bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessing Nitrate Contamination Risks in Groundwater: A Machine Learning Approach
Authors: Awais Muhammad , Aslam Bilal , Maqsoom Ahsen , Khalil Umer , Ullah Fahim , Azam Sheheryar , Imran Muhammad
Published: October 2021

Groundwater is one of the primary sources for the daily water requirements of the masses, but it is subjected to contamination due to the pollutants, such as nitrate, percolating through the soil with water. Especially in built-up areas, groundwater vulnerability and contamination are of major concern, and require appropriate consideration. The present study develops a novel framework for assessing groundwater nitrate contamination risk for the area along the Karakoram Highway, which is a part of the China Pakistan Economic Corridor (CPEC) route in northern Pakistan. A groundwater vulnerability map was prepared using the DRASTIC model. The nitrate concentration data from a previous study were used to formulate the nitrate contamination map. Three machine learning (ML) models, i.e., Support Vector Machine (SVM), Multivariate Discriminant Analysis (MDA), and Boosted Regression Trees (BRT), were used to analyze the probability of groundwater contamination incidence. Furthermore, groundwater contamination probability maps were obtained utilizing the ensemble modeling approach. The models were calibrated and validated through calibration trials, using the area under the receiver operating characteristic curve method (AUC), where a minimum AUC threshold value of 80% was achieved. Results indicated the accuracy of the models to be in the range of 0.82–0.87. The final groundwater contamination risk map highlights that 34% of the area is moderately vulnerable to groundwater contamination, and 13% of the area is exposed to high groundwater contamination risk. The findings of this study can facilitate decision-making regarding the location of future built-up areas properly in order to mitigate the nitrate contamination that can further reduce the associated health risks.
Apoptotic Effect of Brassinin via Inhibition of CNOT2 and Activation of p53 and Its Combination Effect with Doxorubicin
Authors: Park Woon Yi , Park Ji Eon , Jung Ji Hoon
Published: October 2021

Brassinin derived from Chinese cabbage has been reported to act as an anti-cancer agent on prostate, liver, and colon cancer cells. However, its mechanism and impact are largely unknown in colon cancer cells. Here, we first published a report that Brassinin induces apoptosis and inhibits the survival of colon cancer cells by activating p53. We found that Brassinin induces p53 and p21 dose- and time-dependent manner in wild type of p53 colon cancer cells. Interestingly, Brassinin induces apoptosis in wild-type of p53 cancer cells, but not in null-type of p53 cancer cells dose dependently. Additionally, Brassinin induces apoptosis through L5. Furthermore, Brassinin enhanced the apoptotic effect with doxorubicin by activating p53. Altogether, our findings suggest that Brassinin is a new p53 regulator via induce apoptosis and inhibit the proliferation in colon cancer cells.
Islanding Detection Strategy for Wind Farm Based on Performance Analysis of Passive Indices Having Negligible NDZ
Authors: Shafique Nouman , Raza Safdar , Munir Hafiz Mudassir , Bukhari Syed Sabir Hussain , Ro Jong-Suk
Published: October 2021

Distributed generation (DG) resources integration into power system results in environmental and economic benefits. However, technical challenges may create many problems for the distribution system. Islanding detection is the topmost technical perspective regarding distribution system protection. This paper devised a passive islanding detection strategy that employed voltage phase angle (VPA). The VPA is selected after the performance assessment of 6 passive indices. Comparative study proves that VPA has the best accuracy and sensitivity compared to other indices parameters. The proposed technique is employed on a generic system that easily distinguished islanding situations from non-islanding cases such as load increment, load decrement, capacitor energization, capacitor de-energization, motor starting, motor unloading and various types of faults switching scenarios. The protective method is simple and has a quick interpretation algorithm as compared to other existing methods. The study is carried out on IEEE 1547 general test system in MATLAB/SIMULINK environment. The proposed strategy has nearly zero non-detection zone.
From Canterbury to the Duero—An Early Example of Becket’s Martyrdom Iconography in the Kingdom of Castile
Authors: Poza Yagüe Marta
Published: October 2021

The church of San Miguel of Almazán (Soria, Spain) houses a twelfth-century antependium ornamented with scenes of Thomas Becket’s martyrdom. Discovered during restoration works in 1936, its origin and its original location are unknown. The aim of this article is twofold—to frame its manufacture chronologically in light of recent research on late-Romanesque sculpture in Castile, and to use this information to discover who commissioned this work: The bishops of Sigüenza, whose diocese included Almazán? The canons of the monastery of Allende Duero built at the foot of Almazán’s town wall? Or, as has always been claimed, the Castilian Monarchs Alfonso VIII and Eleanor of England, who were the chief promoters of the Becket cult in their dominions? Whatever the answer, this relief is one of the earliest examples of Canterbury saint iconography in the Crown of Castile.
Tracers from Biomass Burning Emissions and Identification of Biomass Burning
Authors: Li Wenjing , Ge Pengxiang , Chen Mindong , Tang Jiajie , Cao Maoyu , Cui Yan , Hu Kun , Nie Dongyang
Published: October 2021

The major organic compositions from biomass burning emissions are monosaccharide derivatives from the breakdown of cellulose, generally accompanied by small amounts of straight-chain, aliphatic, oxygenated compounds, and terpenoids from vegetation waxes, resins/gums, and other biopolymers. Levoglucosan from cellulose can be utilized as a specific or general indicator for biomass combustion emissions in aerosol samples. There are other important compounds, such as dehydroabietic acid, syringaldehyde, syringic acid, vanillic acid, vanillin, homovanillic acid, 4-hydroxybenzoic acid, and p-coumaric acid, which are additional key indicators of biomass burning. In this review, we will address these tracers from different types of biomass burning and the methods used to identify the sources in ambient aerosols. First, the methods of inferring biomass burning types by the ratio method are summarized, including levoglucosan/mannose, syringic acid/vanillic acid, levolgucosan/K+, vanillic acid/4-hydroxybenzoic acid, levoglucosan/OC, and levoglucosan/EC to infer the sources of biomass burning, such as crop residual burning, wheat burning, leaf burning, peatland fire, and forest fire in Asia. Second, we present the source tracer ratio methods that determine the biomass combustion types and their contributions. Finally, we introduce the PCA (Principal component analysis) and PMF (Positive matrix factor) methods to identify the type of biomass burning and its contributions according to emission factors of different species in various plants such as softwood, hardwood, and grass.
The UrbEm Hybrid Method to Derive High-Resolution Emissions for City-Scale Air Quality Modeling
Authors: Ramacher Martin Otto Paul , Kakouri Anastasia , Speyer Orestis , Feldner Josefine , Karl Matthias , Timmermans Renske , Denier van der Gon Hugo , Kuenen Jeroen , Gerasopoulos Evangelos , Athanasopoulou Eleni
Published: October 2021

As cities are growing in size and complexity, the estimation of air pollution exposure requires a detailed spatial representation of air pollution levels, rather than homogenous fields, provided by global- or regional-scale models. A critical input for city-scale modeling is a timely and spatially resolved emission inventory. Bottom–up approaches to create urban-scale emission inventories can be a demanding and time-consuming task, whereas local emission rates derived from a top–down approach may lack accuracy. In the frame of this study, the UrbEm approach of downscaling gridded emission inventories is developed, investing upon existing, open access, and credible emission data sources. As a proof-of-concept, the regional anthropogenic emissions by Copernicus Atmospheric Monitoring Service (CAMS) are handled with a top–down approach, creating an added-value product of anthropogenic emissions of trace gases and particulate matter for any city (or area) of Europe, at the desired spatial resolution down to 1 km. The disaggregation is based on contemporary proxies for the European area (e.g., Global Human Settlement population data, Urban Atlas 2012, Corine, OpenStreetMap data). The UrbEm approach is realized as a fully automated software tool to produce a detailed mapping of industrial (point), (road-) transport (line), and residential/agricultural/other (area) emission sources. Line sources are of particular value for air quality studies at the urban scale, as they enable explicit treatment of line sources by models capturing among others the street canyon effect and offer an overall better representation of the critical road transport sector. The UrbEm approach is an efficient solution for such studies and constitutes a fully credible option in case high-resolution emission inventories do not exist for a city (or area) of interest. The validity of UrbEm is examined through the evaluation of high-resolution air pollution predictions over Athens and Hamburg against in situ measurements. In addition to a better spatial representation of emission sources and especially hotspots, the air quality modeling results show that UrbEm outputs, when compared to a uniform spatial disaggregation, have an impact on NO2 predictions up to 70% for urban regions with complex topographies, which corresponds to a big improvement of model accuracy (FAC2 > 0.5), especially at the source-impacted sites.
Analysis of Small-Scale Spatial Variability of Fog at Paris Charles de Gaulle Airport
Authors: Lestringant Renaud , Bergot Thierry
Published: October 2021

The small-scale variability of fog over Paris-CdG airport was explored by using the twelve visibility measurements installed on runways. The variability inside this sub-kilometre area is significant for fog, whatever the studied fog characteristics. These results confirm that about 50% of fog is thin and heterogeneous at the airport scale. This study indicated that one point of measurement may be far from the representativeness of sub-kilometre scale area and can create problems when used for verifying numerical models. The fog characteristics cannot be captured by a local measurement of visibility, and it is not possible to deduce fog extension at the local scale from a local measurement, even for low visibility such as for LVP cases (Low Visibility Procedures). This work demonstrated with a perfect forecast framework that a large dispersion of forecast scores could be obtained when using one observation at the local-scale due to representativeness errors of visibility measurements. This dispersion has the same order of magnitude as the current NWP forecast quality of fog. An attempt to quantify the scale heterogeneity of fog was made using the Gini index. This index has allowed highlighting the appearance of waves during the dissipation phase of fog.
Long-Term Study on Medium-Scale Traveling Ionospheric Disturbances Observed over the South American Equatorial Region
Authors: Essien Patrick , Figueiredo Cosme Alexandre Oliveira Barros , Takahashi Hisao , Wrasse Cristiano Max , Barros Diego , Klutse Nana Ama Browne , Lomotey Solomon Otoo , Ayorinde Toyese Tunde , Gobbi Delano , Bilibio Anderson V.
Published: October 2021

Using data collected by the GNSS dual-frequency receivers network, de-trended TEC maps were generated to identify and characterize the medium-scale traveling ionospheric disturbances (MSTIDs) over the South American equatorial region (latitude: 0∘ to 15∘ S and longitude: 30∘ to 55∘ W) during solar cycle 24 (from January 2014 to December 2019). A total of 712 MSTIDs were observed during quiet geomagnetic conditions. The Frequency of occurrence of MSTID is high during the solar maximum and low in the minimum phase. This might be due to the solar cycle dependence of gravity wave activity in the lower atmosphere and gravity wave propagation conditions in the thermosphere. The predominant daytime MSTIDs, representing 80% of the total observations, occurred in winter (June-August season in the southern hemisphere) with the secondary peak in the equinox; while the evening time MSTIDs, representing 18% of the entire events, occurred in summer (December to February season) and equinox (March to May and September to November), and the remaining 2% of the MSTIDs were observed during nighttime. The seasonal variation of the MSTID events was attributed to the source mechanisms generating them, the wind filtering and dissipation effects, and the local time dependency. The horizontal wavelengths of the MSTIDs were mostly concentrated between 500 and 800 km, with the mean value of 667 ± 131 km. The observed periods ranged from 30 to 45 min with the mean value of 36 ± 7 min. The observed horizontal phase speeds were distributed around 200 to 400 m/s, with the corresponding mean of 301 ± 75 m/s. The MSTIDs in the winter solstice and equinoctial months preferentially propagated northeastward and northwestward. Meanwhile, during the summer solstice, they propagated in all directions. The anisotropy of the propagation direction might be due to several reasons: the wind and dissipative filtering effects, ion drag effects, the primary source region, and the presence of the secondary or tertiary gravity waves in the thermosphere. Atmospheric gravity waves from strong convective sources might be the primary precursor for the observed equatorial MSTIDs. In all seasons, we noted that the MSTIDs propagating southeastward were probably excited by the likely gravity waves generated by the intertropical convergence zone (ITCZ).
On the Accuracy of Random Phase Approximation for Dynamical Structure Factors in Cold Atomic Gases
Authors: Kelly Patrick , Vitali Ettore
Published: October 2021

Many-body physics poses one of the greatest challenges to science in the 21st century. Still more daunting is the problem of accurately calculating the properties of quantum many-body systems in the strongly correlated regime. Cold atomic gases provide an excellent test ground, for both experimentalists and theorists, to study the exotic and sometimes counterintuitive behavior of quantum many-body problems. Of particular interest is the appearance of collective excitations in these systems, such as the famous Goldstone mode and the elusive Higgs mode. It is particularly important to assess the robustness of theoretical and computational techniques to study such excitations. We build on the unprecedented opportunity provided by the fact that, in some cases, exact numerical predictions can be obtained through quantum Monte Carlo. We use these predictions to assess the accuracy of the Random Phase Approximation, which is widely considered to be a method of choice for the study of the collective excitations in a cold atomic Fermi gas modeled with a Fermi–Hubbard Hamiltonian. We found good agreement between the two methodologies for the dynamic properties, particularly for the position of the Goldstone mode. We also explored the possibility of using a renormalized, effective potential in place of the physical potential. We determined that using a renormalized potential is likely too simplistic a method for improving the accuracy of generalized Random Phase Approximation and that a more sophisticated approach is needed.
High-Performance Amorphous Carbon Coated LiNi0.6Mn0.2Co0.2O2 Cathode Material with Improved Capacity Retention for Lithium-Ion Batteries
Authors: Kathribail Anish Raj , Rezqita Arlavinda , Lager Daniel , Hamid Raad , Surace Yuri , Berecibar Maitane , Van Mierlo Joeri , Hubin Annick , Jahn Marcus , Kahr Jürgen
Published: October 2021

Coating conducting polymers onto active cathode materials has been proven to mitigate issues at high current densities stemming from the limited conducting abilities of the metal-oxides. In the present study, a carbon coating was applied onto nickel-rich NMC622 via polymerisation of furfuryl alcohol, followed by calcination, for the first time. The formation of a uniform amorphous carbon layer was observed with scanning- and transmission-electron microscopy (SEM and TEM) and X-ray photoelectron spectroscopy (XPS). The stability of the coated active material was confirmed and the electrochemical behaviour as well as the cycling stability was evaluated. The impact of the heat treatment on the electrochemical performance was studied systematically and was shown to improve cycling and high current performance alike. In-depth investigations of polymer coated samples show that the improved performance can be correlated with the calcination temperatures. In particular, a heat treatment at 400 °C leads to enhanced reversibility and capacity retention even after 400 cycles. At 10C, the discharge capacity for carbon coated NMC increases by nearly 50% compared to uncoated samples. This study clearly shows for the first time the synergetic effects of a furfuryl polymer coating and subsequent calcination leading to improved electrochemical performance of nickel-rich NMC622.
Designer Exosomes: Smart Nano-Communication Tools for Translational Medicine
Authors: Harishkumar Madhyastha , Radha Madhyastha , Yuichi Nakajima , Muthukalianan Gothandam Kodiveri , Kaoru Ohe , Shiomori Koichiro , Sakai Kentaro , Nozomi Watanabe
Published: October 2021

Exosomes are the master transporters of genes, RNAs, microRNAs, proteins, and lipids. They have applications in major diseases, including cancer, cardiovascular diseases, neurological disorders, and diabetes mellitus. Delivery of the exosomes to recipient cells is governed by the functional heterogenicity of the tissues. Engineered exosomes are promising tools in tissue regeneration. In addition to their role as intracellular communication cargos, exosomes are increasingly primed as standard biomarkers in the progression of diseases, thereby solving the diagnostic dilemma. Futuristic empowerment of exosomes with OMICS strategy can undoubtedly be a bio-tool in translational medicine. This review discusses the advent transformation of exosomes in regenerative medicine and limitations that are caveats to broader applications in clinical use.
Where Do We Stand in Stem Cell Therapy for the Management of Diabetes Mellitus?—A Scientometric Research Trend Analysis from 1990 to 2020
Authors: Muthu Sathish , Jeyaraman Madhan , Jeyaraman Naveen , Rajendran Ramya Lakshmi , Gangadaran Prakash
Published: October 2021

Stem cell therapy has been considered a promising strategy in the management of both type I and type II diabetes mellitus (DM) because of its immunomodulatory and regenerative capability to restore the beta cell number and function. Various modalities of cellular therapy like transplantation of pancreatic islet cells, transplantation of pancreatic ductal stem cells, and mesenchymal stromal cell transplantation have been tried, and the modality is undergoing rapid advancements that may become the reality in the near future. In the course of its evolution, it is essential to have a comprehensive summary of the progress for a greater capacity to refine our future directives. With technological developments like data mining, graphic drawing, and information analytics combined with computational statistics, visualization of scientific metrology has become a reality. With a newer perspective, we intend to use scientometric tools including text mining, co-word analysis, word frequency analysis, co-citation analysis, cluster network analysis, to perform a systematic and comprehensive analysis of the research trend in stem cell therapy in the management of DM over the past three decades (1990–2020) and to identify the future research hotspots.
Chemo-Sensitization of CD133+ Cancer Stem Cell Enhances the Effect of Mesenchymal Stem Cell Expressing TRAIL in Non-Small Cell Lung Cancer Cell Lines
Authors: Fakiruddin Kamal Shaik , Lim Moon Nian , Nordin Norshariza , Rosli Rozita , Abdullah Syahril
Published: October 2021

Pre-clinical studies have demonstrated the efficacy of mesenchymal stem cells (MSCs) expressing tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) or MSC-TRAIL against several tumors. However, due to the existence of cancer stem cells (CSCs), some tumors, including non-small cell lung cancer (NSCLC), exhibit TRAIL resistance. This study was designed to evaluate the capacity of using first-line chemotherapies including cisplatin, 5-fluorouracil (5-FU) and vinorelbine to act as a chemo-sensitizer on CD133+ (prominin-1 positive) CSCs derived from NSCLC cell lines (A549, H460 and H2170) for the purpose of MSC-TRAIL-induced inhibition. We showed that MSC-TRAIL was resistant to all three chemotherapies compared to the NSCLC cell lines, suggesting that the chemotherapies had little effect on MSC-TRAIL viability. Pre-treatment using either cisplatin or 5-FU, but not with vinorelbine, was able to increase the efficacy of MSC-TRAIL to kill the TRAIL-resistant A549-derived CSCs. The study also demonstrated that both 5-FU and vinorelbine were an effective chemo-sensitizer, used to increase the anti-tumor effect of MSC-TRAIL against H460- and H2170-derived CSCs. Furthermore, pre-treatment using cisplatin was noted to enhance the effect of MSC-TRAIL in H460-derived CSCs; however, this effect was not detected in the H2170-derived CSCs. These findings suggest that a pre-treatment using certain chemotherapies in NSCLC could enhance the anti-tumor effect of MSC-TRAIL to target the CSCs, and therefore the combination of chemotherapies and MSC-TRAIL may serve as a novel approach for the treatment of NSCLC.
Exogenous Albumin Is Crucial for Pig Sperm to Elicit In Vitro Capacitation Whereas Bicarbonate Only Modulates Its Efficiency
Authors: Chaves Bruna Resende , Pinoti Pavaneli Ana Paula , Blanco-Prieto Olga , Pinart Elisabeth , Bonet Sergi , Zangeronimo Márcio Gilberto , Rodríguez-Gil Joan E. , Yeste Marc
Published: October 2021

This work sought to address whether the presence of exogenous bicarbonate is required for pig sperm to elicit in vitro capacitation and further progesterone-induced acrosome exocytosis. For this purpose, sperm were either incubated in a standard in vitro capacitation medium or a similar medium with different concentrations of bicarbonate (either 0 mM, 5 mM, 15 mM or 38 mM) and BSA (either 0 mg/mL or 5 mg/mL). The achievement of in vitro capacitation and progesterone-induced acrosomal exocytosis was tested through the analysis of sperm motility, plasma membrane integrity and lipid disorder, acrosome exocytosis, intracellular calcium levels, mitochondria membrane potential, O2 consumption rate and the activities of both glycogen synthase kinase 3 alpha (GSK3α) and protein kinase A (PKA). While sperm incubated in media without BSA or BSA/bicarbonate, they did not achieve in vitro capacitation; those incubated in media with BSA achieved the capacitated status under any bicarbonate concentration, even when bicarbonate was absent. Moreover, there were differences related to the concentration of bicarbonate, since sperm incubated in media with BSA and with no bicarbonate or 5 mM bicarbonate showed lower overall efficiency in achieving in vitro capacitation than those incubated in the presence of BSA and 15 mM or 38 mM bicarbonate. Additionally, at the end of the experiment, sperm incubated in the presence of BSA and 38 mM bicarbonate showed significantly (p < 0.05) lower values of motility and plasma membrane integrity than those incubated in media with BSA and lower concentrations of bicarbonate. In conclusion, BSA is instrumental for pig sperm to elicit in vitro capacitation and trigger the subsequent progesterone-induced acrosome exocytosis. Furthermore, while exogenous bicarbonate does not seem to be essential to launch sperm capacitation, it does modulate its efficiency.
Effect of Bariatric Surgery on Metabolic Diseases and Underlying Mechanisms
Authors: Ji Yu , Lee Hangil , Kaura Shawn , Yip James , Sun Hao , Guan Longfei , Han Wei , Ding Yuchuan
Published: October 2021

Obesity is a highly prevalent public health concern, attributed to multifactorial causes and limited in treatment options. Several comorbidities are closely associated with obesity such as the development of type 2 diabetes mellitus (T2DM), cardiovascular and cerebrovascular diseases, and nonalcoholic fatty liver disease (NAFLD). Bariatric surgery, which can be delivered in multiple forms, has been remarked as an effective treatment to decrease the prevalence of obesity and its associated comorbidities. The different types of bariatric surgery create a variety of new pathways for food to metabolize in the body and truncate the stomach’s caliber. As a result, only a small quantity of food is tolerated, and the body mass index noticeably decreases. This review describes the improvements of obesity and its comorbidities following bariatric surgery and their mechanism of improvement. Additionally, endocrine function improvements after bariatric surgery, which contributes to the patients’ health improvement, are described, including the role of glucagon-like peptide-1 (GLP-1), fibroblast growth factors 19 and 21 (FGF-19, FGF-21), and pancreatic peptide YY (PYY). Lastly, some of the complications of bariatric surgery, including osteoporosis, iron deficiency/anemia, and diarrhea, as well as their potential mechanisms, are described.
Advance in Hydrothermal Bio-Oil Preparation from Lignocellulose: Effect of Raw Materials and Their Tissue Structures
Authors: Zhang Libo , Dou Xintong , Yang Zhilin , Yang Xiao , Guo Xuqiang
Published: October 2021

The conversion of abundant forest- and agricultural-residue-based lignocellulosic materials into high-quality bio-oil by the mild hydrothermal method has great potential in the field of biomass utilization. Some excellent research on biomass hydrothermal process has been completed, including temperature, time, catalyst addition, etc. Meanwhile, some research related to the biomass raw material tissue structure has been illustrated by adopting mode components (cellulose, hemicellulose, lignin, protein, lipid, etc.) or their mixtures. The interesting fact is that although some real lignocellulose has approximate composition, their hydrothermal products and distributions show individual differences, which means the interaction within biomass raw material components tremendously affected the reaction pathway. Unfortunately, to our knowledge, there is no review article with a specific focus on the effects of raw materials and their tissue structure on the lignocellulose hydrothermal process. In this review, research progress on the effects of model and mixed cellulose/hemicellulose/lignin effects on hydrothermal products is initially summarized. Additionally, the real lignocellulosic raw materials structure effects during the thermal process are summed up. This article will inspire researchers to focus more attention on wood fiber biomass conversion into liquid fuels or high-value-added chemicals, as well as promote the development of world energy change.
Pre-Clinical Models in Implant Dentistry: Past, Present, Future
Authors: Blanc-Sylvestre Nicolas , Bouchard Philippe , Chaussain Catherine , Bardet Claire
Published: October 2021

Biomedical research seeks to generate experimental results for translation to clinical settings. In order to improve the transition from bench to bedside, researchers must draw justifiable conclusions based on data from an appropriate model. Animal testing, as a prerequisite to human clinical exposure, is performed in a range of species, from laboratory mice to larger animals (such as dogs or non-human primates). Minipigs appear to be the animal of choice for studying bone surgery around intraoral dental implants. Dog models, well-known in the field of dental implant research, tend now to be used for studies conducted under compromised oral conditions (biofilm). Regarding small animal models, research studies mostly use rodents, with interest in rabbit models declining. Mouse models remain a reference for genetic studies. On the other hand, over the last decade, scientific advances and government guidelines have led to the replacement, reduction, and refinement of the use of all animal models in dental implant research. In new development strategies, some in vivo experiments are being progressively replaced by in vitro or biomaterial approaches. In this review, we summarize the key information on the animal models currently available for dental implant research and highlight (i) the pros and cons of each type, (ii) new levels of decisional procedures regarding study objectives, and (iii) the outlook for animal research, discussing possible non-animal options.
IL-36α and Lipopolysaccharide Cooperatively Induce Autophagy by Triggering Pro-Autophagic Biased Signaling
Authors: Al-Luhaibi Zaid I. I. , Dernovics Áron , Seprényi György , Ayaydin Ferhan , Boldogkői Zsolt , Veréb Zoltán , Megyeri Klára
Published: October 2021

Autophagy is an intracellular catabolic process that controls infections both directly and indirectly via its multifaceted effects on the innate and adaptive immune responses. It has been reported that LPS stimulates this cellular process, whereas the effect of IL-36α on autophagy remains largely unknown. We therefore investigated how IL-36α modulates the endogenous and LPS-induced autophagy in THP-1 cells. The levels of LC3B-II and autophagic flux were determined by Western blotting. The intracellular localization of LC3B was measured by immunofluorescence assay. The activation levels of signaling pathways implicated in autophagy regulation were evaluated by using a phosphokinase array. Our results showed that combined IL-36α and LPS treatment cooperatively increased the levels of LC3B-II and Beclin-1, stimulated the autophagic flux, facilitated intracellular redistribution of LC3B, and increased the average number of autophagosomes per cell. The IL36α/LPS combined treatment increased phosphorylation of STAT5a/b, had minimal effect on the Akt/PRAS40/mTOR pathway, and reduced the levels of phospho-Yes, phospho-FAK, and phospho-WNK1. Thus, this cytokine/PAMP combination triggers pro-autophagic biased signaling by several mechanisms and thus cooperatively stimulates the autophagic cascade. An increased autophagic activity of innate immune cells simultaneously exposed to IL-36α and LPS may play an important role in the pathogenesis of Gram-negative bacterial infections.
OM-85 Broncho-Vaxom®, a Bacterial Lysate, Reduces SARS-CoV-2 Binding Proteins on Human Bronchial Epithelial Cells
Authors: Fang Lei , Zhou Liang , Tamm Michael , Roth Michael
Published: October 2021

In clinical studies, OM-85 Broncho-Vaxom®, a bacterial lysate, reduced viral respiratory tract infection. Infection of epithelial cells by SARS-CoV-2 depends on the interaction of its spike-protein (S-protein) with host cell membrane proteins. In this study, we investigated the effect of OM-85 on the expression of S-protein binding proteins by human bronchial epithelial cells. Human bronchial epithelial cells were treated with OM-85 over 5 days. The expression of SARS-CoV-2 receptor angiotensin converting enzyme 2 (ACE2), transmembrane protease serine subtype 2 (TMPRSS2), dipeptidyl peptidase-4 (DPP4), and a disintegrin and metalloprotease 17 (ADAM17) were determined by Western blotting and quantitative RT-PCR. Soluble (s)ACE2, heparan sulfate, heparanase, and hyaluronic acid were assessed by ELISA. OM-85 significantly reduced the expression of ACE2 (p < 0.001), TMPRSS2 (p < 0.001), DPP4 (p < 0.005), and cellular heparan sulfate (p < 0.01), while ADAM17 (p < 0.02) expression was significantly upregulated. Furthermore, OM-85 increased the level of sACE2 (p < 0.05), hyaluronic acid (p < 0.002), and hyaluronan synthase 1 (p < 0.01). Consequently, the infection by a SARS-CoV-2 spike protein pseudo-typed lentivirus was reduced in cells pretreated with OM-85. All effects of OM-85 were concentration- and time-dependent. The results suggest that OM-85 might reduce the binding of SARS-CoV-2 S-protein to epithelial cells by modification of host cell membrane proteins and specific glycosaminoglycans. Thus, OM-85 might be considered as an add-on for COVID-19 therapy.
A Smart Health (sHealth)-Centric Method toward Estimation of Sleep Deficiency Severity from Wearable Sensor Data Fusion
Authors: Rahman Md Juber , Morshed Bashir I. , Preza Chrysanthe
Published: October 2021

Sleep deficiency impacts the quality of life and may have serious health consequences in the long run. Questionnaire-based subjective assessment of sleep deficiency has many limitations. On the other hand, objective assessment of sleep deficiency is challenging. In this study, we propose a polysomnography-based mathematical model for computing baseline sleep deficiency severity score and then investigated the estimation of sleep deficiency severity using features available only from wearable sensor data including heart rate variability and single-channel electroencephalography for a dataset of 500 subjects. We used Monte-Carlo feature selection (MCFS) and inter-dependency discovery for selecting the best features and removing multi-collinearity. For developing the Regression model we investigated both the frequentist and the Bayesian approaches. An artificial neural network achieved the best performance of RMSE = 5.47 and an R-squared value of 0.67 for sleep deficiency severity estimation. The developed method is comparable to conventional methods of Functional Outcome of Sleep Questionnaire and Epworth Sleepiness Scale for assessing the impact of sleep apnea on sleep deficiency. Moreover, the results pave the way for reliable and interpretable sleep deficiency severity estimation using single-channel EEG.
Access to Mental Health Care during the First Wave of the COVID-19 Pandemic in Italy: Results from the COMET Multicentric Study
Authors: Menculini Giulia , Tortorella Alfonso , Albert Umberto , Carmassi Claudia , Carrà Giuseppe , Cirulli Francesca , Dell’Osso Bernardo , Luciano Mario , Nanni Maria Giulia , Pompili Maurizio , Sani Gabriele , Volpe Umberto , Fiorillo Andrea , Sampogna Gaia
Published: October 2021

The COVID-19 pandemic represents an unprecedented public health emergency, with consequences at the political, social, and economic levels. Mental health services have been called to play a key role in facing the impact of the pandemic on the mental health of the general population. In the period March–May 2020, an online survey was implemented as part of the Covid Mental Health Trial (COMET), a multicentric collaborative study carried out in Italy, one of the Western countries most severely hit by the pandemic. The present study aims to investigate the use of mental health resources during the first wave of the pandemic. The final sample consisted of 20,712 participants, mainly females (N = 14,712, 71%) with a mean age of 40.4 ± 14.3 years. Access to mental health services was reported in 7.7% of cases. Among those referred to mental health services, in 93.9% of cases (N = 1503 subjects) a psychological assessment was requested and in 15.7% of cases (N = 252) a psychiatric consultation. People reporting higher levels of perceived loneliness (OR 1.079, 95% CI 1.056–1.101, p < 0.001), practicing smart-working (OR 1.122, 95% CI 0.980–1.285, p = 0.095), using avoidant (OR 1.586, 95% CI 1.458–1.725, p < 0.001) and approach (OR 1.215, 95% CI 1.138–1.299, p < 0.001) coping strategies more frequently accessed mental health services. On the other hand, having higher levels of perceived social support (OR 0.833, 95% CI 0.795–0.873, p < 0.001) was associated with a reduced probability to access mental health services. The COVID-19 pandemic represents a new threat to the mental health and well-being of the general population, therefore specific strategies should be implemented to promote access to mental healthcare during the pandemic and afterwards.
Molecular Classification of Breast Cancer Utilizing Long Non-Coding RNA (lncRNA) Transcriptomes Identifies Novel Diagnostic lncRNA Panel for Triple-Negative Breast Cancer
Authors: Shaath Hibah , Elango Ramesh , Alajez Nehad M.
Published: October 2021

Breast cancer remains the world’s most prevalent cancer, responsible for around 685,000 deaths globally despite international research efforts and advances in clinical management. While estrogen receptor positive (ER+), progesterone receptor positive (PR+), and human epidermal growth factor receptor positive (HER2+) subtypes are easily classified and can be targeted, there remains no direct diagnostic test for triple-negative breast cancer (TNBC), except for the lack of receptors expression. The identification of long non-coding RNAs (lncRNAs) and the roles they play in cancer progression has recently proven to be beneficial. In the current study, we utilize RNA sequencing data to identify lncRNA-based biomarkers associated with TNBC, ER+ subtypes, and normal breast tissue. The Marker Finder algorithm identified the lncRNA transcript panel most associated with each molecular subtype and the receiver operating characteristic (ROC) analysis was used to validate the diagnostic potential (area under the curve (AUC) of ≥8.0 and p value < 0.0001). Focusing on TNBC, findings from the discovery cohort were validated in an additional two cohorts, identifying 13 common lncRNA transcripts enriched in TNBC. Binary regression analysis identified a four lncRNA transcript signature (ENST00000425820.1, ENST00000448208.5, ENST00000521666.1, and ENST00000650510.1) with the highest diagnostic power for TNBC. The ENST00000671612.1 lncRNA transcript correlated with worse refractory free survival (RFS). Our data provides a step towards finding a novel diagnostic lncRNA-based panel for TNBC with potential therapeutic implications.
Disruption of Tumor Suppressors HNF4α/HNF1α Causes Tumorigenesis in Liver
Authors: Teeli Aamir Salam , Łuczyńska Kamila , Haque Effi , Gayas Mohmmad Abrar , Winiarczyk Dawid , Taniguchi Hiroaki
Published: October 2021

The hepatocyte nuclear factor-4α (HNF4α) and hepatocyte nuclear factor-1α (HNF1α) are transcription factors that influence the development and maintenance of homeostasis in a variety of tissues, including the liver. As such, disruptions in their transcriptional networks can herald a number of pathologies, such as tumorigenesis. Largely considered tumor suppressants in liver cancer, these transcription factors regulate key events of inflammation, epithelial–mesenchymal transition, metabolic reprogramming, and the differentiation status of the cell. High-throughput analysis of cancer cell genomes has identified a number of hotspot mutations in HNF1α and HNF4α in liver cancer. Such results also showcase HNF1α and HNF4α as important therapeutic targets helping us step into the era of personalized medicine. In this review, we update current findings on the roles of HNF1α and HNF4α in liver cancer development and progression. It covers the molecular mechanisms of HNF1α and HNF4α dysregulation and also highlights the potential of HNF4α as a therapeutic target in liver cancer.
Functional and Clinical Significance of Dysregulated microRNAs in Liver Cancer
Authors: Huang Po-Shuan , Liao Chia-Jung , Huang Ya-Hui , Yeh Chau-Ting , Chen Cheng-Yi , Tang Hui-Chi , Chang Cheng-Chih , Lin Kwang-Huei
Published: October 2021

Liver cancer is the leading cause of cancer-related mortality in the world. This mainly reflects the lack of early diagnosis tools and effective treatment methods. MicroRNAs (miRNAs) are a class of non-transcribed RNAs, some of which play important regulatory roles in liver cancer. Here, we discuss microRNAs with key impacts on liver cancer, such as miR-122, miR-21, miR-214, and miR-199. These microRNAs participate in various physiological regulatory pathways of liver cancer cells, and their modulation can have non-negligible effects in the treatment of liver cancer. We discuss whether these microRNAs can be used for better clinical diagnosis and/or drug development. With the advent of novel technologies, fast, inexpensive, and non-invasive RNA-based biomarker research has become a new mainstream approach. However, the clinical application of microRNA-based markers has been limited by the high sequence similarity among them and the potential for off-target problems. Therefore, researchers particularly value microRNAs that are specific to or have special functions in liver cancer. These include miR-122, which is specifically expressed in the liver, and miR-34, which is necessary for the replication of the hepatitis C virus in liver cancer. Clinical treatment drugs have been developed based on miR-34 and miR-122 (MRX34 and Miravirsen, respectively), but their side effects have not yet been overcome. Future research is needed to address these weaknesses and establish a feasible microRNA-based treatment strategy for liver cancer.
Cell-Cell Fusion Mediated by Viruses and HERV-Derived Fusogens in Cancer Initiation and Progression
Authors: Dittmar Thomas , Weiler Julian , Luo Tianjiao , Hass Ralf
Published: October 2021

Cell fusion is a well-known, but still scarcely understood biological phenomenon, which might play a role in cancer initiation, progression and formation of metastases. Although the merging of two (cancer) cells appears simple, the entire process is highly complex, energy-dependent and tightly regulated. Among cell fusion-inducing and -regulating factors, so-called fusogens have been identified as a specific type of proteins that are indispensable for overcoming fusion-associated energetic barriers and final merging of plasma membranes. About 8% of the human genome is of retroviral origin and some well-known fusogens, such as syncytin-1, are expressed by human (cancer) cells. Likewise, enveloped viruses can enable and facilitate cell fusion due to evolutionarily optimized fusogens, and are also capable to induce bi- and multinucleation underlining their fusion capacity. Moreover, multinucleated giant cancer cells have been found in tumors derived from oncogenic viruses. Accordingly, a potential correlation between viruses and fusogens of human endogenous retroviral origin in cancer cell fusion will be summarized in this review.
Liquid Biopsy to Detect Minimal Residual Disease: Methodology and Impact
Authors: Honoré Natasha , Galot Rachel , van Marcke Cédric , Limaye Nisha , Machiels Jean-Pascal
Published: October 2021

One reason why some patients experience recurrent disease after a curative-intent treatment might be the persistence of residual tumor cells, called minimal residual disease (MRD). MRD cannot be identified by standard radiological exams or clinical evaluation. Tumor-specific alterations found in the blood indirectly diagnose the presence of MRD. Liquid biopsies thus have the potential to detect MRD, allowing, among other things, the detection of circulating tumor DNA (ctDNA), circulating tumor cells (CTC), or tumor-specific microRNA. Although liquid biopsy is increasingly studied, several technical issues still limit its clinical applicability: low sensitivity, poor standardization or reproducibility, and lack of randomized trials demonstrating its clinical benefit. Being able to detect MRD could give clinicians a more comprehensive view of the risk of relapse of their patients and could select patients requiring treatment escalation with the goal of improving cancer survival. In this review, we are discussing the different methodologies used and investigated to detect MRD in solid cancers, their respective potentials and issues, and the clinical impacts that MRD detection will have on the management of cancer patients.
Long Term Efficacy and Assessment of Tumor Response of Transarterial Chemoembolization in Neuroendocrine Liver Metastases: A 15-Year Monocentric Experience
Authors: Touloupas Caroline , Faron Matthieu , Hadoux Julien , Deschamps Frédéric , Roux Charles , Ronot Maxime , Yevich Steven , Joskin Julien , Gelli Maximiliano , Barbé Rémy , Lamartina Livia , Tissot Hubert , Scoazec Jean-Yves , Malka David , Ducreux Michel , Baudin Eric , de Baère Thierry , Tselikas Lambros
Published: October 2021

Background: transarterial chemoembolization (TACE) is an established treatment for neuroendocrine tumor (NET) liver metastases. The aim was to evaluate the long-term treatment efficacy of TACE for NET liver metastases, and correlate imaging response with survival. Methods: this IRB-approved, single-center, retrospective study evaluated all TACE procedures performed for NET liver metastases from 2003–2017 for imaging tumor response (RECIST and mRECIST), time to liver progression (TTLP), time to untreatable progression with TACE (TTUP), and overall survival (OS). Patient, tumor, and treatment characteristics were analyzed as prognostic factors. Survival curves according to the Kaplan–Meier method were compared by Log-rank test. Tumor responses according to RECIST and mRECIST were correlated with OS. Results: 555 TACE procedures were performed in 202 NET patients (38% grade 1, 60% grade 2) with primary tumors originating from pancreas, small bowel, and lung (39, 26, and 22% respectively). Median follow-up was 8.2 years (90–139 months). Median TTLP and TTUP were 19.3 months (95%CI 16.3–22.3) and 26.2 months (95%CI 22.3–33.1), respectively. Median OS was 5.3 years (95%CI 4.2–6.7), and was higher among mRECIST responders (80.5 months; 95%CI 64.6–89.8) than in non-responders (39.6 months; 95%CI = 32.8–60.2; p < 0.001). In multivariable analysis, age, tumor grade and liver involvement predicted worse OS, whereas administration of somatostatin analogs correlated with improved OS. Conclusion: TACE for NET liver metastases provides objective response and sustained local disease control rates. RECIST and mRECIST responses correlate with OS.
Tetraspanin 5 (TSPAN5), a Novel Gatekeeper of the Tumor Suppressor DLC1 and Myocardin-Related Transcription Factors (MRTFs), Controls HCC Growth and Senescence
Authors: Schreyer Laura , Mittermeier Constanze , Franz Miriam J. , Meier Melanie A. , Martin Dietmar E. , Maier Kerstin C. , Huebner Kerstin , Schneider-Stock Regine , Singer Stephan , Holzer Kerstin , Fischer Dagmar , Ribback Silvia , Liebl Bernhard , Gudermann Thomas , Aigner Achim , Muehlich Susanne
Published: October 2021

Human hepatocellular carcinoma (HCC) is among the most lethal and common cancers in the human population, and new molecular targets for therapeutic intervention are urgently needed. Deleted in liver cancer 1 (DLC1) was originally identified as a tumor suppressor gene in human HCC. DLC1 is a Rho-GTPase-activating protein (RhoGAP) which accelerates the return of RhoGTPases to an inactive state. We recently described that the restoration of DLC1 expression induces cellular senescence. However, this principle is not amenable to direct therapeutic targeting. We therefore performed gene expression profiling for HepG2 cells depleted of DLC1 to identify druggable gene targets mediating the effects of DLC1 on senescence induction. This approach revealed that versican (VCAN), tetraspanin 5 (TSPAN5) and N-cadherin (CDH2) were strongly upregulated upon DLC1 depletion in HCC cells, but only TSPAN5 affected the proliferation of HCC cells and human HCC. The depletion of TSPAN5 induced oncogene-induced senescence (OIS), mediated by the p16INK4a/pRb pathways. Mechanistically, silencing TSPAN5 reduced actin polymerization and thereby myocardin-related transcription factor A- filamin A (MRTF-A-FLNA) complex formation, resulting in decreased expression of MRTF/SRF-dependent target genes and senescence induction in vitro and in vivo. Our results identify TSPAN5 as a novel druggable target for HCC.