bluuebunny/crossref_metadata_2025 huggingface dataset:
Rare Event Analysis for Minimum Hellinger Distance Estimators via Large Deviation Theory
Authors: Vidyashankar Anand N. , Collamore Jeffrey F.
Published: March 2021

Hellinger distance has been widely used to derive objective functions that are alternatives to maximum likelihood methods. While the asymptotic distributions of these estimators have been well investigated, the probabilities of rare events induced by them are largely unknown. In this article, we analyze these rare event probabilities using large deviation theory under a potential model misspecification, in both one and higher dimensions. We show that these probabilities decay exponentially, characterizing their decay via a “rate function” which is expressed as a convex conjugate of a limiting cumulant generating function. In the analysis of the lower bound, in particular, certain geometric considerations arise that facilitate an explicit representation, also in the case when the limiting generating function is nondifferentiable. Our analysis involves the modulus of continuity properties of the affinity, which may be of independent interest.
Automatized Evaluation of Students’ CAD Models
Authors: Bojcetic Nenad , Valjak Filip , Zezelj Dragan , Martinec Tomislav
Published: March 2021

The article describes an attempt to address the automatized evaluation of student three-dimensional (3D) computer-aided design (CAD) models. The driving idea was conceptualized under the restraints of the COVID pandemic, driven by the problem of evaluating a large number of student 3D CAD models. The described computer solution can be implemented using any CAD computer application that supports customization. Test cases showed that the proposed solution was valid and could be used to evaluate many students’ 3D CAD models. The computer solution can also be used to help students to better understand how to create a 3D CAD model, thereby complying with the requirements of particular teachers.
Identification of Degrading Effects in the Operation of Neighboring Photovoltaic Systems in Urban Environments
Authors: Radovanovic Ilija , Popovic Ivan
Published: March 2021

As photovoltaics technologies have emerged as one of the most promising renewable energy resources in urban environments, monitoring and maintaining of such systems have gained significance. In order to support reliable system operation during the projected in-field operation lifetime, effective strategies for identifying potential problems in photovoltaic systems operation are needed. In this paper, novel methods for the identification of degrading effects in the operation of neighboring photovoltaic systems are presented. The proposed methods are applicable for identifying panel aging properties, soiling effects, and the operation of photovoltaic systems under different shading scenarios. Since the proposed methods are based on the cross-correlation of the operation of neighboring systems, they are particularly suitable performance assessment in urban environments. The proposed identification methods are integrated according to the adopted fog computing model, providing a scalable solution capable of uniform integration into the distributed applications for monitoring and maintenance of photovoltaic systems in urban areas. The details regarding the implementation of the identification methods in the form of data processing services and service operation and dependencies are also provided in this paper. The identification methods, integration concept, and related service operation are verified through the presented case study.
Propagation of Random Errors by the Discrete Wavelet Transform Algorithm
Authors: Roj Jerzy , Dróżdż Łukasz
Published: March 2021

The paper presents considerations concerning the transfer of random errors from the input to the output of the Discrete Wavelet Transform (DWT) algorithm. The concept of determining an uncertainty of its output data based on the probabilistic error description has been presented. The DWT is discussed as the product of the vector of input quantities and the matrix of algorithm coefficients. Calculations of the uncertainty of a single output result of the algorithm are described with assumption that the input quantities are burdened by random errors of known distributions. Theoretical considerations have been verified by simulation experiments using the Monte Carlo method. Determining the uncertainty at the DWT output is possible due to the specific properties of transferring random errors by linear and additive algorithms.
Performance Analysis of Deep Neural Network Controller for Autonomous Driving Learning from a Nonlinear Model Predictive Control Method
Authors: Lee Taekgyu , Kang Yeonsik
Published: March 2021

Nonlinear model predictive control (NMPC) is based on a numerical optimization method considering the target system dynamics as constraints. This optimization process requires large amount of computation power and the computation time is often unpredictable which may cause the control update rate to overrun. Therefore, the performance must be carefully balanced against the computational time. To solve the computation problem, we propose a data-based control technique based on a deep neural network (DNN). The DNN is trained with closed-loop driving data of an NMPC. The proposed "DNN control technique based on NMPC driving data" achieves control characteristics comparable to those of a well-tuned NMPC within a reasonable computation period, which is verified with an experimental scaled-car platform and realistic numerical simulations.
Yo-Yo Inspired Triboelectric Nanogenerator
Authors: Heo Deokjae , Chung Jihoon , Shin Gunsub , Seok Minhyeong , Lee Chanhee , Lee Sangmin
Published: March 2021

Recently, as the demand for sustainable and renewable energy to power a large number of small electronics and sensors has increased, various mechanical energy harvesters such as electromagnetic, piezoelectric, and triboelectric generators have been highlighted because they have no environmental constraints to generate electricity and function as sustainable power sources. Among these generators, triboelectric nanogenerators (TENGs), which produce electrical energy via triboelectrification and electrostatic induction, are a promising energy harvesting technology that can utilize existing materials or the structure of existing commercial products. Considering the vast number of independent portable electronics used today, the development of hand-driven TENGs is important. There is great demand for TENG considering both commercial product-inspired designs, which are the merit of TENG itself, and the hand-driven type. However, relevant studies are still lacking, and therefore further studies in these areas are required. In this study, we developed a novel triboelectric nanogenerator (Y-TENG) inspired by the Yo-Yo that can produce a sustainable electric output by hand motion input. One generator of Y-TENG produced a maximum VOC of 10 V and an ICC of 0.7 μA. Peak/root mean square (RMS) voltage output-based quantitative analysis for the optimized number of blades and dielectric material was performed. The proposed Y-TENG was able to continuously light up three light-emitting diodes (LEDs) while the Y-TENG moved up and down.
Evaluation of Building Energy Performance with Optimal Control of Movable Shading Device Integrated with PV System
Authors: Jung Dong Eun , Lee Chanuk , Lee Kwang Ho , Shin Minjae , Do Sung Lok
Published: March 2021

Among the envelope components (e.g., walls, roofs, floors, and windows, etc.) affecting the cooling and heating load of buildings, windows are the most thermally vulnerable. Shading devices can minimize the thermal load on windows due to solar radiation and decrease radiation effects. However, the load changes due to convection and conduction should be considered. Therefore, when a shading device is applied to a window, control logic for thermal blocking and heat retention is necessary to prevent the load changes. In addition, by combining the opposite features of photovoltaic (PV) that require solar radiation and the shading device to block solar radiation, energy-saving and production can be achieved simultaneously. Therefore, this study minimized the thermal effects of windows using a movable shading device integrated with PV and evaluated the PV power generation. This study evaluated the effects on window heat transfer by applying artificial intelligence techniques, which have recently attracted attention, to system operation. To achieve this, artificial neural network (ANN)-based control logic was developed, and the control performance of the system was assessed using simulations. In ANN control, the window heat transfer was 86.3% lower in a cooling period and 9.7% lower in a heating period compared with that of a shading device fixed at 45°. Furthermore, the PV system produced 3.0 to 3.1% more electric power under optimal control during the cooling period.
Electric Vehicle Charger Static and Dynamic Modelling for Power System Studies
Authors: Tian Hengqing , Tzelepis Dimitrios , Papadopoulos Panagiotis N.
Published: March 2021

Electric Vehicles (EVs) are becoming increasingly available and are expected to be a large part of the load in future power systems. EV chargers are a relatively new type of load and are mainly interfaced with the grid through power electronics. It is therefore important to investigate the impact they have on power system dynamic behaviour. In this paper, two detailed EV charger models (representing a typical slow and fast charger) were investigated. The aim was to test the capability of standard static—and more importantly, dynamic—load models, commonly used in power system studies, to represent the static and dynamic behaviour of EV chargers. Different control parameter settings for two types of EV chargers were investigated, as were the limits of standard power system dynamic load model structures’ accurate representation. Typical parameter sets have also been provided for cases where proper representation was possible.
Modelling of Coupled Heat and Mass Transfer in a Water-Cooled Falling-Film Absorber Working with an Aqueous Alkaline Nitrate Solution
Authors: Álvarez María E. , Bourouis Mahmoud
Published: March 2021

A theoretical model was developed to investigate a falling-film absorber on horizontal tubes with an aqueous alkaline nitrate solution as working fluid. The absorbent, composed of an aqueous solution of nitrates (Li, K, Na) in salt mass percentages of 53%, 28%, and 19% respectively, offers favourable thermal stability, corrosiveness, and heat and mass transfer conditions which can be appropriate for absorption cooling cycles driven by high-temperature heat sources. The mathematical model developed characterises the heat and mass transfer processes and the flow regime effect (droplet-formation, droplet-fall, and falling-film) on the falling-film absorber. The results show the importance of the falling-film and droplet-formation flow regimes in the absorption process. The solution temperature and concentration profiles inside the absorber were established together with their values at the exit. The results obtained by the theoretical model were well in agreement with the experimental data obtained by the authors in a previous study. Deviations in predicting the solution and cooling water temperatures at the absorber exit were around 1 °C and for the concentration of the solution leaving the absorber, around 0.49%. The mathematical model also predicts the absorption rate at 4.7 g·m−2·s−1 for the absorber design and operating conditions used in the present work. This value is 22% higher than the experimental value obtained by the authors in their previous experimental work. The deviation is attributed to approximations incorporated into the model, especially as regards surface wettability and calculation of the mass transfer coefficients for each flow regime.
The Main Controlling Factors of Glutenite Development and Their Impacts on Oil Energy Extraction
Authors: Wang Yuping , Dong Chunmei , Lin Chengyan , Hou Qingjie
Published: March 2021

The glutenite reservoirs discovered in the Jiyang depression in Bohai Bay contribute greatly to proven oil and gas resources, which have reached 1.27 billion cubic meters. Both insufficient studies on the glutenite distribution and incomplete understanding of the corresponding geology restrict further oil energy extraction. Hence, it is necessary to study the controlling factors of glutenite development. Sedimentation, tectonic faults, geophysical data, etc., was used in this paper to study these factors. Four main controlling factors involved in the development of glutenite fan bodies have been studied and summarized: the fault ramp controls the glutenite fan, the fault characteristics control the glutenite acreage, the fault throw controls the thickness of the glutenite, and the dimensions of the incised valleys control the glutenite transport capacity. Based on this geological understanding, this paper analyzes the relationship between oil productivity data and the factors controlling conglomerate development. With this, the reservoir in the study area is divided into a high production area, medium production area, and low production area. The C913 well was deployed in the predicted high production area. The daily oil production reached 88 t/d, and the energy exploitation effect was good. Therefore, this study provides important guidance for the further extraction of oil energy.
CPC-Based Minimizing of Balancing Compensators in Four-Wire Nonsinusoidal Asymmetrical Systems
Authors: Sołjan Zbigniew , Hołdyński Grzegorz , Zajkowski Maciej
Published: March 2021

The article presents the possibility of using the currents’ physical components (CPC) theory to generate the reference current of the active power filter (APF). The solution proposed by the authors is based on the cooperation of minimizing balancing compensators (MBC), which, due to their use in 4-wire systems, have been divided into two structures. The first compensator, which purpose is to minimize and balance the reactive current and the unbalanced current of the zero sequence, is built in the star system (STAR-MBC). The purpose of the second compensator, which operation occurs in the delta system (DELTA-MBC), is to minimize and balance the other two components, i.e., the unbalanced current of the negative sequence and the unbalanced current of the positive sequence. The two structures cooperating with each other significantly reduce the currents associated with the reactive elements, i.e., reactive current, and the unbalanced current. As mentioned, these currents are reduced but not compensated to zero or to the reference value. In order for the compensation and balancing to bring the preferable effect, an APF system should be included, which will cooperate with MBC compensators. This solution is presented in this publication. The control of the active part of the hybrid active power filter (HAPF), which was presented in the paper, consists of the reflection of the waveform of the nonsinusoidal active current. In this approach, no current shift in relation to voltage is obtained, but the waveforms of these quantities remain distorted. The reactive current is compensated and the unbalanced currents are balanced. The second definition of generating a reference current can also be used. Through this approach, the active current with a sinusoidal waveform is achieved. The second approach allows for an additional reduction of the three-phase RMS value of the load’s current. In both of these approaches, the active currents flowing through the lines will reflect the amplitude and phase asymmetry that is present in the supply voltage. The APF system will follow the changes in power or load conditions and generate the correct value for the reference current. The calculations presented in the article, as well as the current and voltage waveforms, were created as a result of the constructed mathematical models, which were used for theoretical illustrations. Calculations and waveforms were generated based on a script written in Matlab.
Efficient, Sustainable, and Multifunctional Carbon Offsetting to Boost Forest Management: A Comparative Case Study
Authors: Fouqueray Timothée , Génin Lucile , Trommetter Michel , Frascaria-Lacoste Nathalie
Published: March 2021

Research highlights: Funding forest management with subsidies from carbon offsetters is a well-documented mechanism in tropical regions. This article provides complementary insights into the use of voluntary offset contracts in temperate forests. Background and objectives: The mitigation of greenhouse emissions has become a major global issue, leading to changes in forest management to increase the capacity of forests to store carbon. This can lead to conflicts of use with other forest ecosystem services such as timber production or biodiversity conservation. Our main goal is to describe collective actions to fund carbon-oriented forestry with subsidies from carbon offsetters and to analyze how their governance and functioning prevent conflicts pertaining to multi-functionality. Materials and methods: We assembled an interdisciplinary research team comprising two ecologists, a social scientist, and an economist. Drawing on a conceptual framework of ecosystem services, social interdependencies, and collective action, we based our qualitative analysis on semi-structured interviews from two French case studies. Results: Carbon-oriented intermediary forest organizations offer offset contracts to private firms and public bodies. Communication is geared toward the mitigation outcomes of the contracts as well as their beneficial side effects in providing the ecosystem services of interest to the offsetters. Subsidies then act as a financial lever to fund carbon-oriented forestry operations. Scientific committees and reporting methodologies serve as environmental, social, and economic safeguards. Conclusions: These new intermediary forest organizations use efficient forest operations and evaluation methodologies to improve forest carbon storage. Their main innovation lies in their collective governance rooted in regional forest social-ecological systems. Their consideration of multi-functionality and socioeconomic issues can be seen as an obstacle to rapid development, but they ensure sustainability and avoid conflicts between producers and beneficiaries of forest ecosystem services. Attention must be paid to interactions with broader spatial and temporal carbon policies.
Next-Generation Sequencing-Based Pre-Implantation Genetic Testing for Aneuploidy (PGT-A): First Report from Saudi Arabia
Authors: Alyafee Yusra , Alam Qamre , Tuwaijri Abeer Al , Umair Muhammad , Haddad Shahad , Alharbi Meshael , Alrabiah Hayat , Al-Ghuraibi Maha , Al-Showaier Sahar , Alfadhel Majid
Published: March 2021

Recently, high-throughput next-generation sequencing (NGS)-based preimplantation genetic testing for aneuploidies techniques came into use. This technique is essential for successful embryo transfer and accomplishing pregnancy, thus reducing the time and cost of additional cycles. In this study, we describe our first experience in introducing an NGS-based preimplantation genetic testing for aneuploidy (PGT-A) service using next-generation sequencing in King Abdulaziz Medical City located in Riyadh, Saudi Arabia. Our main goal was to report the successful implementation of this new technology in clinical practice and highlight the factors that may affect the results. In total, 200 blastomere biopsies were obtained from 36 in vitro fertilization (IVF) cycles from Saudi couples suffering from prolonged infertility or recurrent embryo transfer failure. NGS-based PGT-A was performed in all embryos. The results were analyzed in five age groups, showing that aneuploidy rates increased with maternal age. Moreover, the results also showed that complex abnormal embryos with (2–5) aneuploidy are the most common type of embryos. Additionally, our data showed that chromosome 16-related abnormality was the most frequent abnormality detected among all reported abnormalities. In conclusion, our study suggests that NGS-based PGT-A is an applicable and reliable technique for routine-based embryo screening, especially for couples suffering from recurrent miscarriages or multiple embryo transfer failures.
Landscape of Chimeric RNAs in Non-Cancerous Cells
Authors: Chen Chen , Haddox Samuel , Tang Yue , Qin Fujun , Li Hui
Published: March 2021

Gene fusions and their products (RNA and protein) have been traditionally recognized as unique features of cancer cells and are used as ideal biomarkers and drug targets for multiple cancer types. However, recent studies have demonstrated that chimeric RNAs generated by intergenic alternative splicing can also be found in normal cells and tissues. In this study, we aim to identify chimeric RNAs in different non-neoplastic cell lines and investigate the landscape and expression of these novel candidate chimeric RNAs. To do so, we used HEK-293T, HUVEC, and LO2 cell lines as models, performed paired-end RNA sequencing, and conducted analyses for chimeric RNA profiles. Several filtering criteria were applied, and the landscape of chimeric RNAs was characterized at multiple levels and from various angles. Further, we experimentally validated 17 chimeric RNAs from different classifications. Finally, we examined a number of validated chimeric RNAs in different cancer and non-cancer cells, including blood from healthy donors, and demonstrated their ubiquitous expression pattern.
Telecommuting, Off-Time Work, and Intrusive Leadership in Workers’ Well-Being
Authors: Magnavita Nicola , Tripepi Giovanni , Chiorri Carlo
Published: March 2021

Telecommuting is a flexible form of work that has progressively spread over the last 40 years and which has been strongly encouraged by the measures to limit the COVID-19 pandemic. There is still limited evidence on the effects it has on workers’ health. In this survey we invited 905 workers of companies that made a limited use of telecommuting to fill out a questionnaire to evaluate intrusive leadership of managers (IL), the request for work outside traditional hours (OFF-TAJD), workaholism (Bergen Work Addiction Scale (BWAS)), effort/reward imbalance (ERI), happiness, and common mental issues (CMIs), anxiety and depression, assessed by the Goldberg scale (GADS). The interaction between these variables has been studied by structural equation modeling (SEM). Intrusive leadership and working after hours were significantly associated with occupational stress. Workaholism is a relevant moderator of this interaction: intrusive leadership significantly increased the stress of workaholic workers. Intrusive leadership and overtime work were associated with reduced happiness, anxiety, and depression. These results indicate the need to guarantee the right to disconnect to limit the effect of the OFF-TAJD. In addition to this, companies should implement policies to prevent intrusive leadership and workaholism.
Association of Self-Reported Physical Fitness with Pregnancy Related Symptoms the GESTAFIT Project
Authors: Marín-Jiménez Nuria , Borges-Cosic Milkana , Ocón-Hernández Olga , Coll-Risco Irene , Flor-Alemany Marta , Baena-García Laura , Castro-Piñero José , Aparicio Virginia A.
Published: March 2021

We explored the association of physical fitness (PF) with pregnancy-related symptoms, at the 16th and 34th gestational weeks (g.w.). The International Fitness Scale and the Pregnancy Symptoms Inventory were employed to assess self-reported PF and pregnancy-related symptoms, respectively. At the 16th g.w. greater self-reported overall PF was associated with lower incidence of urinary frequency (p = 0.020); greater overall PF, cardiorespiratory fitness (CRF), muscular strength and speed-agility were associated with lower incidence of tiredness-fatigue (all, p < 0.05); greater overall PF and speed-agility were associated with lower incidence of poor sleep (both, p < 0.05); greater CRF and flexibility were associated with lower limitations by tiredness-fatigue (both, p < 0.05); and greater flexibility was associated with lower limitations by poor sleep (p = 0.021). At the 34th g.w. greater self-reported overall PF, CRF and muscular strength were associated with lower incidence of tiredness-fatigue (all, p < 0.05); greater CRF was associated with lower incidence of poor sleep (p = 0.019); and, greater flexibility was associated with lower incidence of increased vaginal discharge (p = 0.023). Adequate levels of PF, especially CRF, may help women to cope with the most endorsed pregnancy-related symptoms and its limitations, especially tiredness-fatigue and poor sleep.
Impact of Violent Experiences and Social Support on R-NSSI Behavior among Middle School Students in China
Authors: Liu Kun , Yang Xueyan , Xin Moye
Published: March 2021

Repetitive nonsuicidal self-injury (R-NSSI) is an extreme manifestation of nonsuicidal self-injury (NSSI) behavior that causes bodily harm and emotional and personality disorders. It is a growing concern, especially among adolescents; therefore, this study aims to provide empirical support for effective interventions on R-NSSI behavior among adolescents in China. We used data of about 1180 students from a survey conducted in seven middle schools in Xi’an, China, and applied multiple logistic regression to analyze NSSI and R-NSSI among male and female students, including their influencing factors. We found no significant difference between male and female students’ R-NSSI; however, regarding influencing factors, male students had more violent experiences and less social support than female students. Parental and familial factors played the most prominent role in social support. Social support was found to be a main-effect mechanism in the effect of violent experiences on R-NSSI among male students, whereas the mechanism had both a main effect and a certain buffer effect among female students. R-NSSI was found to be more prevalent among younger children, children with siblings, and those with romantic relationship experiences. We also found that healthy adolescent development involves the participation of families and schools. Health education should be conducted according to the students’ sex and characteristics.
Vaccine Willingness and Impact of the COVID-19 Pandemic on Women’s Perinatal Experiences and Practices—A Multinational, Cross-Sectional Study Covering the First Wave of the Pandemic
Authors: Ceulemans Michael , Foulon Veerle , Panchaud Alice , Winterfeld Ursula , Pomar Léo , Lambelet Valentine , Cleary Brian , O’Shaughnessy Fergal , Passier Anneke , Richardson Jonathan Luke , Allegaert Karel , Nordeng Hedvig
Published: March 2021

The COVID-19 pandemic may be of particular concern for pregnant and breastfeeding women. We aimed to explore their beliefs about the coronavirus and COVID-19 vaccine willingness and to assess the impact of the pandemic on perinatal experiences and practices. A multinational, cross-sectional, web-based study was performed in six European countries between April and July 2020. The anonymous survey was promoted via social media. In total, 16,063 women participated (including 6661 pregnant and 9402 breastfeeding women). Most responses were collected from Belgium (44%), Norway (18%) and the Netherlands (16%), followed by Switzerland (11%), Ireland (10%) and the UK (3%). Despite differences between countries, COVID-19 vaccine hesitancy was identified among 40–50% of the respondents at the end of the first wave of the pandemic and was higher among pregnant women. Education level and employment status were associated with vaccine hesitancy. The first wave had an adverse impact on pregnancy experiences and disrupted access to health services and breastfeeding support for many women. In the future, access to health care and support should be maintained at all times. Evidence-based and tailored information on COVID-19 vaccines should also be provided to pregnant and breastfeeding women to avoid unfounded concerns about the vaccines and to support shared decision making in this population.
Beneficial Impacts of Alpha-Eleostearic Acid from Wild Bitter Melon and Curcumin on Promotion of CDGSH Iron-Sulfur Domain 2: Therapeutic Roles in CNS Injuries and Diseases
Authors: Kung Woon-Man , Lin Muh-Shi
Published: March 2021

Neuroinflammation and abnormal mitochondrial function are related to the cause of aging, neurodegeneration, and neurotrauma. The activation of nuclear factor κB (NF-κB), exaggerating these two pathologies, underlies the pathogenesis for the aforementioned injuries and diseases in the central nervous system (CNS). CDGSH iron-sulfur domain 2 (CISD2) belongs to the human NEET protein family with the [2Fe-2S] cluster. CISD2 has been verified as an NFκB antagonist through the association with peroxisome proliferator-activated receptor-β (PPAR-β). This protective protein can be attenuated under circumstances of CNS injuries and diseases, thereby causing NFκB activation and exaggerating NFκB-provoked neuroinflammation and abnormal mitochondrial function. Consequently, CISD2-elevating plans of action provide pathways in the management of various disease categories. Various bioactive molecules derived from plants exert protective anti-oxidative and anti-inflammatory effects and serve as natural antioxidants, such as conjugated fatty acids and phenolic compounds. Herein, we have summarized pharmacological characters of the two phytochemicals, namely, alpha-eleostearic acid (α-ESA), an isomer of conjugated linolenic acids derived from wild bitter melon (Momordica charantia L. var. abbreviata Ser.), and curcumin, a polyphenol derived from rhizomes of Curcuma longa L. In this review, the unique function of the CISD2-elevating effect of α-ESA and curcumin are particularly emphasized, and these natural compounds are expected to serve as a potential therapeutic target for CNS injuries and diseases.
Recent Advances in Oligonucleotide Therapeutics in Oncology
Authors: Xiong Haoyu , Veedu Rakesh N. , Diermeier Sarah D.
Published: March 2021

Cancer is one of the leading causes of death worldwide. Conventional therapies, including surgery, radiation, and chemotherapy have achieved increased survival rates for many types of cancer over the past decades. However, cancer recurrence and/or metastasis to distant organs remain major challenges, resulting in a large, unmet clinical need. Oligonucleotide therapeutics, which include antisense oligonucleotides, small interfering RNAs, and aptamers, show promising clinical outcomes for disease indications such as Duchenne muscular dystrophy, familial amyloid neuropathies, and macular degeneration. While no approved oligonucleotide drug currently exists for any type of cancer, results obtained in preclinical studies and clinical trials are encouraging. Here, we provide an overview of recent developments in the field of oligonucleotide therapeutics in oncology, review current clinical trials, and discuss associated challenges.
Contrasting Rootstock-Mediated Growth and Yield Responses in Salinized Pepper Plants (Capsicum annuum L.) Are Associated with Changes in the Hormonal Balance
Authors: Gálvez Amparo , Albacete Alfonso , Martínez-Andújar Cristina , del Amor Francisco M. , López-Marín Josefa
Published: March 2021

Salinity provokes an imbalance of vegetative to generative growth, thus impairing crop productivity. Unlike breeding strategies, grafting is a direct and quick alternative to improve salinity tolerance in horticultural crops, through rebalancing plant development. Providing that hormones play a key role in plant growth and development and stress responses, we hypothesized that rootstock-mediated reallocation of vegetative growth and yield under salinity was associated with changes in the hormonal balance. To test this hypothesis, the hybrid pepper variety (Capsicum annuum L. “Gacela F1”) was either non-grafted or grafted onto three commercial rootstocks (Creonte, Atlante, and Terrano) and plants were grown in a greenhouse under control (0 mM NaCl) and moderate salinity (35 mM NaCl) conditions. Differential vegetative growth versus fruit yield responses were induced by rootstock and salinity. Atlante strongly increased shoot and root fresh weight with respect to the non-grafted Gacela plants associated with improved photosynthetic rate and K+ homeostasis under salinity. The invigorating effect of Atlante can be explained by an efficient balance between cytokinins (CKs) and abscisic acid (ABA). Creonte improved fruit yield and maintained the reproductive to vegetative ratio under salinity as a consequence of its capacity to induce biomass reallocation and to avoid Na+ accumulation in the shoot. The physiological responses associated with yield stability in Creonte were mediated by the inverse regulation of CKs and the ethylene precursor 1-aminocyclopropane-1-carboxylic acid. Finally, Terrano limited the accumulation of gibberellins in the shoot thus reducing plant height. Despite scion compactness induced by Terrano, both vegetative and reproductive biomass were maintained under salinity through ABA-mediated control of water relations and K+ homeostasis. Our data demonstrate that the contrasting developmental and physiological responses induced by the rootstock genotype in salinized pepper plants were critically mediated by hormones. This will be particularly important for rootstock breeding programs to improve salinity tolerance by focusing on hormonal traits.
The Glioblastoma Microenvironment: Morphology, Metabolism, and Molecular Signature of Glial Dynamics to Discover Metabolic Rewiring Sequence
Authors: Virtuoso Assunta , Giovannoni Roberto , De Luca Ciro , Gargano Francesca , Cerasuolo Michele , Maggio Nicola , Lavitrano Marialuisa , Papa Michele
Published: March 2021

Different functional states determine glioblastoma (GBM) heterogeneity. Brain cancer cells coexist with the glial cells in a functional syncytium based on a continuous metabolic rewiring. However, standard glioma therapies do not account for the effects of the glial cells within the tumor microenvironment. This may be a possible reason for the lack of improvements in patients with high-grade gliomas therapies. Cell metabolism and bioenergetic fitness depend on the availability of nutrients and interactions in the microenvironment. It is strictly related to the cell location in the tumor mass, proximity to blood vessels, biochemical gradients, and tumor evolution, underlying the influence of the context and the timeline in anti-tumor therapeutic approaches. Besides the cancer metabolic strategies, here we review the modifications found in the GBM-associated glia, focusing on morphological, molecular, and metabolic features. We propose to analyze the GBM metabolic rewiring processes from a systems biology perspective. We aim at defining the crosstalk between GBM and the glial cells as modules. The complex networking may be expressed by metabolic modules corresponding to the GBM growth and spreading phases. Variation in the oxidative phosphorylation (OXPHOS) rate and regulation appears to be the most important part of the metabolic and functional heterogeneity, correlating with glycolysis and response to hypoxia. Integrated metabolic modules along with molecular and morphological features could allow the identification of key factors for controlling the GBM-stroma metabolism in multi-targeted, time-dependent therapies.
The PI3Kδ Inhibitor Idelalisib Diminishes Platelet Function and Shows Antithrombotic Potential
Authors: Barrachina María N. , Izquierdo Irene , Hermida-Nogueira Lidia , Morán Luis A. , Pérez Amparo , Arroyo Ana B. , García-Barberá Nuria , González-Conejero Rocío , Troitiño Sara , Eble Johannes A. , Rivera José , Martínez Constantino , Loza María I. , Domínguez Eduardo , García Ángel
Published: March 2021

Background: Clinical management of ischemic events and prevention of vascular disease is based on antiplatelet drugs. Given the relevance of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) as a candidate target in thrombosis, the main goal of the present study was to identify novel antiplatelet agents within the existing inhibitors blocking PI3K isoforms. Methods: We performed a biological evaluation of the pharmacological activity of PI3K inhibitors in platelets. The effect of the inhibitors was evaluated in intracellular calcium release and platelet functional assays, the latter including aggregation, adhesion, and viability assays. The in vivo drug antithrombotic potential was assessed in mice undergoing chemically induced arterial occlusion, and the associated hemorrhagic risk evaluated by measuring the tail bleeding time. Results: We show that PI3K Class IA inhibitors potently block calcium mobilization in human platelets. The PI3K p110δ inhibitor Idelalisib inhibits platelet aggregation mediated by ITAM receptors GPVI and CLEC-2, preferentially by the former. Moreover, Idelalisib also inhibits platelet adhesion and aggregation under shear and adhesion to collagen. Interestingly, an antithrombotic effect was observed in mice treated with Idelalisib, with mild bleeding effects at high doses of the drug. Conclusion: Idelalisib may have antiplatelet effects with minor bleeding effects, which provides a rationale to evaluate its antithrombotic efficacy in humans.
Therapeutic miR-21 Silencing Reduces Cardiac Fibrosis and Modulates Inflammatory Response in Chronic Chagas Disease
Authors: Nonaka Carolina Kymie Vasques , Sampaio Gabriela Louise , de Aragão França Luciana , Cavalcante Bruno Raphael , Silva Katia Nunes , Khouri Ricardo , Torres Felipe Guimarães , Meira Cassio Santana , de Souza Santos Emanuelle , Macedo Carolina Thé , Paredes Bruno Diaz , Rocha Vinicius Pinto Costa , Rogatto Silvia Regina , Ribeiro dos Santos Ricardo , Souza Bruno Solano de Freitas , Soares Milena Botelho Pereira
Published: March 2021

Chagas disease, caused by the parasite Trypanosoma cruzi (T. cruzi), remains a serious public health problem for which there is no effective treatment in the chronic stage. Intense cardiac fibrosis and inflammation are hallmarks of chronic Chagas disease cardiomyopathy (CCC). Previously, we identified upregulation of circulating and cardiac miR-21, a pro-fibrotic microRNA (miRNA), in subjects with CCC. Here, we explored the potential role of miR-21 as a therapeutic target in a model of chronic Chagas disease. PCR array-based 88 microRNA screening was performed in heart samples obtained from C57Bl/6 mice chronically infected with T. cruzi and serum samples collected from CCC patients. MiR-21 was found upregulated in both human and mouse samples, which was corroborated by an in silico analysis of miRNA-mRNA target prediction. In vitro miR-21 functional assays (gain-and loss-of-function) were performed in cardiac fibroblasts, showing upregulation of miR-21 and collagen expression upon transforming growth factor beta 1 (TGFβ1) and T. cruzi stimulation, while miR-21 blockage reduced collagen expression. Finally, treatment of T. cruzi-infected mice with locked nucleic acid (LNA)-anti-miR-21 inhibitor promoted a significant reduction in cardiac fibrosis. Our data suggest that miR-21 is a mediator involved in the pathogenesis of cardiac fibrosis and indicates the pharmacological silencing of miR-21 as a potential therapeutic approach for CCC.
Lipid Emulsion Enhances Vasoconstriction Induced by Dexmedetomidine in the Isolated Endothelium-Intact Aorta
Authors: Lee Soo Hee , Ok Seong-Ho , Ahn Seung Hyun , Kim Hyun-Jin , Bae Sung Il , Kim Ji-Yoon , Park Kyeong-Eon , Hwang Yeran , Sohn Ju-Tae
Published: March 2021

This study aimed to examine the effect of lipid emulsion (LE) on the vasoconstriction induced by dexmedetomidine (DMT) in the isolated rat aorta and elucidate the associated cellular mechanism. The effect of LE, NW-nitro-L-arginine methyl ester (L-NAME), and methyl-β-cyclodextrin (MβCD) on the DMT-induced contraction was examined. We investigated the effect of LE on the DMT-induced cyclic guanosine monophosphate (cGMP) formation and DMT concentration. The effect of DMT, LE, 4-Amino-3-(4-chlorophenyl)-1-(t-butyl)-1H-pyrazolo[3,4-d]pyrimidine,4-Amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2), and rauwolscine on the phosphorylation of endothelial nitric oxide synthase (eNOS), caveolin-1, and Src kinase was examined in the human umbilical vein endothelial cells. L-NAME, MβCD, and LE (1%, standardized mean difference (SMD): 2.517) increased the DMT-induced contraction in the endothelium-intact rat aorta. LE (1%) decreased the DMT (10−6 M) concentration (SMD: −6.795) and DMT-induced cGMP formation (SMD: −2.132). LE (1%) reversed the DMT-induced eNOS (Ser1177 and Thr496) phosphorylation. PP2 inhibited caveolin-1 and eNOS phosphorylation induced by DMT. DMT increased the Src kinase phosphorylation. Thus, LE (1%) enhanced the DMT-induced contraction by inhibition of NO synthesis, which may be caused by the decreased DMT concentration. DMT-induced NO synthesis may be caused by the increased eNOS (Ser1177) phosphorylation and decreased eNOS (Thr495) phosphorylation potentially mediated by Src kinase-induced caveolin-1 phosphorylation.
Disease Modeling and Disease Gene Discovery in Cardiomyopathies: A Molecular Study of Induced Pluripotent Stem Cell Generated Cardiomyocytes
Authors: Kumar Satish , Curran Joanne E. , Kumar Kashish , DeLeon Erica , Leandro Ana C. , Peralta Juan , Williams-Blangero Sarah , Blangero John
Published: March 2021

The in vitro modeling of cardiac development and cardiomyopathies in human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) provides opportunities to aid the discovery of genetic, molecular, and developmental changes that are causal to, or influence, cardiomyopathies and related diseases. To better understand the functional and disease modeling potential of iPSC-differentiated CMs and to provide a proof of principle for large, epidemiological-scale disease gene discovery approaches into cardiomyopathies, well-characterized CMs, generated from validated iPSCs of 12 individuals who belong to four sibships, and one of whom reported a major adverse cardiac event (MACE), were analyzed by genome-wide mRNA sequencing. The generated CMs expressed CM-specific genes and were highly concordant in their total expressed transcriptome across the 12 samples (correlation coefficient at 95% CI =0.92 ± 0.02). The functional annotation and enrichment analysis of the 2116 genes that were significantly upregulated in CMs suggest that generated CMs have a transcriptomic and functional profile of immature atrial-like CMs; however, the CMs-upregulated transcriptome also showed high overlap and significant enrichment in primary cardiomyocyte (p-value = 4.36 × 10−9), primary heart tissue (p-value = 1.37 × 10−41) and cardiomyopathy (p-value = 1.13 × 10−21) associated gene sets. Modeling the effect of MACE in the generated CMs-upregulated transcriptome identified gene expression phenotypes consistent with the predisposition of the MACE-affected sibship to arrhythmia, prothrombotic, and atherosclerosis risk.
Mitochondrial Fuel Dependence on Glutamine Drives Chemo-Resistance in the Cancer Stem Cells of Hepatocellular Carcinoma
Authors: Lee Alan Chun Kit , Lau Pui Man , Kwan Yiu Wa , Kong Siu Kai
Published: March 2021

Chemo-resistance hinders treatment of patients with hepatocellular carcinoma. Although there are many models that can be found in the literature, the root mechanism to explain chemo-resistance is still not fully understood. To gain a better understanding of this phenomenon, a chemo-resistant line, R-HepG2, was developed from a chemo-sensitive HepG2 line through an exposure of doxorubicin (DOX). The R-HepG2 exhibited a cancer stem cell (CSC) phenotype with an over-expression of P-glycoprotein (P-gp), conferring it a significant enhancement in drug efflux and survival. With these observations, we hypothesize that metabolic alteration in this drug-resistant CSC is the root cause of chemo-resistance. Our results show that, unlike other metabolic-reprogrammed CSCs that exhibit glycolytic phenotype described by the “Warburg effect”, the R-HepG2 was metabolically quiescent with glucose independence, high metabolic plasticity, and relied on glutamine metabolism via the mitochondria for its chemo-resistance Intriguingly, drug efflux by P-gp in R-HepG2 depended on the mitochondrial ATP fueled by glutamine instead of glycolytic ATP. Armed with these observations, we blocked the glutamine metabolism in the R-HepG2 and a significant reduction of DOX efflux was obtained. We exploited this metabolic vulnerability using a combination of DOX and metformin in a glutamine-free condition to target the R-HepG2, resulting in a significant DOX sensitization. In conclusion, our findings highlight the metabolic modulation of chemo-resistance in CSCs. We delineate the altered metabolism that drives chemo-resistance and offer a new approach to target this CSC through metabolic interventions.
Regulation of Caspase-8 Activity at the Crossroads of Pro-Inflammation and Anti-Inflammation
Authors: Han Jun-Hyuk , Park Jooho , Kang Tae-Bong , Lee Kwang-Ho
Published: March 2021

Caspase-8 has been classified as an apoptotic caspase, and its initial definition was an initiator of extrinsic cell death. During the past decade, the concept of caspase-8 functioning has been changed by findings of its additional roles in diverse biological processes. Although caspase-8 was not originally thought to be involved in the inflammation process, many recent works have determined that caspase-8 plays an important role in the regulatory functions of inflammatory processes. In this review, we describe the recent advances in knowledge regarding the manner in which caspase-8 modulates the inflammatory responses concerning inflammasome activation, cell death, and cytokine induction.
Cytokinin Type-B Response Regulators Promote Bulbil Initiation in Lilium lancifolium
Authors: He Guoren , Yang Panpan , Cao Yuwei , Tang Yuchao , Wang Ling , Song Meng , Wang Jing , Xu Leifeng , Ming Jun
Published: March 2021

The bulbil is an important vegetative reproductive organ in triploid Lilium lancifolium whose development is promoted by cytokinins. Type-B response regulators (RRs) are critical regulators that mediate primary cytokinin responses and promote cytokinin-induced gene expression. However, the function of cytokinin type-B Arabidopsis RRs (ARRs) in regulating bulbil formation is unclear. In this study, we identified five type-B LlRRs, LlRR1, LlRR2, LlRR10, LlRR11 and LlRR12, in L. lancifolium for the first time. The five LlRRs encode proteins of 715, 675, 573, 582 and 647 amino acids. All of the regulators belong to the B-I subfamily, whose members typically contain a conserved CheY-homologous receiver (REC) domain and an Myb DNA-binding (MYB) domain at the N-terminus. As transcription factors, all five type-B LlRRs localize at the nucleus and are widely expressed in plant tissues, especially during axillary meristem (AM) formation. Functional analysis showed that type-B LlRRs are involved in bulbil formation in a functionally redundant manner and can activate LlRR9 expression. In summary, our study elucidates the process by which cytokinins regulate bulbil initiation in L. lancifolium through type-B LlRRs and lays a foundation for research on the molecular mechanism of bulbil formation in the lily.