bluuebunny/crossref_metadata_2025 huggingface dataset:
Phthalate Esters in Tap Water, Southern Thailand: Daily Exposure and Cumulative Health Risk in Infants, Lactating Mothers, Pregnant and Nonpregnant Women
Authors: Okpara Kingsley Ezechukwu , Phoungthong Khamphe , Agbozu Iwekumo , Edwin-Isotu Edeh , Techato Kuaanan
Published: February 2022

Human exposure to phthalate esters (PAEs) via drinking water has generated public health concerns due to their endocrine disruptive abilities. This study reports on the occurrence and fate of six PAEs in raw and tap water samples collected from provincial waterworks located in Songkhla Province, Southern Thailand. In addition, the daily exposure and cumulative health risk of susceptible populations due to drinking tap water were evaluated by using four different reference dose (RfDs) sources. The maximum concentrations of PAEs in raw water were between 1.68 and 4.84 and 0.52 and 1.24 µg/L in tap water. Moreover, the levels of PAEs in the tap water samples indicated the poor PAEs removal efficiency of the conventional treatment process (59.9–69.1%). The contribution of water to the daily intake of PAEs did not exceed 0.37% in all the groups. Furthermore, both the individual and cumulative risk assessment showed negligible noncarcinogenic and antiandrogenic risk for all the groups. Nevertheless, the cumulative risk showed an increasing trend in the order of infants > lactating mothers > pregnant women > nonpregnant women, suggesting that infants are more vulnerable. In additional, the newly proposed RfDAA yielded higher hazard quotient and hazard index estimates, which indicates it is a more sensitive tool than other RfDs for the assessment of the individual and mixture risk of pollutants. The carcinogenic risk of DEHP was acceptable in every group. However, we recommend a future cumulative risk assessment of vulnerable groups considering their simultaneous exposure to all chemicals that have antiandrogenic effects via tap water.
Changes in the Lifestyle of the Spanish University Population during Confinement for COVID-19
Authors: Sumalla-Cano Sandra , Forbes-Hernández Tamara , Aparicio-Obregón Silvia , Crespo Jorge , Eléxpuru-Zabaleta María , Gracia-Villar Mónica , Giampieri Francesca , Elío Iñaki
Published: February 2022

The aim of this study was to evaluate the influence of the lockdown due to the COVID-19 pandemic, on eating and physical activity behavior, in a university population. A healthy diet such as the Mediterranean Diet (MD) pattern, rich in fruit and vegetables, can prevent degenerative diseases such as obesity, diabetes, cardiovascular diseases, etc. We conducted a cross-sectional study and data were collected by an anonymous online questionnaire. Participants completed a survey consisting of 3 sections: sociodemographic data; dietary behavior and physical activity; the Mediterranean Diet questionnaire (MEDAS-14) and the Emotional Eater Questionnaire (EEQ). A total of 168 participants completed the questionnaire: 66.7% were women, 79.2% were from Spain, 76.8% were students, 76.2% lived in their family home and 66.1% were of normal weight. During lockdown our population shopped for groceries 1 time or less per week (76.8%); maintained the same consumption of fruits (45.2%), vegetables (50.6%), dairy products (61.9%), pulses (64.9%), fish/seafood (57.7%), white meat (77.4%), red and processed meat (71.4%), pastries and snacks (48.2%), rice/pasta/potatoes (70.2%) and nuts (62.5%), spirits (98.8%) and sugary drinks (91.7%). Cooking time increased (73.2%) and the consumption decreased of low alcohol drinks (60.1%), spirits (75%) and sugary drinks (57.1%), and physical activity also diminished (49.4%). University Employees (UE) gained more weight (1.01 ± 0.02) than students (0.99 ± 0.03) (p < 0.05) during the confinement period. A total of 79.8% of the participants obtained a Medium/High Adherence to the MD during lockdown. Emotional and very emotional eaters were higher in the female group (p < 0.01). In the event of further confinement, strategies should be implemented to promote a balanced and healthy diet together with the practice of physical activity, taking special care of the female and UE groups.
A Vector Field Approach to Estimating Environmental Exposure Using Human Activity Data
Authors: Guo Zijian , Liu Xintao , Zhao Pengxiang
Published: February 2022

Environmental exposure of people plays an important role in assessing the quality of human life. The most existing methods that estimate the environmental exposure either focus on the individual level or do not consider human mobility. This paper adopts a vector field generated from the observed locations of human activities to model the environmental exposure at the population level. An improved vector-field-generation method was developed by considering people’s decision-making factors, and we proposed two indicators, i.e., the total exposure indicator (TEI) and the average exposure indicator (AEI), to assess various social groups’ environmental exposure. A case study about the risky environmental exposure of coronavirus disease 2019 (COVID-19) was conducted in Guangzhou, China. Over 900 participants with various socioeconomic backgrounds were involved in the questionnaire, and the survey-based activity locations were extracted to generate the vector field using the improved method. COVID-19 pandemic exposure (or risk) was estimated for different social groups. The findings show that people in the low-income group have an 8% to 10% higher risk than those in the high-income group. This new method of vector field may benefit geographers and urban researchers, as it provides opportunities to integrate human activities into the metrics of pandemic risk, spatial justice, and other environmental exposures.
Measuring Spatial Accessibility to Hospitals of Acute Myocardial Infarction in Multi Period Scale: A Case Study in Shijingshan District, Beijing, China
Authors: Su Yuwei , Wang Jingyong , Wang Jiangping , Wang Guoen
Published: February 2022

The hospital accessibility of Acute Myocardial Infarction (AMI) emergency treatment is of great importance, not only for improving the survival rate of patients but also for protecting the basic human right to health care. Traditional AMI emergency treatment research often does not consider ways to shorten the travel time to hospitals for AMI patients and does not reflect the actual time it takes to travel to hospitals, which is critical to AMI emergency treatment. To avoid these shortcomings, this study proposes a method of accessibility measurement based on Web Mapping API (Application Programming Interface) to obtain travel time to hospitals during different periods, then calculated the AMI hospital accessibility based on these detailed data. This study considered the Shijingshan District, Beijing, China, as an empirical case. The study discovered significant differences in the temporal and spatial characteristics of the AMI hospital accessibility on weekdays and weekends. The analysis revealed that travel time to hospitals and traffic congestion are the two main factors affecting AMI hospital accessibility. The research results shed new light on the accessibility of urban medical facilities and provide a scientific basis with which local governments can optimize the spatial structure of medical facilities.
Repertoire and Efficiency of Students’ Strategies for General-Reference Maps
Authors: Trokšiar David , Havelková Lenka , Hanus Martin
Published: February 2022

Maps are not just powerful tools to communicate spatial information; they also have significant educational potential to develop students’ knowledge, skills, and thinking. To fully exploit this potential, deep research is needed into map-use processes considering the variability of map types and the cognitive complexity of map operations. Whereas research on map reading is relatively common, the research into cognitively more demanding operations is lacking. Therefore, this study employed an eye-tracking experiment combined with a follow-up questionnaire with 20 upper-secondary students to examine the strategies students choose when analyzing general-reference maps. Specifically, attention is paid to the strategy repertoire, distribution, efficiency, and adaptiveness of strategy choice. Subsequently, the study is focused on students’ perception of strategies. According to the results, participants used a rich repertoire of strategies (although many of them unconsciously) and adapted the strategy choice to task demands. The solution efficiency varied among task demands, as did the efficiency of individual strategies and their combinations. The research design allowed a comparison with earlier studies on strategies for thematic map use. The results should be of interest to cartographers (to design effective educational tools) and educators (to educate map users complexly and effectively).
Lymphatics in Tumor Progression and Immunomodulation
Authors: Li Claire Y. , Brown Stav , Mehrara Babak J. , Kataru Raghu P.
Published: February 2022

The lymphatic system consists of a unidirectional hierarchy of vessels responsible for fluid homeostasis, lipid absorption, and the transport of immune cells and antigens to secondary lymphoid organs. In cancer, lymphatics play complex and heterogenous roles that can promote or inhibit tumor growth. While lymphatic proliferation and remodeling promote tumor dissemination, functional lymphatics are necessary for generating an effective immune response. Recent reports have noted lymphatic-dependent effects on the efficacy of immunotherapy. These findings suggest that the impact of lymphatic vessels on tumor progression is organ- and context-specific and that a greater understanding of the interaction of tumor cells, lymphatics, and the tumor microenvironment can unveil novel therapies.
Review of the Mechanisms of Snake Venom Induced Pain: It’s All about Location, Location, Location
Authors: Nielsen Vance G. , Wagner Michael T.
Published: February 2022

Pain—acute, chronic and debilitating—is the most feared neurotoxicity resulting from a survivable venomous snake bite. The purpose of this review is to present in a novel paradigm what we know about the molecular mechanisms responsible for pain after envenomation. Progressing from known pain modulating peptides and enzymes, to tissue level interactions with venom resulting in pain, to organ system level pain syndromes, to geographical level distribution of pain syndromes, the present work demonstrates that understanding the mechanisms responsible for pain is dependent on “location, location, location”. It is our hope that this work can serve to inspire the molecular and epidemiologic investigations needed to better understand the neurotoxic mechanisms responsible for these snake venom mediated diverse pain syndromes and ultimately lead to agent specific treatments beyond anti-venom alone.
Matrix Metalloproteinase-10 in Kidney Injury Repair and Disease
Authors: Sun Xiaoli , Liu Youhua
Published: February 2022

Matrix metalloproteinase-10 (MMP-10) is a zinc-dependent endopeptidase with the ability to degrade a broad spectrum of extracellular matrices and other protein substrates. The expression of MMP-10 is induced in acute kidney injury (AKI) and chronic kidney disease (CKD), as well as in renal cell carcinoma (RCC). During the different stages of kidney injury, MMP-10 may exert distinct functions by cleaving various bioactive substrates including heparin-binding epidermal growth factor (HB-EGF), zonula occludens-1 (ZO-1), and pro-MMP-1, -7, -8, -9, -10, -13. Functionally, MMP-10 is reno-protective in AKI by promoting HB-EGF-mediated tubular repair and regeneration, whereas it aggravates podocyte dysfunction and proteinuria by disrupting glomerular filtration integrity via degrading ZO-1. MMP-10 is also involved in cancerous invasion and emerges as a promising therapeutic target in patients with RCC. As a secreted protein, MMP-10 could be detected in the circulation and presents an inverse correlation with renal function. Due to the structural similarities between MMP-10 and the other MMPs, development of specific inhibitors targeting MMP-10 is challenging. In this review, we summarize our current understanding of the role of MMP-10 in kidney diseases and discuss the potential mechanisms of its actions.
Pharmacological Inhibition of Spermine Oxidase Suppresses Excitotoxicity Induced Neuroinflammation in Mouse Retina
Authors: Alfarhan Moaddey , Liu Fang , Shan Shengshuai , Pichavaram Prahalathan , Somanath Payaningal R. , Narayanan S. Priya
Published: February 2022

Polyamine oxidation plays a major role in neurodegenerative diseases. Previous studies from our laboratory demonstrated that spermine oxidase (SMOX, a member of the polyamine oxidase family) inhibition using MDL 72527 reduced neurodegeneration in models of retinal excitotoxicity and diabetic retinopathy. However, the mechanisms behind the neuroprotection offered by SMOX inhibition are not completely studied. Utilizing the experimental model of retinal excitotoxicity, the present study determined the impact of SMOX blockade in retinal neuroinflammation. Our results demonstrated upregulation in the number of cells positive for Iba-1 (ionized calcium-binding adaptor molecule 1), CD (Cluster Differentiation) 68, and CD16/32 in excitotoxicity-induced retinas, while MDL 72527 treatment reduced these changes, along with increases in the number of cells positive for Arginase1 and CD206. When retinal excitotoxicity upregulated several pro-inflammatory genes, MDL 72527 treatment reduced many of them and increased anti-inflammatory genes. Furthermore, SMOX inhibition upregulated antioxidant signaling (indicated by elevated Nrf2 and HO-1 levels) and reduced protein-conjugated acrolein in excitotoxic retinas. In vitro studies using C8-B4 cells showed changes in cellular morphology and increased reactive oxygen species formation in response to acrolein (a product of SMOX activity) treatment. Overall, our findings indicate that the inhibition SMOX pathway reduced neuroinflammation and upregulated antioxidant signaling in the retina.
Effect of Aphidicolin, a Reversible Inhibitor of Eukaryotic Nuclear DNA Replication, on the Production of Genetically Modified Porcine Embryos by CRISPR/Cas9
Authors: Navarro-Serna Sergio , Piñeiro-Silva Celia , Luongo Chiara , Parrington John , Romar Raquel , Gadea Joaquín
Published: February 2022

Mosaicism is the most important limitation for one-step gene editing in embryos by CRISPR/Cas9 because cuts and repairs sometimes take place after the first DNA replication of the zygote. To try to minimize the risk of mosaicism, in this study a reversible DNA replication inhibitor was used after the release of CRISPR/Cas9 in the cell. There is no previous information on the use of aphidicolin in porcine embryos, so the reversible inhibition of DNA replication and the effect on embryo development of different concentrations of this drug was first evaluated. The effect of incubation with aphidicolin was tested with CRISPR/Cas9 at different concentrations and different delivery methodologies. As a result, the reversible inhibition of DNA replication was observed, and it was concentration dependent. An optimal concentration of 0.5 μM was established and used for subsequent experiments. Following the use of this drug with CRISPR/Cas9, a halving of mosaicism was observed together with a detrimental effect on embryo development. In conclusion, the use of reversible inhibition of DNA replication offers a way to reduce mosaicism. Nevertheless, due to the reduction in embryo development, it would be necessary to reach a balance for its use to be feasible.
Multi-Omic Profiling of Macrophages Treated with Phospholipids Containing Omega-3 and Omega-6 Fatty Acids Reveals Complex Immunomodulatory Adaptations at Protein, Lipid and Metabolic Levels
Authors: Maurício Tatiana , Aveiro Susana , Guedes Sofia , Lopes Diana , Melo Tânia , Neves Bruno M. , Domingues Rosário , Domingues Pedro
Published: February 2022

In recent years, several studies have demonstrated that polyunsaturated fatty acids have strong immunomodulatory properties, altering several functions of macrophages. In the present work, we sought to provide a multi-omic approach combining the analysis of the lipidome, the proteome, and the metabolome of RAW 264.7 macrophages supplemented with phospholipids containing omega-3 (PC 18:0/22:6; ω3-PC) or omega-6 (PC 18:0/20:4; ω6-PC) fatty acids, alone and in the presence of lipopolysaccharide (LPS). Supplementation of macrophages with ω3 and ω6 phospholipids plus LPS produced a significant reprogramming of the proteome of macrophages and amplified the immune response; it also promoted the expression of anti-inflammatory proteins (e.g., pleckstrin). Supplementation with the ω3-PC and ω6-PC induced significant changes in the lipidome, with a marked increase in lipid species linked to the inflammatory response, attributed to several pro-inflammatory signalling pathways (e.g., LPCs) but also to the pro-resolving effect of inflammation (e.g., PIs). Finally, the metabolomic analysis demonstrated that supplementation with ω3-PC and ω6-PC induced the expression of several metabolites with a pronounced inflammatory and anti-inflammatory effect (e.g., succinate). Overall, our data show that supplementation of macrophages with ω3-PC and ω6-PC effectively modulates the lipidome, proteome, and metabolome of these immune cells, affecting several metabolic pathways involved in the immune response that are triggered by inflammation.
Curcumin as an Enhancer of Therapeutic Efficiency of Chemotherapy Drugs in Breast Cancer
Authors: Farghadani Reyhaneh , Naidu Rakesh
Published: February 2022

Female breast cancer is the world’s most prevalent cancer in 2020. Chemotherapy still remains a backbone in breast cancer therapy and is crucial in advanced and metastatic breast cancer treatment. The clinical efficiency of chemotherapy regimens is limited due to tumor heterogeneity, chemoresistance, and side effects. Chemotherapeutic drug combinations with natural products hold great promise for enhancing their anticancer efficacy. Curcumin is an ideal chemopreventive and chemotherapy agent owning to its multitargeting function on various regulatory molecules, key signaling pathways, and pharmacological safety. This review aimed to elucidate the potential role of curcumin in enhancing the efficacy of doxorubicin, paclitaxel, 5-fluorouracil, and cisplatin via combinational therapy. Additionally, the molecular mechanisms underlying the chemosensitizing activity of these combinations have been addressed. Overall, based on the promising therapeutic potential of curcumin in combination with conventional chemotherapy drugs, curcumin is of considerable value to develop as an adjunct for combination chemotherapy with current drugs to treat breast cancer. Furthermore, this topic may provide the frameworks for the future research direction of curcumin–chemotherapy combination studies and may benefit in the development of a novel therapeutic strategy to maximize the clinical efficacy of anticancer drugs while minimizing their side effects in the future breast cancer treatment.
Phosphodiesterases and Compartmentation of cAMP and cGMP Signaling in Regulation of Cardiac Contractility in Normal and Failing Hearts
Authors: Calamera Gaia , Moltzau Lise Román , Levy Finn Olav , Andressen Kjetil Wessel
Published: February 2022

Cardiac contractility is regulated by several neural, hormonal, paracrine, and autocrine factors. Amongst these, signaling through β-adrenergic and serotonin receptors generates the second messenger cyclic AMP (cAMP), whereas activation of natriuretic peptide receptors and soluble guanylyl cyclases generates cyclic GMP (cGMP). Both cyclic nucleotides regulate cardiac contractility through several mechanisms. Phosphodiesterases (PDEs) are enzymes that degrade cAMP and cGMP and therefore determine the dynamics of their downstream effects. In addition, the intracellular localization of the different PDEs may contribute to regulation of compartmented signaling of cAMP and cGMP. In this review, we will focus on the role of PDEs in regulating contractility and evaluate changes in heart failure.
The Osteogenesis Imperfecta Type V Mutant BRIL/IFITM5 Promotes Transcriptional Activation of MEF2, NFATc, and NR4A in Osteoblasts
Authors: Maranda Vincent , Gaumond Marie-Hélène , Moffatt Pierre
Published: February 2022

BRIL (bone restricted ifitm-like; also known as IFITM5) is a transmembrane protein expressed in osteoblasts. Although its role in skeletal development and homeostasis is unknown, mutations in BRIL result in rare dominant forms of osteogenesis imperfecta. The pathogenic mechanism has been proposed to be a gain-of or neomorphic function. To understand the function of BRIL and its OI type V mutant (MALEP BRIL) and whether they could activate signaling pathways in osteoblasts, we performed a luciferase reporter assay screen based on the activity of 26 transcription factors. When overexpressed in MC3T3-E1 and MLO-A5 cells, the MALEP BRIL activated the reporters dependent on MEF2, NFATc, and NR4A significantly more. Additional co-transfection experiments with MEF2C and NFATc1 and a number of their modulators (HDAC4, calcineurin, RCAN, FK506) confirmed the additive or synergistic activation of the pathways by MALEP, and suggested a coordinated regulation involving calcineurin. Endogenous levels of Nr4a members, as well as Ptgs2, were upregulated by MALEP BRIL. Y2H and co-immunoprecipitation indicated that BRIL interacted with CAML, but its contribution as the most upstream stimulator of the Ca2+-calcineurin-MEF2/NFATc cascade was not confirmed convincingly. Altogether the data presented provide the first ever readout to monitor for BRIL activity and suggest a potential gain-of-function causative effect for MALEP BRIL in OI type V, leading to perturbed signaling events and gene expression.
Anthocyanins: Traditional Uses, Structural and Functional Variations, Approaches to Increase Yields and Products’ Quality, Hepatoprotection, Liver Longevity, and Commercial Products
Authors: Mohammed Hamdoon A. , Khan Riaz A.
Published: February 2022

Anthocyanins are water-soluble, colored compounds of the flavonoid class, abundantly found in the fruits, leaves, roots, and other parts of the plants. The fruit berries are prime sources and exhibit different colors. The anthocyanins utility as traditional medicament for liver protection and cure, and importance as strongest plants-based anti-oxidants have conferred these plants products different biological activities. These activities include anti-inflammation, liver protective, analgesic, and anti-cancers, which have provided the anthocyanins an immense commercial value, and has impelled their chemistry, biological activity, isolation, and quality investigations as prime focus. Methods in extraction and production of anthocyanin-based products have assumed vital economic importance. Different extraction techniques in aquatic solvents mixtures, eutectic solvents, and other chemically reactive extractions including low acid concentrations-based extractions have been developed. The prophylactic and curative therapy roles of the anthocyanins, together with no reported toxicity has offered much-needed impetus and economic benefits to these classes of compounds which are commercially available. Information retrieval from various search engines, including the PubMed®, ScienceDirect®, Scopus®, and Google Scholar®, were used in the review preparation. This imparted an outlook on the anthocyanins occurrence, roles in plants, isolation-extraction, structures, biosynthetic as well as semi- and total-synthetic pathways, product quality and yields enhancements, including uses as part of traditional medicines, and uses in liver disorders, prophylactic and therapeutic applications in liver protection and longevity, liver cancer and hepatocellular carcinoma. The review also highlights the integrated approach to yields maximizations to meet the regular demands of the anthocyanins products, also as part of the extract-rich preparations together with a listing of marketed products available for human consumption as nutraceuticals/food supplements.
Fatty Acid Binding Protein 6 Inhibition Decreases Cell Cycle Progression, Migration and Autophagy in Bladder Cancers
Authors: Lin Chieh-Hsin , Chang Hsin-Han , Lai Chien-Rui , Wang Hisao-Hsien , Tsai Wen-Chiuan , Tsai Yu-Ling , Changchien Chih-Ying , Cheng Yu-Chen , Wu Sheng-Tang , Chen Ying
Published: February 2022

Bladder cancer (BC) has a high recurrence rate worldwide. The aim of this study was to evaluate the role of fatty acid binding protein 6 (FABP6) in proliferation and migration in human bladder cancer cells. Cell growth was confirmed by MTT and colony formation assay. Western blotting was used to explore protein expressions. Wound healing and Transwell assays were performed to evaluate the migration ability. A xenograft animal model with subcutaneous implantation of BC cells was generated to confirm the tumor progression. Knockdown of FABP6 reduced cell growth in low-grade TSGH-8301 and high-grade T24 cells. Cell cycle blockade was observed with the decrease of CDK2, CDK4, and Ki67 levels in FABP6-knockdown BC cells. Interestingly, knockdown of FBAP6 led to downregulation of autophagic markers and activation of AKT-mTOR signaling. The application of PI3K/AKT inhibitor decreased cell viability mediated by FABP6-knockdown additionally. Moreover, FABP6-knockdown reduced peroxisome proliferator-activated receptor γ and retinoid X receptor α levels but increased p-p65 expression. Knockdown of FABP6 also inhibited BC cell motility with focal adhesive complex reduction. Finally, shFABP6 combined with cisplatin suppressed tumor growth in vivo. These results provide evidence that FABP6 may be a potential target in BC cells progression.
EMBER—Embedding Multiple Molecular Fingerprints for Virtual Screening
Authors: Mendolia Isabella , Contino Salvatore , De Simone Giada , Perricone Ugo , Pirrone Roberto
Published: February 2022

In recent years, the debate in the field of applications of Deep Learning to Virtual Screening has focused on the use of neural embeddings with respect to classical descriptors in order to encode both structural and physical properties of ligands and/or targets. The attention on embeddings with the increasing use of Graph Neural Networks aimed at overcoming molecular fingerprints that are short range embeddings for atomic neighborhoods. Here, we present EMBER, a novel molecular embedding made by seven molecular fingerprints arranged as different “spectra” to describe the same molecule, and we prove its effectiveness by using deep convolutional architecture that assesses ligands’ bioactivity on a data set containing twenty protein kinases with similar binding sites to CDK1. The data set itself is presented, and the architecture is explained in detail along with its training procedure. We report experimental results and an explainability analysis to assess the contribution of each fingerprint to different targets.
Discrimination between NSIP- and IPF-Derived Fibroblasts Based on Multi-Parameter Characterization of Their Growth, Morphology and Physic-Chemical Properties
Authors: Orzechowska Barbara , Awsiuk Kamil , Wnuk Dawid , Pabijan Joanna , Stachura Tomasz , Soja Jerzy , Sładek Krzysztof , Raczkowska Joanna
Published: February 2022

Background: The aim of the research presented here was to find a set of parameters enabling discrimination between three types of fibroblasts, i.e., healthy ones and those derived from two disorders mimicking each other: idiopathic pulmonary fibrosis (IPF), and nonspecific interstitial pneumonia (NSIP). Methods: The morphology and growth of cells were traced using fluorescence microscopy and analyzed quantitatively using cell proliferation and substrate cytotoxicity indices. The viability of cells was recorded using MTS assays, and their stiffness was examined using atomic force microscopy (AFM) working in force spectroscopy (FS) mode. To enhance any possible difference in the examined parameters, experiments were performed with cells cultured on substrates of different elasticities. Moreover, the chemical composition of cells was determined using time-of-flight secondary ion mass spectrometry (ToF-SIMS), combined with sophisticated analytical tools, i.e., Multivariate Curve Resolution (MCR) and Principal Component Analysis (PCA). Results: The obtained results demonstrate that discrimination between cell lines derived from healthy and diseased patients is possible based on the analysis of the growth of cells, as well as their physical and chemical properties. In turn, the comparative analysis of the cellular response to altered stiffness of the substrates enables the identification of each cell line, including distinguishing between IPF- and NSIP-derived fibroblasts.
Microgravity Modifies the Phenotype of Fibroblast and Promotes Remodeling of the Fibroblast–Keratinocyte Interaction in a 3D Co-Culture Model
Authors: Fedeli Valeria , Cucina Alessandra , Dinicola Simona , Fabrizi Gianmarco , Catizone Angela , Gesualdi Luisa , Ceccarelli Simona , Harrath Abdel Halim , Alwasel Saleh H. , Ricci Giulia , Pedata Paola , Bizzarri Mariano , Monti Noemi
Published: February 2022

Microgravity impairs tissue organization and critical pathways involved in the cell–microenvironment interplay, where fibroblasts have a critical role. We exposed dermal fibroblasts to simulated microgravity by means of a Random Positioning Machine (RPM), a device that reproduces conditions of weightlessness. Molecular and structural changes were analyzed and compared to control samples growing in a normal gravity field. Simulated microgravity impairs fibroblast conversion into myofibroblast and inhibits their migratory properties. Consequently, the normal interplay between fibroblasts and keratinocytes were remarkably altered in 3D co-culture experiments, giving rise to several ultra-structural abnormalities. Such phenotypic changes are associated with down-regulation of α-SMA that translocate in the nucleoplasm, altogether with the concomitant modification of the actin-vinculin apparatus. Noticeably, the stress associated with weightlessness induced oxidative damage, which seemed to concur with such modifications. These findings disclose new opportunities to establish antioxidant strategies that counteract the microgravity-induced disruptive effects on fibroblasts and tissue organization.
Ferroptosis in Cancer Immunotherapy—Implications for Hepatocellular Carcinoma
Authors: Kusnick Johanna , Bruneau Alix , Tacke Frank , Hammerich Linda
Published: February 2022

Ferroptosis is a recently recognized iron-dependent form of non-apoptotic regulated cell death (RCD) characterized by lipid peroxide accumulation to lethal levels. Cancer cells, which show an increased iron dependency to enable rapid growth, seem vulnerable to ferroptosis. There is also increasing evidence that ferroptosis might be immunogenic and therefore could synergize with immunotherapies. Hepatocellular carcinoma (HCC) is the most common primary liver tumor with a low survival rate due to frequent recurrence and limited efficacy of conventional chemotherapies, illustrating the urgent need for novel drug approaches or combinatorial strategies. Immunotherapy is a new treatment approach for advanced HCC patients. In this setting, ferroptosis inducers may have substantial clinical potential. However, there are still many questions to answer before the mystery of ferroptosis is fully unveiled. This review discusses the existing studies and our current understanding regarding the molecular mechanisms of ferroptosis with the goal of enhancing response to immunotherapy of liver cancer. In addition, challenges and opportunities in clinical applications of potential candidates for ferroptosis-driven therapeutic strategies will be summarized. Unraveling the role of ferroptosis in the immune response could benefit the development of promising anti-cancer therapies that overcome drug resistance and prevent tumor metastasis.
MEduKG: A Deep-Learning-Based Approach for Multi-Modal Educational Knowledge Graph Construction
Authors: Li Nan , Shen Qiang , Song Rui , Chi Yang , Xu Hao
Published: February 2022

The popularity of information technology has given rise to a growing interest in smart education and has provided the possibility of combining online and offline education. Knowledge graphs, an effective technology for knowledge representation and management, have been successfully utilized to manage massive educational resources. However, the existing research on constructing educational knowledge graphs ignores multiple modalities and their relationships, such as teacher speeches and their relationship with knowledge. To tackle this problem, we propose an automatic approach to construct multi-modal educational knowledge graphs that integrate speech as a modal resource to facilitate the reuse of educational resources. Specifically, we first propose a fine-tuned Bidirectional Encoder Representation from Transformers (BERT) model based on education lexicon, called EduBERT, which can adaptively capture effective information in the education field. We also add a Bidirectional Long Short-Term Memory-Conditional Random Field (BiLSTM-CRF) to effectively identify educational entities. Then, the locational information of the entity is incorporated into BERT to extract the educational relationship. In addition, to cover the shortage of traditional text-based knowledge graphs, we focus on collecting teacher speech to construct a multi-modal knowledge graph. We propose a speech-fusion method that links these data into the graph as a class of entities. The numeric results show that our proposed approach can manage and present various modes of educational resources and that it can provide better education services.
Lexical Diversity in Statistical and Neural Machine Translation
Authors: Brglez Mojca , Vintar Špela
Published: February 2022

Neural machine translation systems have revolutionized translation processes in terms of quantity and speed in recent years, and they have even been claimed to achieve human parity. However, the quality of their output has also raised serious doubts and concerns, such as loss in lexical variation, evidence of “machine translationese”, and its effect on post-editing, which results in “post-editese”. In this study, we analyze the outputs of three English to Slovenian machine translation systems in terms of lexical diversity in three different genres. Using both quantitative and qualitative methods, we analyze one statistical and two neural systems, and we compare them to a human reference translation. Our quantitative analyses based on lexical diversity metrics show diverging results; however, translation systems, particularly neural ones, mostly exhibit larger lexical diversity than their human counterparts. Nevertheless, a qualitative method shows that these quantitative results are not always a reliable tool to assess true lexical diversity and that a lot of lexical “creativity”, especially by neural translation systems, is often unreliable, inconsistent, and misguided.
Synthesis and Structure of a Ferrocenylsilane-Bridged Bisphosphine
Authors: Sasamori Takahiro , Ueno Hiromu , Morisako Shogo
Published: February 2022

A bisferrocenylsilane-bridged bisphosphine, i.e., a bisphosphine bridged by bis(1’-dicyclohexylphosphino-1-ferrocenyl)dimethoxysilane, was synthesized and structurally characterized. Its redox behavior was examined by cyclic voltammetry and differential pulse voltammetry, which revealed two-step oxidation processes.
Coumarins Synthesis and Transformation via C–H Bond Activation—A Review
Authors: Szwaczko Katarzyna
Published: February 2022

For several decades, coumarins have attracted considerable attention due to the fact of their application in diverse fields such as medical science and biomedical research as well as several industrial branches. Recently, many compounds containing the coumarin moiety have been intensively studied, mainly due to the fact of their biological activities such as antitumor, antioxidative, anti-HIV, vasorelaxant, antimicrobial, and anticancer. They are also widely used as fluorescent dyes and probes because of their great structural flexibility and large fluorescent quantum yields. For this reason, numerous attempts have been made to develop new and more practical methods for the synthesis of these compounds. This review aims at providing a comprehensive overview of coumarin synthesis methods by direct C–H bond activation in order to demonstrate the current state-of-the-art methods as well as the current limitations.
Effectiveness of Different Irrigant Activation Systems on Smear Layer Removal: A Scanning Electron Microscopic Study
Authors: Miguéns-Vila Ramón , Martín-Biedma Benjamín , Aboy-Pazos Saleta , Uroz-Torres David , Álvarez-Nóvoa Pablo , Dablanca-Blanco Ana Belén , Varela-Aneiros Iván , Castelo-Baz Pablo
Published: February 2022

The aim of this study was to evaluate the effectiveness of smear layer removal after the use of different irrigation methods (passive ultrasonic irrigation (PUI), continuous ultrasonic irrigation (CUI), apical negative pressure irrigation and conventional irrigation) using scanning electron microscopy (SEM) as an analytical tool. A total of 100 single-canal teeth were decoronated and randomly divided into five groups (n = 20) according to the irrigation method used: conventional irrigation with front outlet syringe, conventional irrigation with lateral outlet syringe, apical negative pressure irrigation (EndoVac), PUI with Irrisafe and CUI with ProUltra PiezoFlow ultrasonic irrigation needle. Root canal preparation was performed with the ProTaper Gold system up to the F4 instrument, and 5.25% NaOCl was used as an irrigant. After chemical-mechanical preparation, the roots were split longitudinally, and the coronal, middle and apical thirds were examined. SEM digital photomicrographs were taken at ×1000 magnification to evaluate the amount of smear layer in each root canal third; CUI significantly removed more smear layer than any other irrigant activation protocol (p < 0.05); CUI was more effective in removing the smear layer than the other irrigation protocols. However, none of the irrigation protocols were able to produce root canals completely free from smear layer.
Switching from Adalimumab Originator to Biosimilar: Clinical Experience in Patients with Hidradenitis Suppurativa
Authors: Montero-Vilchez Trinidad , Cuenca-Barrales Carlos , Rodriguez-Tejero Andrea , Martinez-Lopez Antonio , Arias-Santiago Salvador , Molina-Leyva Alejandro
Published: February 2022

Adalimumab is currently the only biological medicine approved by the FDA for the treatment of hidradenitis suppurativa (HS). The breakout of biosimilar drugs made them more accessible due to their impact on pharmacoeconomics. However, packaging, formulation, or excipients are unique characteristics of each drug. In that way, switching from adalimumab originator to biosimilar and between biosimilars could have implications in the clinical practice. The objective of this study is to describe our clinical experience in switching from adalimumab originator to biosimilar and switching back again. A single-center retrospective cohort study was conducted that included seventeen patients with HS treated with adalimumab originator in the maintenance phase, and that achieved Hidradenitis Suppurativa Clinical Response (HiSCR), who were switched to adalimumab biosimilar for no medical reasons. The reason for the change was to improve pharmacoeconomic efficiency, following our hospital policies on biologics. Median duration with adalimumab originator treatment before switching was 48 weeks. After switching, 41.2% of patients maintained HiSCR response without additional issues, while 58.8% (10/17) reported problems after the change. Switching from adalimumab originator to biosimilar in well-controlled patients could imply problems in efficacy and adherence. Switching back to adalimumab originator appears to solve most of the problems, but some patients can lose confidence in the drug and discontinue it. It would be worthwhile to evaluate the benefit–risk ratio individually when switching an HS patient to adalimumab biosimilar.
Antibodies to Porphyromonas gingivalis Are Increased in Patients with Severe Periodontitis, and Associate with Presence of Specific Autoantibodies and Myocardial Infarction
Authors: de Vries Charlotte , Ruacho Guillermo , Kindstedt Elin , Potempa Barbara Aleksandra , Potempa Jan , Klinge Björn , Lundberg Pernilla , Svenungsson Elisabet , Lundberg Karin
Published: February 2022

There is accumulating data suggesting that periodontitis is associated with increased risk of systemic and autoimmune diseases, including cardiovascular disease, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), and there is an unmet need to identify these individuals early. With the periodontal bacteria Porphyromonas gingivalis (Pg) as one of the key drivers of periodontitis, we set out to investigate whether antibodies to Pg virulence factor arginine gingipain (Rgp) could serve as a biomarker for periodontitis patients at increased risk of autoimmunity and systemic disease. We measured serum anti-Rgp IgG in three study populations: PAROKRANK (779 individuals with myocardial infarction (MI); 719 controls), where 557 had periodontitis, and 312 were positive for autoantibodies associated with RA/SLE; the PerioGene North pilot (41 periodontitis; 39 controls); and an SLE case/control study (101 SLE; 100 controls). Anti-Rgp IgG levels were increased in severe periodontitis compared to controls (p < 0.0001), in individuals positive for anti-citrullinated protein antibodies (p = 0.04) and anti-dsDNA antibodies (p = 0.035), compared to autoantibody-negative individuals; and in MI patients versus matched controls (p = 0.035). Our data support longitudinal studies addressing the role of anti-Rgp antibodies as biomarkers for periodontitis patients at increased risk of developing autoimmunity linked to RA and SLE, and mechanisms underpinning these associations.
Postural Stability in Single-Leg Quiet Stance in Highly Trained Athletes: Sex and Sport Differences
Authors: Trajković Nebojša , Smajla Darjan , Kozinc Žiga , Šarabon Nejc
Published: February 2022

This study aimed to determine if there is a difference in postural stability in highly trained adolescents and young adult athletes regarding sex and sport. The participants were young athletes (n = 464) from seven different sports. We considered the center of pressure (CoP) velocity (total, anterior–posterior (AP) and medial–lateral (ML)), CoP amplitude (AP and ML), and CoP frequency (AP and ML), as assessed by single-leg quiet stance test. Significant interactions were found between sex and sport for all CoP variables (p < 0.02). Additionally, a significant main effect of sport was also found in all CoP variables (p = 0.01). Regarding sex, significant effects were found for all CoP amplitude variables (p = 0.01), as well as for CoP velocity variables, except for CoP ML (p = 0.06). Moreover, there was no sex effect for CoP frequency AP (p = 0.18). The results of the current study confirm the claim that the criteria for optimal postural strategies for elite athletes likely depend on a given sport.
Refining Tumor Treatment in Sinonasal Cancer Using Delta Radiomics of Multi-Parametric MRI after the First Cycle of Induction Chemotherapy
Authors: Corino Valentina D. A. , Bologna Marco , Calareso Giuseppina , Resteghini Carlo , Sdao Silvana , Orlandi Ester , Licitra Lisa , Mainardi Luca , Bossi Paolo
Published: February 2022

Background: Response to induction chemotherapy (IC) has been predicted in patients with sinonasal cancer using early delta radiomics obtained from T1- and T2-weighted images and apparent diffusion coefficient (ADC) maps, comparing results with early radiological evaluation by RECIST. Methods: Fifty patients were included in the study. For each image (at baseline and after the first IC cycle), 536 radiomic features were extracted as follows: semi-supervised principal component analysis components, explaining 97% of the variance, were used together with a support vector machine (SVM) to develop a radiomic signature. One signature was developed for each sequence (T1-, T2-weighted and ADC). A multiagent decision-making algorithm was used to merge multiple signatures into one score. Results: The area under the curve (AUC) for mono-modality signatures was 0.79 (CI: 0.65–0.88), 0.76 (CI: 0.62–0.87) and 0.93 (CI: 0.75–1) using T1-, T2-weighted and ADC images, respectively. The fuse signature improved the AUC when an ADC-based signature was added. Radiological prediction using RECIST criteria reached an accuracy of 0.78. Conclusions: These results suggest the importance of early delta radiomics and of ADC maps to predict the response to IC in sinonasal cancers.
An Evaluation of the Performance of Sea Ice Thickness Forecasts to Support Arctic Marine Transport
Authors: Bilge Tarkan Aslan , Fournier Nicolas , Mignac Davi , Hume-Wright Laura , Bertino Laurent , Williams Timothy , Tietsche Steffen
Published: February 2022

In response to declining sea ice cover, human activity in the Arctic is increasing, with access to the Arctic Ocean becoming more important for socio-economic reasons. Accurate knowledge of sea ice conditions is therefore becoming increasingly important for reducing the risk and operational cost of human activities in the Arctic. Satellite-based sea ice charting is routinely used for tactical ice management, but the marine sector does not yet make optimal use of sea ice thickness (SIT) or sea ice concentration (SIC) forecasts on weekly timescales. This is because forecasts have not achieved sufficient accuracy, verification and resolution to be used in situations where maritime safety is paramount, and assessing the suitability of forecasts can be difficult because they are often not available in the appropriate format. In this paper, existing SIT forecasts currently available on the Copernicus Marine Service (CMS) or elsewhere in the public domain are evaluated for the first time. These include the seven-day forecasts from the UK Met Office, MET Norway, the Nansen Environmental and Remote Sensing Center (NERSC) and the European Centre for Medium-Range Weather Forecasts (ECMWF). Their forecast skills were assessed against unique in situ data from five moorings deployed between 2016 and 2019 by the Barents Sea Metocean and Ice Network (BASMIN) and Barents Sea Exploration Collaboration (BaSEC) Joint Industry Projects. Assessing these models highlights the importance of data assimilation in short-term forecasting of SIT and suggests that improved assimilation of sea ice data could increase the utility of forecasts for navigational purposes. This study also demonstrates that forecasts can achieve similar or improved correlation with observations when compared to a persistence model at a lead time of seven days, providing evidence that, when used in conjunction with sea ice charts, SIT forecasts could provide valuable information on future sea ice conditions.