA to shorter, exon-dense primary gene transcripts. Here, we present our guidelines for designing, evaluating and optimising splice switching antisense oligomers in vitro. These systematic approaches assess several critical factors such as the selection of target splicing motifs, choice of cells, various delivery reagents and crucial aspects of validating assays for the screening of antisense oligonucleotides composed of 2′-O-methyl modified bases on a phosphorothioate backbone.
Fibrin-Hyaluronic Acid Hydrogel (RegenoGel) with Fibroblast Growth Factor-18 for In Vitro 3D Culture of Human and Bovine Nucleus Pulposus Cells
Authors: Häckel Sonja , Zolfaghar Mona , Du Jie , Hoppe Sven , Benneker Lorin M. , Garstka Nathalie , Peroglio Marianna , Alini Mauro , Grad Sibylle , Yayon Avner , Li Zhen
Published: October 2019

We investigated the effects of a fibrin-hyaluronic acid hydrogel (FBG–HA) and fibroblast growth factor 18 (FGF-18) for nucleus pulposus (NP) regeneration. Healthy bovine (n = 4) and human degenerated NP cells (n = 4) were cultured for 14 days in FBG-HA hydrogel with FGF-18 (∆51-mutant or wild-type) in the culture medium. Gene expression, DNA content, and glycosaminoglycan (GAG) synthesis were evaluated on day 7 and 14. Additionally, histology was performed. Human NP cells cultured in FBG-HA hydrogel showed an increase in collagen type II (COL2) and carbonic anhydrase XII (CA12) gene expression after 14 or 7 days of culture, respectively. GAG release into the conditioned medium increased over 14 days. Healthy bovine NP cells showed increased gene expression of ACAN from day 7 to day 14. Wild type FGF-18 up-regulated CA12 gene expression of human NP cells. Histology revealed an increase of proteoglycan deposition upon FGF-18 stimulation in bovine but not in human NP cells. The FBG-HA hydrogel had a positive modulatory effect on human degenerated NP cells. Under the tested conditions, no significant effect of FGF-18 was observed on cell proliferation or GAG synthesis in human NP cells.
Ibuprofen-Loaded Hyaluronic Acid Nanofibrous Membranes for Prevention of Postoperative Tendon Adhesion through Reduction of Inflammation
Authors: Chen Chien-Tzung , Chen Chih-Hao , Sheu Chialin , Chen Jyh-Ping
Published: October 2019

A desirable multi-functional nanofibrous membrane (NFM) for prevention of postoperative tendon adhesion should be endowed with abilities to prevent fibroblast attachment and penetration and exert anti-inflammation effects. To meet this need, hyaluronic acid (HA)/ibuprofen (IBU) (HAI) NFMs were prepared by electrospinning, followed by dual ionic crosslinking with FeCl3 (HAIF NFMs) and covalent crosslinking with 1,4-butanediol diglycidyl ether (BDDE) to produce HAIFB NFMs. It is expected that the multi-functional NFMs will act as a physical barrier to prevent fibroblast penetration, HA will reduce fibroblast attachment and impart a lubrication effect for tendon gliding, while IBU will function as an anti-inflammation drug. For this purpose, we successfully fabricated HAIFB NFMs containing 20% (HAI20FB), 30% (HAI30FB), and 40% (HAI40FB) IBU and characterized their physico-chemical properties by scanning electron microscopy, Fourier transformed infrared spectroscopy, thermal gravimetric analysis, and mechanical testing. In vitro cell culture studies revealed that all NFMs except HAI40FB possessed excellent effects in preventing fibroblast attachment and penetration while preserving high biocompatibility without influencing cell proliferation. Although showing significant improvement in mechanical properties over other NFMs, the HAI40FB NFM exhibited cytotoxicity towards fibroblasts due to the higher percentage and concentration of IBU released form the membrane. In vivo studies in a rabbit flexor tendon rupture model demonstrated the efficacy of IBU-loaded NFMs (HAI30FB) over Seprafilm® and NFMs without IBU (HAFB) in reducing local inflammation and preventing tendon adhesion based on gross observation, histological analyses, and biomechanical functional assays. We concluded that an HAI30FB NFM will act as a multi-functional barrier membrane to prevent peritendinous adhesion after tendon surgery.
Antithrombotic Effects of Paeoniflorin from Paeonia suffruticosa by Selective Inhibition on Shear Stress-Induced Platelet Aggregation
Authors: Ngo Thien , Kim Keunyoung , Bian Yiying , Noh Hakjun , Lim Kyung-Min , Chung Jin-Ho , Bae Ok-Nam
Published: October 2019

Antiplatelet agents are important in the pharmacotherapeutic regime for many cardiovascular diseases, including thrombotic disorders. However, bleeding, the most serious adverse effect associated with current antiplatelet therapy, has led to many efforts to discover novel anti-platelet drugs without bleeding issues. Of note, shear stress-induced platelet aggregation (SIPA) is a promising target to overcome bleeding since SIPA happens only in pathological conditions. Accordingly, this study was carried out to discover antiplatelet agents selectively targeting SIPA. By screening various herbal extracts, Paeonia suffruticosa and its major bioactive constituent, paeoniflorin, were identified to have significant inhibitory effects against shear-induced aggregation in human platelets. The effects of paeoniflorin on intraplatelet calcium levels, platelet degranulation, and integrin activation in high shear stress conditions were evaluated by a range of in vitro experiments using human platelets. The inhibitory effect of paeoniflorin was determined to be highly selective against SIPA, through modulating von Willebrand Factor (vWF)-platelet glycoprotein Ib (GP Ib) interaction. The effects of paeoniflorin on platelet functions under high shear stress were confirmed in the ex vivo SIPA models in rats, showing the good accordance with the anti-SIPA effects on human platelets. Treatment with paeoniflorin significantly prevented arterial thrombosis in vivo from the dose of 10 mg/kg without prolonging bleeding time or blood clotting time in rats. Collectively, our results demonstrated that paeoniflorin can be a novel anti-platelet agent selectively targeting SIPA with an improved safety profile.
Identification of a Novel Oligosaccharide in Maple Syrup as a Potential Alternative Saccharide for Diabetes Mellitus Patients
Authors: Sato Kanta , Nagai Noriaki , Yamamoto Tetsushi , Mitamura Kuniko , Taga Atsushi
Published: October 2019

The incidence of diabetes mellitus (DM) is increasing rapidly and is associated with changes in dietary habits. Although restrictions in the use of sweeteners may prevent the development of DM, this might reduce the quality of life of patients with DM. Therefore, there has been a great deal of research into alternative sweeteners. In the search for such sweeteners, we analyzed the carbohydrate content of maple syrup and identified a novel oligosaccharide composed of fructose and glucose, linked at the C-4 of glucose and the C-6 of fructose. This oligosaccharide inhibited the release of fructose from sucrose by invertase (IC50: 1.17 mmol/L) and the decomposition of maltose by α-(1-4) glucosidase (IC50: 1.72 mmol/L). In addition, when orally administered together with sucrose to rats with DM, the subsequent plasma glucose concentrations were significantly lower than if the rats had been administered sucrose alone, without having any effect on the insulin concentration. These findings suggest that this novel oligosaccharide might represent a useful alternative sweetener for inclusion in the diet of patients with DM and may also have therapeutic benefits.
Differences in Expression of Human Leukocyte Antigen Class II Subtypes and T Cell Subsets in Behçet’s Disease with Arthritis
Authors: Islam S. M. Shamsul , Kim Hyoun-Ah , Choi Bunsoon , Jung Ju-Yang , Lee Sung-Min , Suh Chang-Hee , Sohn Seonghyang
Published: October 2019

It has been reported Human Leukocyte Antigen (HLA) gene polymorphism is a risk factor for the development of Behçet’s disease (BD). In this study, the association of HLA class II subtypes HLA-DP, DQ, DR, and T cell subsets in BD patients with arthritis was evaluated. Frequencies of HLA-DP, DQ, DR positive cells, and T cell subsets in peripheral blood leukocytes (PBL) were measured by flow cytometric analysis in BD, and compared to rheumatoid arthritis as disease controls and healthy controls. Frequencies of HLA-DQ were significantly decreased in whole PBL and granulocytes of BD active patients as compared to healthy controls. In monocytes populations, proportions of HLA-DR positive cells were significantly increased in BD active patients as compared to healthy controls. Proportions of CD4+CCR7+ and CD8+CCR7+ cells were significantly higher in BD active patients than in BD inactive in whole PBL. Frequencies of CD4+CD62L- and CD8+CD62L- cells in lymphocytes were significantly decreased in active BD than those in inactive BD. There were also correlations between disease activity markers and T cell subsets. Our results revealed HLA-DP, DQ, and DR expressing cell frequencies and several T cell subsets were significantly correlated with BD arthritis symptoms.