bluuebunny/crossref_metadata_2025 huggingface dataset:
A Training Method for Low Rank Convolutional Neural Networks Based on Alternating Tensor Compose-Decompose Method
Authors: Lee Sukho , Kim Hyein , Jeong Byeongseon , Yoon Jungho
Published: January 2021

Over the past decade, deep learning-based computer vision methods have been shown to surpass previous state-of-the-art computer vision techniques in various fields, and have made great progress in various computer vision problems, including object detection, object segmentation, face recognition, etc. Nowadays, major IT companies are adding new deep-learning-based computer technologies to edge devices such as smartphones. However, since the computational cost of deep learning-based models is still high for edge devices, research is being actively carried out to compress deep learning-based models while not sacrificing high performance. Recently, many lightweight architectures have been proposed for deep learning-based models which are based on low-rank approximation. In this paper, we propose an alternating tensor compose-decompose (ATCD) method for the training of low-rank convolutional neural networks. The proposed training method can better train a compressed low-rank deep learning model than the conventional fixed-structure based training method, so that a compressed deep learning model with higher performance can be obtained in the end of the training. As a representative and exemplary model to which the proposed training method can be applied, we propose a rank-1 convolutional neural network (CNN) which has a structure alternatively containing 3-D rank-1 filters and 1-D filters in the training stage and a 1-D structure in the testing stage. After being trained, the 3-D rank-1 filters can be permanently decomposed into 1-D filters to achieve a fast inference in the test time. The reason that the 1-D filters are not being trained directly in 1-D form in the training stage is that the training of the 3-D rank-1 filters is easier due to the better gradient flow, which makes the training possible even in the case when the fixed structured network with fixed consecutive 1-D filters cannot be trained at all. We also show that the same training method can be applied to the well-known MobileNet architecture so that better parameters can be obtained than with the conventional fixed-structure training method. Furthermore, we show that the 1-D filters in a ResNet like structure can also be trained with the proposed method, which shows the fact that the proposed method can be applied to various structures of networks.
Hybrid Approach to the First Order Reliability Method in the Reliability Analysis of a Spatial Structure
Authors: Dudzik Agnieszka , Potrzeszcz-Sut Beata
Published: January 2021

The objective of the article involves presenting two approaches to the structure reliability analysis. The primary research method was the First Order Reliability Method (FORM). The Hasofer–Lind reliability index β in conjunction with transformation method in the FORM was adopted as the measure of reliability. The first proposal was combining NUMPRESS software with the non-commercial KRATA program. In this case, the implicit form of the random variables function was created. Limit state function was symbolically given in the standard math notation as a function of the basic random and external variables. The second analysis proposed a hybrid approach enabling the introduction of explicit forms of limit state functions to the reliability program. To create the descriptions of this formula, the neural networks were used and our own original FEM module. The combination of conventional and neural computing can be seen as a hybrid system. The explicit functions were implemented into NUMPRESS software. The values of the reliability index for different descriptions of the mathematical model of the structure were determined. The proposed hybrid approach allowed us to obtain similar results to the results from the reference method.
Adaptive Observer-Based Grid-Synchronization and Sequence Extraction Techniques for Renewable Energy Systems: A Comparative Analysis
Authors: Ahmed Hafiz , Benbouzid Mohamed
Published: January 2021

Various faults and disturbances often make the grid unbalanced and distorted. To make the grid-connected converters resilient to unbalanced and distorted grid, real-time estimation of grid voltage sequences are essential. Adaptive-observer based grid-synchronization techniques are very suitable for this purpose. In this paper, a comparative analysis of three recently proposed adaptive observer-based grid-synchronization technique are presented for frequency estimation and sequence extraction. The considered techniques are: global adaptive observer, gain normalized adaptive observer, and second-order generalized integrator type adaptive observer. Following a fair and systematic gain tuning process, the performances are verified through extensive numerical simulation and experiments. Experimental results demonstrate the merits and demerits of the individual techniques. Academic researchers and industrial practitioners will find the results useful for the selection of adaptive observer-based grid-synchronization and sequence extraction techniques.
Real-Time PCR Confirms Infection with Lagovirus europaeus
Authors: Bębnowska Dominika , Hrynkiewicz Rafał , Niedźwiedzka-Rystwej Paulina
Published: January 2021

Lagovirus europaeus GI.1/GI.2 is an etiological agent causing the highly dangerous rabbit hemorrhagic disease (RHD). Molecular research is the basic tool today that can help solve epidemic problems related to the expansion of pathogens in the world. By using the real-time polymerase chain reaction technique (PCR), we detected three different strains of Lagovirus europaeus/GI.1, which is an RNA virus infecting mainly rabbits. The results showed that the method used was fast, very specific, and effective.
Future Changes in the Global and Regional Sea Level Rise and Sea Surface Temperature Based on CMIP6 Models
Authors: Sung Hyun Min , Kim Jisun , Lee Jae-Hee , Shim Sungbo , Boo Kyung-On , Ha Jong-Chul , Kim Yeon-Hee
Published: January 2021

Estimating future sea level rise (SLR) and sea surface temperature (SST) is essential to implement mitigation and adaptation options within a sustainable development framework. This study estimates regional SLR and SST changes around the Korean peninsula. Two Shared Socioeconomic Pathways (SSP1-2.6 and SSP5-8.5) scenarios and nine Coupled Model Intercomparison Project Phase 6 (CMIP6) model simulations are used to estimate the changes in SLR and SST. At the end of the 21st century, global SLR is expected to be 0.28 m (0.17–0.38 m) and 0.65 m (0.52–0.78 m) for SSP 1–2.6 and SSP5-8.5, respectively. Regional change around the Korean peninsula (0.25 m (0.15–0.35 m; SSP1-2.6) and 0.63 m (0.50–0.76 m; SSP5-8.5)) is similar with global SLR. The discrepancy between global and regional changes is distinct in SST warming rather than SLR. For SSP5-8.5, SST around the Korean peninsula projects is to rise from 0.49 °C to 0.59 °C per decade, which is larger than the global SST trend (0.39 °C per decade). Considering this, the difference of regional SST change is related to the local ocean current change, such as the Kuroshio Current. Additionally, ocean thermal expansion and glacier melting are major contributors to SLR, and the contribution rates of glacier melting increase in higher emission scenarios.
Urban Air Quality Modeling Using Low-Cost Sensor Network and Data Assimilation in the Aburrá Valley, Colombia
Authors: Lopez-Restrepo Santiago , Yarce Andres , Pinel Nicolás , Quintero O.L. , Segers Arjo , Heemink A.W.
Published: January 2021

The use of low air quality networks has been increasing in recent years to study urban pollution dynamics. Here we show the evaluation of the operational Aburrá Valley’s low-cost network against the official monitoring network. The results show that the PM2.5 low-cost measurements are very close to those observed by the official network. Additionally, the low-cost allows a higher spatial representation of the concentrations across the valley. We integrate low-cost observations with the chemical transport model Long Term Ozone Simulation-European Operational Smog (LOTOS-EUROS) using data assimilation. Two different configurations of the low-cost network were assimilated: using the whole low-cost network (255 sensors), and a high-quality selection using just the sensors with a correlation factor greater than 0.8 with respect to the official network (115 sensors). The official stations were also assimilated to compare the more dense low-cost network’s impact on the model performance. Both simulations assimilating the low-cost model outperform the model without assimilation and assimilating the official network. The capability to issue warnings for pollution events is also improved by assimilating the low-cost network with respect to the other simulations. Finally, the simulation using the high-quality configuration has lower error values than using the complete low-cost network, showing that it is essential to consider the quality and location and not just the total number of sensors. Our results suggest that with the current advance in low-cost sensors, it is possible to improve model performance with low-cost network data assimilation.
Understanding the Processes Causing the Early Intensification of Hurricane Dorian through an Ensemble of the Hurricane Analysis and Forecast System (HAFS)
Authors: Hazelton Andrew , Alaka Ghassan J. , Cowan Levi , Fischer Michael , Gopalakrishnan Sundararaman
Published: January 2021

The early stages of a tropical cyclone can be a challenge to forecast, as a storm consolidates and begins to grow based on the local and environmental conditions. A high-resolution ensemble of the Hurricane Analysis and Forecast System (HAFS) is used to study the early intensification of Hurricane Dorian, a catastrophic 2019 storm in which the early period proved challenging for forecasters. There was a clear connection in the ensemble between early storm track and intensity: stronger members moved more northeast initially, although this result did not have much impact on the long-term track. The ensemble results show several key factors determining the early evolution of Dorian. Large-scale divergence northeast of the tropical cyclone (TC) appeared to favor intensification, and this structure was present at model initialization. There was also greater moisture northeast of the TC for stronger members at initialization, favoring more intensification and downshear development of the circulation as these members evolved. This study highlights the complex interplay between synoptic and storm scale processes in the development and intensification of early-stage tropical cyclones.
Mitigation of Gaseous Emissions from Stored Swine Manure with Biochar: Effect of Dose and Reapplication on a Pilot-Scale
Authors: Chen Baitong , Koziel Jacek A. , Banik Chumki , Ma Hantian , Lee Myeongseong , O’Brien Samuel C. , Li Peiyang , Andersen Daniel S. , Białowiec Andrzej , Brown Robert C.
Published: January 2021

Rural communities are affected by gaseous emissions from intensive livestock production. Practical mitigation technologies are needed to minimize emissions from stored manure and improve air quality inside barns. In our previous research, the one-time surficial application of biochar to swine manure significantly reduced emissions of NH3 and phenol. We observed that the mitigation effect decreased with time during the 30-day trials. In this research, we hypothesized that bi-weekly reapplication of biochar could improve the mitigation effect on a wider range of odorous compounds using a larger scale and longer trials. The objective was to evaluate the effectiveness of biochar dose and reapplication on mitigation of targeted gases (NH3, odorous, volatile organic compounds VOCs, odor, greenhouse gases (GHG)) from stored swine manure on a pilot-scale setup over 8-weeks. The bi-weekly reapplication of the lower biochar dose (2 kg/m2) showed much higher significant percentage reductions in emissions for NH3 (33% without and 53% with reapplication) and skatole (42% without and 80% with reapplication), respectively. In addition, the reapplication resulted in the emergence of a statistical significance to the mitigation effect for all other targeted VOCs. Specifically, for indole, the percentage reduction improved from 38% (p = 0.47, without reapplication) to 78% (p = 0.018, with reapplication). For phenol, the percentage reduction improved from 28% (p = 0.71, without reapplication) to 89% (p = 0.005, with reapplication). For p-cresol, the percentage reduction improved from 31% (p = 0.86, without reapplication) to 74% (p = 0.028, with reapplication). For 4-ethyl phenol, the percentage emissions reduction improved from 66% (p = 0.44, without reapplication) to 87% (p = 0.007, with reapplication). The one-time 2 kg/m2 and 4 kg/m2 treatments showed similar effectiveness in mitigating all targeted gases, and no statistical difference was found between the dosages. The one-time treatments showed significant percentage reductions of 33% and 42% and 25% and 48% for NH3 and skatole, respectively. The practical significance is that the higher (one-time) biochar dose may not necessarily result in improved performance over the 8-week manure storage, but the bi-weekly reapplication showed significant improvement in mitigating NH3 and odorous VOCs. The lower dosages and the frequency of reapplication on the larger-scale should be explored to optimize biochar treatment and bring it closer to on-farm trials.
An Algebraic Inequality with Applications to Certain Chen Inequalities
Authors: Mihai Ion , Mihai Radu-Ioan
Published: January 2021

We give a simple proof of the Chen inequality for the Chen invariant δ(2,…,2)︸k terms of submanifolds in Riemannian space forms.
Experimental Study of Burn Damage Progression in a Human Composite Tissue Model
Authors: Hao Dandan , Qu Miao , Nourbakhsh Mahtab
Published: January 2021

Comparative studies of human tissue damage caused by burns are challenging because precise information regarding the temperature, time, and duration of the exposure is often missing. Animal models cannot be fully translated to the human system due to interspecies differences in cutaneous tissues. We used a human composite tissue model to compare tissue damage caused by thermal burns with different dynamics. Equal subcutaneous/cutaneous composite tissue samples from six donors were first exposed to either preheated steel (100 °C) or a precision flame burner (300 °C) and were then maintained in vitro for seven days. Histological and immunohistochemical analyses revealed that flame burns instantly caused deep and stable damage to the subcutaneous tissue, which stayed constant for seven days. By contrast, contact burns inflicted tissue damage that was initially superficial but then expanded deeper into the adipose tissue. This spatiotemporal expansion of tissue damage was essentially accompanied by macrophage and fibroblast activation, which points towards inflammation resolution and wound healing. Our study suggests that thermal differences in burns directly influence the course of tissue damage, the cellular response and, consequently, the likely dynamics of repair processes days after burn injuries.
Cold Atmospheric Plasma, a Novel Approach against Bladder Cancer, with Higher Sensitivity for the High-Grade Cell Line
Authors: Tavares-da-Silva Edgar , Pereira Eurico , Pires Ana S. , Neves Ana R. , Braz-Guilherme Catarina , Marques Inês A. , Abrantes Ana M. , Gonçalves Ana C. , Caramelo Francisco , Silva-Teixeira Rafael , Mendes Fernando , Figueiredo Arnaldo , Botelho Maria Filomena
Published: January 2021

Antitumor therapies based on Cold Atmospheric Plasma (CAP) are an emerging medical field. In this work, we evaluated CAP effects on bladder cancer. Two bladder cancer cell lines were used, HT-1376 (stage III) and TCCSUP (stage IV). Cell proliferation assays were performed evaluating metabolic activity (MTT assay) and protein content (SRB assay). Cell viability, cell cycle, and mitochondrial membrane potential (Δψm) were assessed using flow cytometry. Reactive oxygen and nitrogen species (RONS) and reduced glutathione (GSH) were evaluated by fluorescence. The assays were carried out with different CAP exposure times. For both cell lines, we obtained a significant reduction in metabolic activity and protein content. There was a decrease in cell viability, as well as a cell cycle arrest in S phase. The Δψm was significantly reduced. There was an increase in superoxide and nitric oxide and a decrease in peroxide contents, while GSH content did not change. These results were dependent on the exposure time, with small differences for both cell lines, but overall, they were more pronounced in the TCCSUP cell line. CAP showed to have a promising antitumor effect on bladder cancer, with higher sensitivity for the high-grade cell line.
Flaxseed Lignans and Polyphenols Enhanced Activity in Streptozotocin-Induced Diabetic Rats
Authors: Draganescu Dan , Andritoiu Calin , Hritcu Doina , Dodi Gianina , Popa Marcel Ionel
Published: January 2021

Flaxseeds play an important role in human health due to their chemical composition and recognized beneficial outcomes. This study investigated the antidiabetic effects of present lignans and polyphenols found in the flaxseed extract on streptozotocin (STZ)-induced diabetic rats. The flaxseed administration produced favorable changes in body weight, food and water intake, and glycosylated hemoglobin and blood glucose quantities in the treated diabetic rats. Additionally, significant positive results were observed in the biochemical parameters, namely reduced plasma cholesterol, LDL cholesterol and triglycerides, plasma creatinine, and urea and uric acid levels, highlighting the seeds’ use in traditional medicine. The results were sustained by histopathological observations that showed better tissue preservation following the flaxseed diet. Overall, the consumption of flaxseeds produced moderate reduction in glucose levels and hyperlipidemia, together with improvement in the impaired organs’ function in diabetic rats. The daily administration of polyphenols and lignans compounds could impact therapeutic potential in diabetes management.
Smallholder Farmers’ Practices and African Indigenous Vegetables Affect Soil Microbial Biodiversity and Enzyme Activities in Lake Naivasha Basin, Kenya
Authors: Taskin Eren , Misci Chiara , Bandini Francesca , Fiorini Andrea , Pacini Nic , Obiero Clifford , Sila Daniel Ndaka , Tabaglio Vincenzo , Puglisi Edoardo
Published: January 2021

Loss of soil biodiversity and fertility in Sub-Saharan Africa (SSA) may put the food security of smallholder farmers in peril. Food systems in SSA are seeing the rise of African indigenous vegetables (AIVs) that are underexploited but locally consumed without being considered a primary source of food and income. Here we present a field study, a first of its kind, in which we investigated the effects of different cropping systems and inclusion of AIVs in the farming approach on bacterial and fungal biodiversity and community structures, enzymatic activity, and the alteration status of soils of the smallholder farmers in Kenya. When compared to mainstream farming approaches, the composition and biodiversity of bacteria and fungi under AIV cultivations was significantly different. Tillage had a significant impact only on the fungal communities. Fertilization and soil amendments caused shifts in microbial communities towards specialized degraders and revealed the introduction of specific microorganisms from amendments. Traditional homemade plant protection products did not cause any disturbance to either of soil bacteria or fungi. The soil alteration index based on enzyme activity successfully differentiated the alteration status for the first time in SSA. These findings could be useful for farmers to integrate AIVs with correct sustainable practices for a sustainable future.
Interconversion of Plasma Free Thyroxine Values from Assay Platforms with Different Reference Intervals Using Linear Transformation Methods
Authors: Meng Fanwen , Jonklaas Jacqueline , Leow Melvin Khee-Shing
Published: January 2021

Clinicians often encounter thyroid function tests (TFT) comprising serum/plasma free thyroxine (FT4) and thyroid stimulating hormone (TSH) measured using different assay platforms during the course of follow-up evaluations which complicates reliable comparison and interpretation of TFT changes. Although interconversion between concentration units is straightforward, the validity of interconversion of FT4/TSH values from one assay platform to another with different reference intervals remains questionable. This study aims to establish an accurate and reliable methodology of interconverting FT4 by any laboratory to an equivalent FT4 value scaled to a reference range of interest via linear transformation methods. As a proof-of-concept, FT4 was simultaneously assayed by direct analog immunoassay, tandem mass spectrometry and equilibrium dialysis. Both linear and piecewise linear transformations proved relatively accurate for FT4 inter-scale conversion. Linear transformation performs better when FT4 are converted from a more accurate to a less accurate assay platform. The converse is true, whereby piecewise linear transformation is superior to linear transformation when converting values from a less accurate method to a more robust assay platform. Such transformations can potentially apply to other biochemical analytes scale conversions, including TSH. This aids interpretation of TFT trends while monitoring the treatment of patients with thyroid disorders.
Jasmonates, Ethylene and Brassinosteroids Control Adventitious and Lateral Rooting as Stress Avoidance Responses to Heavy Metals and Metalloids
Authors: Betti Camilla , Della Rovere Federica , Piacentini Diego , Fattorini Laura , Falasca Giuseppina , Altamura Maria Maddalena
Published: January 2021

Developmental and environmental signaling networks often converge during plant growth in response to changing conditions. Stress-induced hormones, such as jasmonates (JAs), can influence growth by crosstalk with other signals like brassinosteroids (BRs) and ethylene (ET). Nevertheless, it is unclear how avoidance of an abiotic stress triggers local changes in development as a response. It is known that stress hormones like JAs/ET and BRs can regulate the division rate of cells from the first asymmetric cell divisions (ACDs) in meristems, suggesting that stem cell activation may take part in developmental changes as a stress-avoidance-induced response. The root system is a prime responder to stress conditions in soil. Together with the primary root and lateral roots (LRs), adventitious roots (ARs) are necessary for survival in numerous plant species. AR and LR formation is affected by soil pollution, causing substantial root architecture changes by either depressing or enhancing rooting as a stress avoidance/survival response. Here, a detailed overview of the crosstalk between JAs, ET, BRs, and the stress mediator nitric oxide (NO) in auxin-induced AR and LR formation, with/without cadmium and arsenic, is presented. Interactions essential in achieving a balance between growth and adaptation to Cd and As soil pollution to ensure survival are reviewed here in the model species Arabidopsis and rice.
Mangiferin as New Potential Anti-Cancer Agent and Mangiferin-Integrated Polymer Systems—A Novel Research Direction
Authors: Morozkina Svetlana N. , Nhung Vu Thi Hong , Generalova Yuliya E. , Snetkov Petr P. , Uspenskaya Mayya V.
Published: January 2021

For a long time, the pharmaceutical industry focused on natural biologically active molecules due to their unique properties, availability and significantly less side-effects. Mangiferin is a naturally occurring C-glucosylxantone that has substantial potential for the treatment of various diseases thanks to its numerous biological activities. Many research studies have proven that mangiferin possesses antioxidant, anti-infection, anti-cancer, anti-diabetic, cardiovascular, neuroprotective properties and it also increases immunity. It is especially important that it has no toxicity. However, mangiferin is not being currently applied to clinical use because its oral bioavailability as well as its absorption in the body are too low. To improve the solubility, enhance the biological action and bioavailability, mangiferin integrated polymer systems have been developed. In this paper, we review molecular mechanisms of anti-cancer action as well as a number of designed polymer-mangiferin systems. Taking together, mangiferin is a very promising anti-cancer molecule with excellent properties and the absence of toxicity.
Role of Retinoic Acid Signaling, FGF Signaling and Meis Genes in Control of Limb Development
Authors: Berenguer Marie , Duester Gregg
Published: January 2021

The function of retinoic acid (RA) during limb development is still debated, as loss and gain of function studies led to opposite conclusions. With regard to limb initiation, genetic studies demonstrated that activation of FGF10 signaling is required for the emergence of limb buds from the trunk, with Tbx5 and RA signaling acting upstream in the forelimb field, whereas Tbx4 and Pitx1 act upstream in the hindlimb field. Early studies in chick embryos suggested that RA as well as Meis1 and Meis2 (Meis1/2) are required for subsequent proximodistal patterning of both forelimbs and hindlimbs, with RA diffusing from the trunk, functioning to activate Meis1/2 specifically in the proximal limb bud mesoderm. However, genetic loss of RA signaling does not result in loss of limb Meis1/2 expression and limb patterning is normal, although Meis1/2 expression is reduced in trunk somitic mesoderm. More recent studies demonstrated that global genetic loss of Meis1/2 results in a somite defect and failure of limb bud initiation. Other new studies reported that conditional genetic loss of Meis1/2 in the limb results in proximodistal patterning defects, and distal FGF8 signaling represses Meis1/2 to constrain its expression to the proximal limb. In this review, we hypothesize that RA and Meis1/2 both function in the trunk to initiate forelimb bud initiation, but that limb Meis1/2 expression is activated proximally by a factor other than RA and repressed distally by FGF8 to generate proximodistal patterning.
Endothelial Dysfunction and Extra-Articular Neurological Manifestations in Rheumatoid Arthritis
Authors: Maiuolo Jessica , Muscoli Carolina , Gliozzi Micaela , Musolino Vincenzo , Carresi Cristina , Paone Sara , Ilari Sara , Mollace Rocco , Palma Ernesto , Mollace Vincenzo
Published: January 2021

Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory autoimmune disease that affects about 1% of the global population, with a female–male ratio of 3:1. RA preferably affects the joints, with consequent joint swelling and deformities followed by ankylosis. However, evidence has accumulated showing that patients suffering from RA can also develop extra-articular manifestations, including cardiovascular disease states, neuropathies, and multiorgan dysfunction. In particular, peripheral nerve disorders showed a consistent impact in the course of the disease (prevalence about 20%) mostly associated to vasculitis of the nerve vessels leading to vascular ischemia, axonal degeneration, and neuronal demyelination. The pathophysiological basis of this RA-associated microvascular disease, which leads to impairment of assonal functionality, is still to be better clarified. However, endothelial dysfunction and alterations of the so-called brain-nerve barrier (BNB) seem to play a fundamental role. This review aims to assess the potential mechanisms underlying the impairment of endothelial cell functionality in the development of RA and to identify the role of dysfunctional endothelium as a causative mechanism of extra-articular manifestation of RA. On the other hand, the potential impact of lifestyle and nutritional interventions targeting the maintenance of endothelial cell integrity in patients with RA will be discussed as a potential option when approaching therapeutic solutions in the course of the disease.
Role of BRCA Mutation and HE4 in Predicting Chemotherapy Response in Ovarian Cancer: A Retrospective Pilot Study
Authors: Plotti Francesco , Terranova Corrado , Guzzo Federica , De Cicco Nardone Carlo , Luvero Daniela , Bartolone Martina , Dionisi Camilla , Benvenuto Domenico , Fabris Silvia , Ciccozzi Massimo , Di Donato Violante , Panici Pierluigi Benedetti , Angioli Roberto
Published: January 2021

Even though 80% of patients with High-Grade Serous Ovarian Cancer respond to standard first-line chemotherapy, a majority of them could relapse in the following five years due to a resistance to platinum. Human Epididymis protein 4 (HE4) is one of the most promising markers in predicting platinum therapy response. This pilot study aims to evaluate the potential role of HE4 value in predicting chemotherapy response in BRCA mutated patients and in BRCA wild-type (non-mutated) ones. We selected 69 patients, affected by High-Grade Serous Ovarian Cancer, and optimally debulked and submitted to standard chemotherapy protocols. HE4 was dosed during every chemotherapy course. Patients were classified as platinum-resistant and platinum-sensitive. According to BRCA mutation test, patients were further divided into BRCA wild-type (53 patients), and BRCA mutated (16 patients). 35 patients out of 69 (52%) were platinum-sensitive (recurrence > 12 months), while 33 patients (48%) were platinum-resistant (recurrence < 12 months). Thus, in the total population, HE4 performed as a marker of chemosensitivity with a sensibility of 79% and a specificity of 97%. In the BRCA WT group, 23 patients out of 53 (43%) were platinum-sensitive, while 30 patients out of 53 (57%) were platinum-resistant. In the BRCA WT group, HE4 performed as a predictive marker of chemosensitivity with a sensibility of 80% and a specificity of 100%. In the BRCA mutated group, 13 patients out of 16 (82%) were platinum-sensitive, while 3 patients (18%) were platinum-resistant. In the BRCA mutated group, HE4 performed as a predictive marker of chemosensitivity in all patients. The ability to detect platinum-resistant patients before tumor relapse probably could open new therapeutic scenarios.
Clinicopathological and Functional Evaluation Reveal NBS1 as a Predictor of Platinum Resistance in Epithelial Ovarian Cancers
Authors: Alblihy Adel , Alabdullah Muslim L. , Ali Reem , Algethami Mashael , Toss Michael S. , Mongan Nigel P. , Rakha Emad A. , Madhusudan Srinivasan
Published: January 2021

Platinum resistance seriously impacts on the survival outcomes of patients with ovarian cancers. Platinum-induced DNA damage is processed through DNA repair. NBS1 is a key DNA repair protein. Here, we evaluated the role of NBS1 in ovarian cancers. NBS1 expression was investigated in clinical cohorts (protein level (n = 331) and at the transcriptomic level (n = 1259)). Pre-clinically, sub-cellular localization of NBS1 at baseline and following cisplatin therapy was tested in platinum resistant (A2780cis, PEO4) and sensitive (A2780, PEO1) ovarian cancer cells. NBS1 was depleted and cisplatin sensitivity was investigated in A2780cis and PEO4 cells. Nuclear NBS1 overexpression was associated with platinum resistance (p = 0.0001). In univariate and multivariate analysis, nuclear NBS1 overexpression was associated with progression free survival (PFS) (p-values = 0.003 and 0.017, respectively) and overall survival (OS) (p-values = 0.035 and 0.009, respectively). NBS1 mRNA overexpression was linked with poor PFS (p = 0.011). Pre-clinically, following cisplatin treatment, we observed nuclear localization of NBS1 in A2780cis and PEO4 compared to A2780 and PEO1 cells. NBS1 depletion increased cisplatin cytotoxicity, which was associated with accumulation of double strand breaks (DSBs), S-phase cell cycle arrest, and increased apoptosis. NBS1 is a predictor of platinum sensitivity and could aid stratification of ovarian cancer therapy.
Endothelial Dysfunction in Pulmonary Hypertension: Cause or Consequence?
Authors: Kurakula Kondababu , Smolders Valérie F. E. D. , Tura-Ceide Olga , Jukema J. Wouter , Quax Paul H. A. , Goumans Marie-José
Published: January 2021

Pulmonary arterial hypertension (PAH) is a rare, complex, and progressive disease that is characterized by the abnormal remodeling of the pulmonary arteries that leads to right ventricular failure and death. Although our understanding of the causes for abnormal vascular remodeling in PAH is limited, accumulating evidence indicates that endothelial cell (EC) dysfunction is one of the first triggers initiating this process. EC dysfunction leads to the activation of several cellular signalling pathways in the endothelium, resulting in the uncontrolled proliferation of ECs, pulmonary artery smooth muscle cells, and fibroblasts, and eventually leads to vascular remodelling and the occlusion of the pulmonary blood vessels. Other factors that are related to EC dysfunction in PAH are an increase in endothelial to mesenchymal transition, inflammation, apoptosis, and thrombus formation. In this review, we outline the latest advances on the role of EC dysfunction in PAH and other forms of pulmonary hypertension. We also elaborate on the molecular signals that orchestrate EC dysfunction in PAH. Understanding the role and mechanisms of EC dysfunction will unravel the therapeutic potential of targeting this process in PAH.
Application of CAR-T Cell Therapy beyond Oncology: Autoimmune Diseases and Viral Infections
Authors: Zmievskaya Ekaterina , Valiullina Aygul , Ganeeva Irina , Petukhov Alexey , Rizvanov Albert , Bulatov Emil
Published: January 2021

Adoptive cell transfer (ACT) has long been at the forefront of the battle with cancer that began last century with the therapeutic application of tumor-infiltrating lymphocytes (TILs) against melanoma. The development of novel ACT approaches led researchers and clinicians to highly efficient technologies based on genetically engineered T lymphocytes, with chimeric antigen receptor (CAR)-T cells as the most prominent example. CARs consist of an extracellular domain that represents the single-chain variable fragment (scFv) of a monoclonal antibody (mAb) responsible for target recognition and the intracellular domain, which was built from up to several signaling motifs that mediated T cell activation. The number of potential targets amenable for CAR-T cell therapy is expanding rapidly, which means that the tremendous success of this approach in oncology could be further translated to treating other diseases. In this review, we outlined modern trends and recent developments in CAR-T cell therapy from an unusual point of view by focusing on diseases beyond cancer, such as autoimmune disorders and viral infections, including SARS-CoV-2.
The Non-Steroidal FXR Agonist Cilofexor Improves Portal Hypertension and Reduces Hepatic Fibrosis in a Rat NASH Model
Authors: Schwabl Philipp , Hambruch Eva , Budas Grant R. , Supper Paul , Burnet Michael , Liles John T. , Birkel Manfred , Brusilovskaya Ksenia , Königshofer Philipp , Peck-Radosavljevic Markus , Watkins William J. , Trauner Michael , Breckenridge David G. , Kremoser Claus , Reiberger Thomas
Published: January 2021

Background: The farnesoid X receptor (FXR) influences hepatic metabolism, inflammation and liver fibrosis as key components of non-alcoholic steatohepatitis (NASH). We studied the effects of the non-steroidal FXR agonist cilofexor (formerly GS-9674) on portal pressure and fibrosis in experimental NASH. Methods: NASH was induced in Wistar rats using a choline-deficient high-fat diet plus intraperitoneal sodium nitrite injections. First, a dose-finding study was performed with 10 mg/kg and 30 mg/kg of cilofexor, focusing on histological readouts. Liver fibrosis was assessed by Picro-Sirius-Red, desmin staining and hepatic hydroxyproline content. Gene expression was determined by RT-PCR. In a subsequent hemodynamic study, rats received 30 mg/kg cilofexor with or without propranolol (25 mg/kg). Portal pressure, systemic hemodynamics and splanchnic blood flow were measured. Results: Cilofexor dose-dependently induced FXR target genes shp, cyp7a1 and fgf15 in hepatic and ileal tissues, paralleled by a dose-dependent reduction in liver fibrosis area (Picro-Sirius-Red) of −41% (10 mg/kg) and −69% (30 mg/kg), respectively. The 30 mg/kg cilofexor dose significantly reduced hepatic hydroxyproline content (−41%), expression of col1a1 (−37%) and pdgfr-β (−36%), as well as desmin area (−42%) in NASH rats. Importantly, cilofexor decreased portal pressure (11.9 ± 2.1 vs. 8.9 ± 2.2 mmHg; p = 0.020) without affecting splanchnic blood-flow or systemic hemodynamics. The addition of propranolol to cilofexor additionally reduced splanchnic inflow (−28%) but also mean arterial pressure (−25%) and heart rate (−37%). Conclusion: The non-steroidal FXR agonist cilofexor decreased portal hypertension and reduced liver fibrosis in NASH rats. While cilofexor seems to primarily decrease sinusoidal resistance in cirrhotic portal hypertension, the combination with propranolol additionally reduced mesenteric hyperperfusion.
Hypertrophy and Insulin Resistance of Epicardial Adipose Tissue Adipocytes: Association with the Coronary Artery Disease Severity
Authors: Naryzhnaya Natalia V. , Koshelskaya Olga A. , Kologrivova Irina V. , Kharitonova Olga A. , Evtushenko Vladimir V. , Boshchenko Alla A.
Published: January 2021

Changes in the structural and functional characteristics of the epicardial adipose tissue (EAT) are recognized as one of the factors in the development of cardiometabolic diseases. However, the generally accepted quantitative assessment of the accumulation of EAT does not reflect the size of adipocyte and presence of adipocyte hypertrophy in this fat depot. Overall contribution of adipocyte hypertrophy to the development and progression of coronary atherosclerosis remains unexplored. Objective: To compare the morphological characteristics of EAT adipocyte and its sensitivity to insulin with the CAD severity, as well as to identify potential factors involved in the realization of this relationship. The present study involved 24 patients (m/f 16/8) aged 53–72 years with stable CAD, who underwent coronary artery bypass graft surgery. Adipocytes were isolated enzymatically from EAT explants obtained during the operation. The severity of CAD was assessed by calculating the Gensini score according to selective coronary angiography. Insulin resistance of EAT adipocytes was evaluated by reactivity to insulin. In patients with an average size of EAT adipocytes equal to or exceeding the median (87 μm) the percentage of hypertrophic adipocytes was twice as high as in patients in whom the average size of adipocytes was less than 87 μm. This group of patients was also characterized by the higher rate of the Gensini score, lower adiponectin levels, and more severe violation of carbohydrate metabolism. We have revealed direct nonparametric correlation between the size of EAT adipocytes and the Gensini score (rs = 0.56, p = 0.00047). The number of hypertrophic EAT adipocytes showed a direct nonparametric correlation with the Gensini score (rs = 0.6, p = 0.002). Inverse nonparametric correlations were found between the serum adiponectin level and size (rs = −0.60, p = 0.001), hypertrophy of adipocytes (rs = −0.67, p = 0.00), and Gensini score (rs = −0.81, p = 0.00007). An inverse nonparametric correlation was found between the Gensini score and sensitivity of EAT adipocytes to insulin, estimated by the intracellular redox response (rs = −0.90, p = 0.037) and decrease in lipolysis rate upon insulin addition (rs = −0.40, p = 0.05). The intracellular redox response of adipocytes to insulin was directly correlated with fasting insulin and inversely with postprandial insulin. Our data indicate that the size and degree of hypertrophy of the epicardial adipocytes are related to the CAD severity. According to our results, insulin resistance of adipocytes may be considered as one of the factors mediating this relationship.
Characterizing Bilingual Effects on Cognition: The Search for Meaningful Individual Differences
Authors: Backer Kristina C. , Bortfeld Heather
Published: January 2021

A debate over the past decade has focused on the so-called bilingual advantage—the idea that bilingual and multilingual individuals have enhanced domain-general executive functions, relative to monolinguals, due to competition-induced monitoring of both processing and representation from the task-irrelevant language(s). In this commentary, we consider a recent study by Pot, Keijzer, and de Bot (2018), which focused on the relationship between individual differences in language usage and performance on an executive function task among multilingual older adults. We discuss their approach and findings in light of a more general movement towards embracing complexity in this domain of research, including individuals’ sociocultural context and position in the lifespan. The field increasingly considers interactions between bilingualism/multilingualism and cognition, employing measures of language use well beyond the early dichotomous perspectives on language background. Moreover, new measures of bilingualism and analytical approaches are helping researchers interrogate the complexities of specific processing issues. Indeed, our review of the bilingualism/multilingualism literature confirms the increased appreciation researchers have for the range of factors—beyond whether someone speaks one, two, or more languages—that impact specific cognitive processes. Here, we highlight some of the most salient of these, and incorporate suggestions for a way forward that likewise encompasses neural perspectives on the topic.
Modulation of Synaptic Plasticity by Vibratory Training in Young and Old Mice
Authors: Cariati Ida , Bonanni Roberto , Pallone Gabriele , Annino Giuseppe , Tancredi Virginia , D’Arcangelo Giovanna
Published: January 2021

In the past 40 years, scientific research has shown how Whole Body Vibration concept represents a strong stimulus for the whole organism. Low (<30 Hz), medium (30–80 Hz), and high (>80 Hz) frequency vibrations can have both positive and negative effects, depending on the oscillation type and duration of exposure to which the body is subjected. However, very little is known about the effects of vibratory training on the brain. In this regard, we verified whether three vibratory training protocols, differing in terms of vibration frequency and exposure time to vibration, could modulate synaptic plasticity in an experimental mouse model, by extracellular recordings in vitro in hippocampal slices of mice of 4 and 24 months old. Our results showed that vibratory training can modulate synaptic plasticity differently, depending on the protocol used, and that the best effects are related to the training protocol characterized by a low vibration frequency and a longer recovery time. Future studies will aim to understand the brain responses to various types of vibratory training and to explore the underlying mechanisms, also evaluating the presence of any structural and functional changes due to vibratory training.
Clinical Outcomes of Interlaminar Percutaneous Endoscopic Decompression for Degenerative Lumbar Spondylolisthesis with Spinal Stenosis
Authors: Sriphirom Pornpavit , Siramanakul Chaiyaporn , Chaipanha Preewut , Saepoo Chalit
Published: January 2021

The use of traditional open decompression alone in degenerative spondylolisthesis can lead to the development of postoperative spinal instability, whereas percutaneous endoscopic decompression can preserve the attachment of intervertebral muscles, facet joint capsules, and ligaments that stabilize the spine. The study’s aim was to determine clinical as well as radiologic outcomes associated with interlaminar percutaneous endoscopic decompression in patients with stable degenerative spondylolisthesis. For this study, 28 patients with stable degenerative spondylolisthesis who underwent percutaneous endoscopic decompression were enrolled. The clinical outcomes in terms of the visual analogue scale (VAS) and Oswestry disability index (ODI) were evaluated. Radiologic outcomes were determined by measuring the ratio of disc height and the vertebral slippage percentage using lateral standing radiographs. The average follow-up period was 25.24 months. VAS and ODI were significantly improved at the final follow-up. In terms of ratio of disc height and vertebral slippage percentage found no significant difference between the preoperative and postoperative periods. One patient underwent further caudal epidural steroid injection. One patient underwent fusion because their radicular pain did not improve. Interlaminar percutaneous endoscopic decompression is an effective procedure with favorable outcomes in selected patients with stable degenerative spondylolisthesis.
AEG-1 Regulates TWIK-1 Expression as an RNA-Binding Protein in Astrocytes
Authors: Jung Hyun-Gug , Kim Ajung , Kim Seung-Chan , Park Jae-Yong , Hwang Eun Mi
Published: January 2021

AEG-1, also called MTDH, has oncogenic potential in numerous cancers and is considered a multifunctional modulator because of its involvement in developmental processes and inflammatory and degenerative brain diseases. However, the role of AEG-1 in astrocytes remains unknown. This study aimed to investigate proteins directly regulated by AEG-1 by analyzing their RNA expression patterns in astrocytes transfected with scramble shRNA and AEG-1 shRNA. AEG-1 knockdown down-regulated TWIK-1 mRNA. Real-time quantitative PCR (qPCR) and immunocytochemistry assays confirmed that AEG-1 modulates TWIK-1 mRNA and protein expression. Electrophysiological experiments further revealed that AEG-1 further regulates TWIK-1-mediated potassium currents in normal astrocytes. An RNA immunoprecipitation assay to determine how AEG-1 regulates the expression of TWIK-1 revealed that AEG-1 binds directly to TWIK-1 mRNA. Furthermore, TWIK-1 mRNA stability was significantly increased upon overexpression of AEG-1 in cultured astrocytes (p < 0.01). Our findings show that AEG-1 serves as an RNA-binding protein to regulate TWIK-1 expression in normal astrocytes.
Pain, Complex Chronic Conditions and Potential Inappropriate Medication in People with Dementia. Lessons Learnt for Pain Treatment Plans Utilizing Data from the Veteran Health Administration
Authors: Husebo Bettina S. , Kerns Robert D. , Han Ling , Skanderson Melissa , Gnjidic Danijela , Allore Heather G.
Published: January 2021

Alzheimer’s disease and related dementias (ADRD), pain and chronic complex conditions (CCC) often co-occur leading to polypharmacy and with potential inappropriate medications (PIMs) use, are important risk factors for adverse drug reactions and hospitalizations in older adults. Many US veterans are at high risk for persistent pain due to age, injury or medical illness. Concerns about inadequate treatment of pain—accompanied by evidence about the analgesic efficacy of opioids—has led to an increase in the use of opioid medications to treat chronic pain in the Veterans Health Administration (VHA) and other healthcare systems. This study aims to investigate the relationship between receipt of pain medications and centrally (CNS) acting PIMs among veterans diagnosed with dementia, pain intensity, and CCC 90-days prior to hospitalization. The final analytic sample included 96,224 (81.7%) eligible older veterans from outpatient visits between October 2012–30 September 2013. We hypothesized that veterans with ADRD, and severe pain intensity may receive inappropriate pain management and CNS-acting PIMs. Seventy percent of the veterans, and especially people with ADRD, reported severe pain intensity. One in three veterans with ADRD and severe pain intensity have an increased likelihood for CNS-acting PIMs, and/or opioids. Regular assessment and re-assessment of pain among older persons with CCC, patient-centered tapering or discontinuation of opioids, alternatives to CNS-acting PIMs, and use of non-pharmacological approaches should be considered.