bluuebunny/crossref_metadata_2025 huggingface dataset:
Digital Impressions in Implant Dentistry: A Literature Review
Authors: Marques Simone , Ribeiro Paulo , Falcão Carlos , Lemos Bernardo Ferreira , Ríos-Carrasco Blanca , Ríos-Santos José Vicente , Herrero-Climent Mariano
Published: January 2021

Introduction. Digital impressions in implant dentistry rely on many variables, and their accuracy, particularly in complete edentulous patients, is not well understood. Aim. The purpose of this literature review was to determine which factors may influence the accuracy of digital impressions in implant dentistry. Emphasized attention was given to the design of the intra-oral scan body (ISB) and scanning techniques. Materials and methods. A Medline, PubMed and EBSCO Host databases search, complemented by a hand search, was performed in order to select relevant reports regarding the appliance of digital impressions in implant dentistry. The search subject included but was not limited to accuracy of digital impressions in implant dentistry, digital scanning techniques, the design and material of the ISBs, and the depth and angulation of the implant. The related titles and abstracts were screened, and the remaining articles that fulfilled the inclusion criteria were selected for full-text readings. Results. The literature search conducted for this review initially resulted in 108 articles, among which only 21 articles fulfilled the criteria for inclusion. Studies were evaluated according to five subjects: accuracy of digital impressions in implant dentistry; the design and material of the intra-oral scan bodies; scanning technique; the influence of implants depth/angulations on the digital impression and accuracy of different intra-oral scanner devices. Conclusions. The accuracy of digital impressions in implant dentistry depends on several aspects. The depth/angulation of the implant, the experience of the operator, the intra-oral scanner used, and environmental conditions may influence the accuracy of digital impressions in implant dentistry. However, it seems that ISBs’ design and material, as well as scanning technique, have a major impact on the trueness and precision of digital impressions in implant dentistry. Future research is suggested for the better understanding of this subject, focusing on the optimization of the ISB design and scanning protocols.
Bayesian Approaches for Confirmatory Trials in Rare Diseases: Opportunities and Challenges
Authors: Ursino Moreno , Stallard Nigel
Published: January 2021

The aim of this narrative review is to introduce the reader to Bayesian methods that, in our opinion, appear to be the most important in the context of rare diseases. A disease is defined as rare depending on the prevalence of the affected patients in the considered population, for example, about 1 in 1500 people in U.S.; about 1 in 2500 people in Japan; and fewer than 1 in 2000 people in Europe. There are between 6000 and 8000 rare diseases and the main issue in drug development is linked to the challenge of achieving robust evidence from clinical trials in small populations. A better use of all available information can help the development process and Bayesian statistics can provide a solid framework at the design stage, during the conduct of the trial, and at the analysis stage. The focus of this manuscript is to provide a review of Bayesian methods for sample size computation or reassessment during phase II or phase III trial, for response adaptive randomization and of for meta-analysis in rare disease. Challenges regarding prior distribution choice, computational burden and dissemination are also discussed.
Identification Framework of Contaminant Spill in Rivers Using Machine Learning with Breakthrough Curve Analysis
Authors: Kwon Siyoon , Noh Hyoseob , Seo Il Won , Jung Sung Hyun , Baek Donghae
Published: January 2021

To minimize the damage from contaminant accidents in rivers, early identification of the contaminant source is crucial. Thus, in this study, a framework combining Machine Learning (ML) and the Transient Storage zone Model (TSM) was developed to predict the spill location and mass of a contaminant source. The TSM model was employed to simulate non-Fickian Breakthrough Curves (BTCs), which entails relevant information of the contaminant source. Then, the ML models were used to identify the BTC features, characterized by 21 variables, to predict the spill location and mass. The proposed framework was applied to the Gam Creek, South Korea, in which two tracer tests were conducted. In this study, six ML methods were applied for the prediction of spill location and mass, while the most relevant BTC features were selected by Recursive Feature Elimination Cross-Validation (RFECV). Model applications to field data showed that the ensemble Decision tree models, Random Forest (RF) and Xgboost (XGB), were the most efficient and feasible in predicting the contaminant source.
Analysis of Factors Related to Working Status of Dental Hygienists in Japan
Authors: Miura Hiroko , Tano Rumi , Oshima Katsuo , Usui Yoshie
Published: January 2021

The super-aged society of Japan is experiencing an increased demand for dental hygienists, of which there is currently a shortage. This study aimed to investigate the factors related to the working status of dental hygienists in Japan. We conducted a survey by mailing a questionnaire on employment to 1444 dental hygienists and obtained 537 valid responses. We conducted a bivariate analysis using either a chi-square test or t-test as well as a multiple logistic regression analysis to determine the factors related to working status. The overall employment rate was 68.2%, with a significant difference between age groups (p < 0.01). Approximately 80% of respondents considered working hours and human relations at the workplace to be important, and more than 70% of respondents considered wages as important. Finally, the following four variables were found to be significantly associated with employment status: training course attendance, a desire to work full-time, consideration of wages as important, and consideration of working hours as important. These findings suggest that it is necessary to improve working conditions and environments, including wages and working hours, as well as provide a more robust system of continued professional development for dental hygienists to increase the workforce.
Susceptibility to Coronavirus (COVID-19) in Occupational Settings: The Complex Interplay between Individual and Workplace Factors
Authors: Leso Veruscka , Fontana Luca , Iavicoli Ivo
Published: January 2021

In the current coronavirus (COVID-19) pandemic, the definition of risk factors for susceptibility to adverse outcomes seems essential to support public and occupational health policies. Some specific issues need to be addressed to understand vulnerability in occupational settings. Among these, individual factors, e.g., age, sex, and preexisting comorbidities (hypertension, cardiovascular diseases, diabetes, obesity, cancer), that can predispose individuals to more severe outcomes and post-COVID-19 symptoms that may represent conditions of acquired susceptibility, possibly impacting the return to—and fitness for—work. Additionally, the risk of contracting COVID-19 through work should be addressed, considering the probability of being in contact with infected people, physical proximity to others, and social aggregation during work. Occupational health settings may represent appropriate scenarios for the early identification of vulnerable subjects, with the final aim to guide risk assessment and management procedures. These should include the systematic surveillance of work-related risk factors, collective preventive policies, stringent actions for specific groups of workers, decisions on occupational placement of employees, and health promotion activities. Concerted actions of general practitioners, hospital specialists, occupational physicians, and all the stakeholders involved in the occupational health and safety management should be focused on planning suitable preventive measures for susceptible subjects.
Current Status and Temporal Trend of Potentially Toxic Elements Pollution in Agricultural Soil in the Yangtze River Delta Region: A Meta-Analysis
Authors: She Shufeng , Hu Bifeng , Zhang Xianglin , Shao Shuai , Jiang Yefeng , Zhou Lianqing , Shi Zhou
Published: January 2021

Potentially toxic elements (PTEs) pollution in the agricultural soil of China, especially in developed regions such as the Yangtze River Delta (YRD) in eastern China, has received increasing attention. However, there are few studies on the long-term assessment of soil pollution by PTEs over large regions. Therefore, in this study, a meta-analysis was conducted to evaluate the current state and temporal trend of PTEs pollution in the agricultural land of the Yangtze River Delta. Based on a review of 118 studies published between 1993 and 2020, the average concentrations of Cd, Hg, As, Pb, Cr, Cu, Zn, and Ni were found to be 0.25 mg kg−1, 0.14 mg kg−1, 8.14 mg kg−1, 32.32 mg kg−1, 68.84 mg kg−1, 32.58 mg kg−1, 92.35 mg kg−1, and 29.30 mg kg−1, respectively. Among these elements, only Cd and Hg showed significant accumulation compared with their background values. The eastern Yangtze River Delta showed a relatively high ecological risk due to intensive industrial activities. The contents of Cd, Pb, and Zn in soil showed an increasing trend from 1993 to 2000 and then showed a decreasing trend. The results obtained from this study will provide guidance for the prevention and control of soil pollution in the Yangtze River Delta.
Feasibility of a Broad Test Battery to Assess Physical Functioning Limitations of People Experiencing Homelessness
Authors: Broderick Julie , Kiernan Sinead , Murphy Niamh , Dowds Joanne , Ní Cheallaigh Cliona
Published: January 2021

Background: People who are homeless experience poor health. Reflective of overall health and factors such as acquired injuries, physical ability or functioning is often low among people who are homeless, but there is a lack of consistency of measures used to evaluate this construct. The aim of this study was to evaluate the feasibility of a broad test battery to evaluate limitations in physical functioning among people who are homeless. Methods: This cross-sectional, observational study occurred in a hospital in Dublin, Ireland. We evaluated lower extremity physical function (Short Physical Performance Battery), falls risk (timed up and go), functional capacity (six-minute walk test), stair-climbing ability (stair climb test), frailty (Clinical Frailty Scale), grip strength (handgrip dynamometer) and muscular mass (calf circumference measurement) in a population of people experiencing homelessness admitted for acute medical care. The test completion rate was evaluated for feasibility. Results: The completion rate varied: 65% (Short Physical Performance Battery), 55.4% (timed up and go), 38% (six-minute walk test), 31% (stair climb test), 97% (Clinical Frailty Scale), 75% (handgrip dynamometer), 74% (calf circumference measurement)). Collectively, the most common reasons for test non-participation were pain (24.1%, n = 40), not feeling well or able enough (20.1%, n = 33), and declined (11%, n = 18). Conclusion: The feasibility of the test battery was mixed as test participation rates varied from 31% to 97%. Physical functioning tests need to be carefully chosen for people who are homeless as many standard tests are unsuitable due to pain and poor physical ability.
A Systematic Scoping Review of Media Campaigns to Develop a Typology to Evaluate Their Collective Impact on Promoting Healthy Hydration Behaviors and Reducing Sugary Beverage Health Risks
Authors: Kraak Vivica I. , Consavage Stanley Katherine
Published: January 2021

Interventions to discourage sugary beverages and encourage water consumption have produced modest and unsustainable behavioral changes to reduce obesity and noncommunicable disease risks. This systematic scoping review examined media campaigns to develop a typology to support healthy hydration nonalcoholic beverage behaviors. Our three-step methodology included the following: (1) review and summarize expert-recommended healthy beverage guidelines; (2) review six English-language electronic databases guided by PRISMA to describe existing campaign types by issue, goal and underlying theory; and (3) develop a media campaign typology to support policies, systems and environments to encourage healthy hydration behaviors. Results showed no international consensus for healthy beverage guidelines, though we describe expert-recommended healthy beverage guidelines for the United States. Of 909 records identified, we included 24 articles describing distinct media campaigns and nine sources that defined models, schemes or taxonomies. The final media campaign typology included: (1) corporate advertising, marketing or entertainment; (2) corporate social responsibility, public relations/cause marketing; (3) social marketing; (4) public information, awareness, education/ health promotion; (5) media advocacy/countermarketing; and (6) political or public policy. This proof-of-concept media campaign typology can be used to evaluate their collective impact and support for a social change movement to reduce sugary beverage health risks and to encourage healthy hydration behaviors.
Spatiotemporal Analysis of AIDS Incidence and Its Influencing Factors on the Chinese Mainland, 2005–2017
Authors: Wang Yige , Zhao Chunhong , Liu Ziping , Gao Decai
Published: January 2021

Acquired Immune Deficiency Syndrome (AIDS) has become one of the most severe public health issues and nowadays around 38 million people are living with the human immunodeficiency virus (HIV). Ensuring healthy lives and promoting well-being is one of 17 United Nations Sustainable Development Goals. Here, we used the Markov chain matrix and geospatial clustering to comprehensively quantify the trends of the AIDS epidemic at the provincial administrate level in the mainland of China from 2005 to 2017. The Geographically Weighted Regression (GWR) model was further adopted to explore four groups of potential influencing factors (i.e., economy, traffic and transportation, medical care, and education) of the AIDS incidence rate in 2017 and their spatially distributed patterns. Results showed that the AIDS prevalence in southeastern China had been dominant and become prevalent in the past decade. The AIDS intensity level had been increasing between 2008 and 2011 but been gradually decreasing afterward. The analysis of the Markov chain matrix indicated that the AIDS epidemic has been generally in control on the Chinese mainland. The economic development was closely related to the rate of AIDS incidence on the Chinese mainland. The GWR result further suggested that medical care and the education effects on AIDS incidence rate can vary with different regions, but significant conclusions cannot be directly demonstrated. Our findings contribute an analytical framework of understanding AIDS epidemic trends and spatial variability of potential underlying factors throughout a complex extent to customize scientific prevention.
Men’s Positive and Negative Experiences Following Acute Myocardial Infarction
Authors: Solano-Ruiz MCarmen , Freitas Genival Fernandes de , Ugarte-Gurrutxaga M. Idoia , Gómez-Cantarino Sagrario , Siles-González José
Published: January 2021

(1) Objective: To describe men’s experiences as acute myocardial infarction sufferers from a social phenomenological perspective, a year after the event (2) Methods: The phenomenological interview was used to capture the participants’ discourse. The data were analyzed according to the theoretical methodological approach of social phenomenology. (3) Results: The discourse analysis of the content produced the following categories, set out according reasons “why”: personal biography, knowledge set, warning signs prior to the illness, experience at the intensive care unit, and rehabilitation process; and reasons “for”: expectations as regards the illness, health professionals, and future social life and work prospects. (4) Conclusions: Participants had not established a healthy condition one year after myocardial infarction, perceiving a very thin line between life and death. Personal biography influences the coping of the disease. They feel like the illness helped them to create new meanings and value of life. They envisage a future full of great restrictions and uncertainty. The results of this study have underlined the need to involve care at all stages of the illness: the physical and emotional dependence upon admittance at the intensive care unit, the need to be cured, the constant demand for information about the illness, the difficulties encountered upon returning home, uncertainty about the future, etc. All these moments indicate that proper nursing care adapted to the specific needs of each individual and their family members must be provided in order to help them to overcome all the stages involved in this process. It is necessary to individualize care because the sense of reality is common and universal, but the ways of expressing are subjective, and it depended on the totality of experiences accumulated throughout life.
Muscular Strength and Quality of Life in Older Adults: The Role of ACTN3 R577X Polymorphism
Authors: Fernández-Araque Ana , Giaquinta-Aranda Andrea , Rodríguez-Díez Jose Andrés , Carretero-Molinero Silvia , López-López Jorge , Verde Zoraida
Published: January 2021

As longevity is increasing, the 65-year-old and older population is projected to increase in the next decades, as are the consequences of age-related muscle deterioration on the quality of life. The purpose of this study was to examine the associations of the ACTN3R577X polymorphism with quality of life and muscular strength in an older Spanish population. In total, 281 older adults participated in this study. Anthropometric measurements, chronic diseases, prescribed medications, quality of life, hand grip strength, and physical activity and nutritional status data were collected. ACTN3 R577X genotyping was determined using Taqman probes. Multivariate regression analysis revealed in adjusted model that, in men, the ACTN3 R577X genotype was significantly associated with hand grip strength (HGS), regression coefficient (β) = 1.23, p = 0.008, dimension 1 of the five-dimension questionnaire EuroQoL (EQ-5D, mobility), (β) = −1.44, p = 0.006, and clinical group risk (CGR) category (β) = −1.38, p = 0.006. In women, a marginal association between the ACTN3 R577X genotype and the CGR category was observed, with a regression coefficient of (β) = −0.97, (p = 0.024). Our findings suggest that the ACTN3 R577X genotype may influence the decline in muscle strength and quality of life in older Spanish adult males.
Challenges and Adaptation of a European Influenza Vaccine Effectiveness Study Platform in Response to the COVID-19 Emergence: Experience from the DRIVE Project
Authors: Carmona Antonio , Muñoz-Quiles Cintia , Stuurman Anke , Descamps Alexandre , Mira-Iglesias Ainara , Torcel-Pagnon Laurence , Díez-Domingo Javier
Published: January 2021

The Development of Robust and Innovative Vaccine Effectiveness (DRIVE) project is a public–private partnership aiming to build capacity in Europe for yearly estimation of brand-specific influenza vaccine effectiveness (IVE). DRIVE is a five-year project funded by IMI (Innovative Medicines Initiative). It was initiated as a response to the guidance on influenza vaccines by EMA (European Medicines Agency), which advised vaccine manufacturers to work with public health institutes to set up a joint IVE study platform. The COVID-19 pandemic reached Europe in February 2020 and overlapped with the 2019/2020 influenza season only in the last weeks. However, several elements of the DRIVE study network were impacted. The pandemic specifically affected the study sites’ routines and the subsequent assessment of the 2019/20 influenza season. Moreover, the current social distancing measures and lockdown policies across Europe are expected to also limit the circulation of influenza for the 2020/21 season, and therefore the impact of COVID-19 will be higher than in the season 2019/20. Consequently, DRIVE has planned to adapt its study platform to the COVID-19 challenge, encompassing several COVID-19 particularities in the study procedures, data collection and IVE analysis for the 2020/21 season. DRIVE will study the feasibility of implementing these COVID-19 components and establish the foundations of future COVID-19 vaccine effectiveness studies.
Metabolic Syndrome in Obese Children—Clinical Prevalence and Risk Factors
Authors: Jankowska Agnieszka , Brzeziński Michał , Romanowicz-Sołtyszewska Anna , Szlagatys-Sidorkiewicz Agnieszka
Published: January 2021

The prevalence of childhood obesity is increasing worldwide. Some obese children can go on to develop metabolic syndrome (MetS), but exactly who among them remains to be determined. The aim of this study was to indicate predisposing factors for metabolic syndrome, especially those that can be modified. The study comprised 591 obese children aged 10–12 years. They were all Caucasian residents of Gdańsk, Poland, with similar demographic backgrounds. Clinical examination, anthropometry, biometric impedance analysis, blood tests (including oral glucose tolerance tests (OGTT) and insulinemia), and dietary and physical activity evaluation were conducted. The results of our study show that the risk factors for MetS or any of its components include male sex, parental (especially paternal) obesity, low body mass at birth, as well as omitting breakfast or dinner. There are few risk factors for metabolic syndrome both in obese adults and children. Some of these predictors can be modified, especially those in relation to lifestyle. Identifying and then influencing these factors may help to reduce the development of metabolic syndrome and consequently improve health and quality of life.
Acknowledgment to Reviewers of International Journal of Financial Studies in 2020
Authors:   International Journal of Financial Studies Editorial Office
Published: January 2021

Peer review is the driving force of journal development, and reviewers are gatekeepers who ensure that International Journal of Financial Studies maintains its standards for the high quality of its published papers [...]
Crowdsourcing without Data Bias: Building a Quality Assurance System for Air Pollution Symptom Mapping
Authors: Samulowska Marta , Chmielewski Szymon , Raczko Edwin , Lupa Michał , Myszkowska Dorota , Zagajewski Bogdan
Published: January 2021

Crowdsourcing is one of the spatial data sources, but due to its unstructured form, the quality of noisy crowd judgments is a challenge. In this study, we address the problem of detecting and removing crowdsourced data bias as a prerequisite for better-quality open-data output. This study aims to find the most robust data quality assurance system (QAs). To achieve this goal, we design logic-based QAs variants and test them on the air quality crowdsourcing database. By extending the paradigm of urban air pollution monitoring from particulate matter concentration levels to air-quality-related health symptom load, the study also builds a new perspective for citizen science (CS) air quality monitoring. The method includes the geospatial web (GeoWeb) platform as well as a QAs based on conditional statements. A four-month crowdsourcing campaign resulted in 1823 outdoor reports, with a rejection rate of up to 28%, depending on the applied. The focus of this study was not on digital sensors’ validation but on eliminating logically inconsistent surveys and technologically incorrect objects. As the QAs effectiveness may depend on the location and society structure, that opens up new cross-border opportunities for replication of the research in other geographical conditions.
Differential Role of Threonine and Tyrosine Phosphorylation in the Activation and Activity of the Yeast MAPK Slt2
Authors: González-Rubio Gema , Sellers-Moya Ángela , Martín Humberto , Molina María
Published: January 2021

The Mitogen-Activated Protein Kinase (MAPK) Slt2 is central to signaling through the yeast Cell Wall Integrity (CWI) pathway. MAPKs are regulated by phosphorylation at both the threonine and tyrosine of the conserved TXY motif within the activation loop (T190/Y192 in Slt2). Since phosphorylation at both sites results in the full activation of MAPKs, signaling through MAPK pathways is monitored with antibodies that detect dually phosphorylated forms. However, most of these antibodies also recognize monophosphorylated species, whose relative abundance and functionality are diverse. By using different phosphospecific antibodies and phosphate-affinity (Phos-tag) analysis on distinct Slt2 mutants, we determined that Y192- and T190-monophosphorylated species coexist with biphosphorylated Slt2, although most of the Slt2 pool remains unphosphorylated following stress. Among the monophosphorylated forms, only T190 exhibited biological activity. Upon stimulation, Slt2 is first phosphorylated at Y192, mainly by the MAPKK Mkk1, and this phosphorylation is important for the subsequent T190 phosphorylation. Similarly, dephosphorylation of Slt2 by the Dual Specificity Phosphatase (DSP) Msg5 is ordered, with dephosphorylation of T190 depending on previous Y192 dephosphorylation. Whereas Y192 phosphorylation enhances the Slt2 catalytic activity, T190 is essential for this activity. The conserved T195 residue is also critical for Slt2 functionality. Mutations that abolish the activity of Slt2 result in a high increase in inactive Y192-monophosphorylated Slt2. The coexistence of different Slt2 phosphoforms with diverse biological significance highlights the importance of the precise detection of the Slt2 phosphorylation status.
Molecular Mechanism of Autosomal Recessive Long QT-Syndrome 1 without Deafness
Authors: Oertli Annemarie , Rinné Susanne , Moss Robin , Kääb Stefan , Seemann Gunnar , Beckmann Britt-Maria , Decher Niels
Published: January 2021

KCNQ1 encodes the voltage-gated potassium (Kv) channel KCNQ1, also known as KvLQT1 or Kv7.1. Together with its ß-subunit KCNE1, also denoted as minK, this channel generates the slowly activating cardiac delayed rectifier current IKs, which is a key regulator of the heart rate dependent adaptation of the cardiac action potential duration (APD). Loss-of-function mutations in KCNQ1 cause congenital long QT1 (LQT1) syndrome, characterized by a delayed cardiac repolarization and a prolonged QT interval in the surface electrocardiogram. Autosomal dominant loss-of-function mutations in KCNQ1 result in long QT syndrome, called Romano–Ward Syndrome (RWS), while autosomal recessive mutations lead to Jervell and Lange-Nielsen syndrome (JLNS), associated with deafness. Here, we identified a homozygous KCNQ1 mutation, c.1892_1893insC (p.P631fs*20), in a patient with an isolated LQT syndrome (LQTS) without hearing loss. Nevertheless, the inheritance trait is autosomal recessive, with heterozygous family members being asymptomatic. The results of the electrophysiological characterization of the mutant, using voltage-clamp recordings in Xenopus laevis oocytes, are in agreement with an autosomal recessive disorder, since the IKs reduction was only observed in homomeric mutants, but not in heteromeric IKs channel complexes containing wild-type channel subunits. We found that KCNE1 rescues the KCNQ1 loss-of-function in mutant IKs channel complexes when they contain wild-type KCNQ1 subunits, as found in the heterozygous state. Action potential modellings confirmed that the recessive c.1892_1893insC LQT1 mutation only affects the APD of homozygous mutation carriers. Thus, our study provides the molecular mechanism for an atypical autosomal recessive LQT trait that lacks hearing impairment.
Tear-Derived Exosome Proteins Are Increased in Patients with Thyroid Eye Disease
Authors: Han Jeong-Sun , Kim Sung Eun , Jin Jun-Qing , Park Na Ri , Lee Ji-Young , Kim Hong Lim , Lee Seong-Beom , Yang Suk-Woo , Lim Dong-Jun
Published: January 2021

Exosomes contain proteins, lipids, RNA, and DNA that mediate intercellular signaling. Exosomes can contribute to the pathological processes of various diseases, although their roles in ocular diseases are unclear. We aimed to isolate exosomes from tear fluids (TF) of patients with Thyroid eye disease (TED) and analyze the exosomal proteins. TFs were collected from eight patients with TED and eight control subjects. The number of TF exosomes were measured using nanoparticle-tracking analysis. The expression of specific proteins in the purified exosome pellets were analyzed using a Proteome Profiler Array Kit. Cultured normal orbital fibroblasts were incubated with TF exosomes from patients with TED and control subjects, and changes in inflammatory cytokine levels were compared. TF exosomes from TED patients showed more exosomes than the control subjects. The expression levels of exosomal proteins vitamin D-binding (VDB) protein, C-reactive protein (CRP), chitinase 3-like 1 (CHI3L1), matrix metalloproteinase-9 (MMP-9), and vascular adhesion molecule-1 (VCAM-1) were significantly increased in patients with TED, compared to those of controls. Orbital fibroblasts exposed to TF exosomes from patients with TED showed significantly higher levels of interleukin (IL)-6, IL-8, and monocyte chemoattractant protein-1 (MCP-1) production than those treated with control TF exosomes. Specific proteins showed higher expression in exosomes from TED patients, implying that they may play keys roles in TED pathogenesis.
The Regulation of Nodule Number in Legumes Is a Balance of Three Signal Transduction Pathways
Authors: Chaulagain Diptee , Frugoli Julia
Published: January 2021

Nitrogen is a major determinant of plant growth and productivity and the ability of legumes to form a symbiotic relationship with nitrogen-fixing rhizobia bacteria allows legumes to exploit nitrogen-poor niches in the biosphere. But hosting nitrogen-fixing bacteria comes with a metabolic cost, and the process requires regulation. The symbiosis is regulated through three signal transduction pathways: in response to available nitrogen, at the initiation of contact between the organisms, and during the development of the nodules that will host the rhizobia. Here we provide an overview of our knowledge of how the three signaling pathways operate in space and time, and what we know about the cross-talk between symbiotic signaling for nodule initiation and organogenesis, nitrate dependent signaling, and autoregulation of nodulation. Identification of common components and points of intersection suggest directions for research on the fine-tuning of the plant’s response to rhizobia.
Assessing Kidney Graft Viability and Its Cells Metabolism during Machine Perfusion
Authors: Bellini Maria Irene , Tortorici Francesco , Amabile Maria Ida , D’Andrea Vito
Published: January 2021

Kidney transplantation is the golden treatment for end-stage renal disease. Static cold storage is currently considered the standard method of preservation, but dynamic techniques, such as machine perfusion (MP), have been shown to improve graft function, especially in kidneys donated by extended criteria donors and donation after circulatory death. With poor organ quality being a major reason for kidneys not being transplanted, an accurate, objective and reliable quality assessment during preservation could add value and support to clinicians’ decisions. MPs are emerging technologies with the potential to assess kidney graft viability and quality, both in the hypothermic and normothermic scenarios. The aim of this review is to summarize current tools for graft viability assessment using MP prior to implantation in relation to the ischemic damage.
Acknowledgment to Reviewers of the International Journal of Molecular Sciences in 2020
Authors:   International Journal of Molecular Sciences Editorial Office
Published: January 2021

Peer review is the driving force of journal development, and reviewers are gatekeepers who ensure that the International Journal of Molecular Sciences maintains its standards for the high quality of its published papers [...]
Cell-Penetrating Doxorubicin Released from Elastin-Like Polypeptide Kills Doxorubicin-Resistant Cancer Cells in In Vitro Study
Authors: Ryu Jung Su , Kratz Felix , Raucher Drazen
Published: January 2021

Elastin-like polypeptides (ELPs) undergo a characteristic phase transition in response to ambient temperature. Therefore, it has been be used as a thermosensitive vector for the delivery of chemotherapy agents since it can be used to target hyperthermic tumors. This novel strategy introduces unprecedented options for treating cancer with fewer concerns about side effects. In this study, the ELP system was further modified with an enzyme-cleavable linker in order to release drugs within tumors. This system consists of an ELP, a matrix metalloproteinase (MMP) substrate, a cell-penetrating peptide (CPP), and a 6-maleimidocaproyl amide derivative of doxorubicin (Dox). This strategy shows up to a 4-fold increase in cell penetration and results in more death in breast cancer cells compared to ELP-Dox. Even in doxorubicin-resistant cells (NCI/ADR and MES-SA/Dx5), ELP-released cell-penetrating doxorubicin demonstrated better membrane penetration, leading to at least twice the killing of resistant cells compared to ELP-Dox and free Dox. MMP-digested CPP-Dox showed better membrane penetration and induced more cancer cell death in vitro. This CPP-complexed Dox released from the ELP killed even Dox-resistant cells more efficiently than both free doxorubicin and non-cleaved ELP-CPP-Dox.
Effect of DNA Glycosylases OGG1 and Neil1 on Oxidized G-Rich Motif in the KRAS Promoter
Authors: Ferino Annalisa , Xodo Luigi E.
Published: January 2021

The promoter of the Kirsten ras (KRAS) proto-oncogene contains, upstream of the transcription start site, a quadruplex-forming motif called 32R with regulatory functions. As guanine under oxidative stress can be oxidized to 8-oxoguanine (8OG), we investigated the capacity of glycosylases 8-oxoguanine glycosylase (OGG1) and endonuclease VIII-like 1 (Neil1) to excise 8OG from 32R, either in duplex or G-quadruplex (G4) conformation. We found that OGG1 efficiently excised 8OG from oxidized 32R in duplex but not in G4 conformation. By contrast, glycosylase Neil1 showed more activity on the G4 than the duplex conformation. We also found that the excising activity of Neil1 on folded 32R depended on G4 topology. Our data suggest that Neil1, besides being involved in base excision repair pathway (BER), could play a role on KRAS transcription.
Emerging Role of Neutrophils in the Thrombosis of Chronic Myeloproliferative Neoplasms
Authors: Ferrer-Marín Francisca , Cuenca-Zamora Ernesto José , Guijarro-Carrillo Pedro Jesús , Teruel-Montoya Raúl
Published: January 2021

Thrombosis is a major cause of morbimortality in patients with chronic Philadelphia chromosome-negative myeloproliferative neoplasms (MPN). In the last decade, multiple lines of evidence support the role of leukocytes in thrombosis of MPN patients. Besides the increase in the number of cells, neutrophils and monocytes of MPN patients show a pro-coagulant activated phenotype. Once activated, neutrophils release structures composed of DNA, histones, and granular proteins, called extracellular neutrophil traps (NETs), which in addition to killing pathogens, provide an ideal matrix for platelet activation and coagulation mechanisms. Herein, we review the published literature related to the involvement of NETs in the pathogenesis of thrombosis in the setting of MPN; the effect that cytoreductive therapies and JAK inhibitors can have on markers of NETosis, and, finally, the novel therapeutic strategies targeting NETs to reduce the thrombotic complications in these patients.
Therapeutic Application of Exosomes in Inflammatory Diseases
Authors: Suh Ju Hun , Joo Hyeon Su , Hong Eun Be , Lee Hyeon Ji , Lee Jung Min
Published: January 2021

Immunomodulation is on the cusp of being an important therapy for treating many diseases, due to the significant role of the immune system in defending the human body. Although the immune system is an essential defense system, overactivity can result in diverse sicknesses such as inflammation and autoimmune disease. Exosomes are emerging as a state-of-the-art therapeutic strategy for treating an overactive immune system. Thus, in this review, we will thoroughly review therapeutic applications of exosomes in various inflammatory and autoimmune diseases. Finally, issues for an outlook to the future of exosomal therapy will be introduced.
Genomic Adaption and Mutational Patterns in a HaCaT Subline Resistant to Alkylating Agents and Ionizing Radiation
Authors: Ullmann Reinhard , Becker Benjamin Valentin , Rothmiller Simone , Schmidt Annette , Thiermann Horst , Kaatsch Hanns Leonhard , Schrock Gerrit , Müller Jessica , Jakobi Julia , Obermair Richard , Port Matthias , Scherthan Harry
Published: January 2021

Sulfur mustard (SM) is a chemical warfare agent that can damage DNA via alkylation and oxidative stress. Because of its genotoxicity, SM is cancerogenic and the progenitor of many chemotherapeutics. Previously, we developed an SM-resistant cell line via chronic exposure of the popular keratinocyte cell line HaCaT to increasing doses of SM over a period of 40 months. In this study, we compared the genomic landscape of the SM-resistant cell line HaCaT/SM to its sensitive parental line HaCaT in order to gain insights into genetic changes associated with continuous alkylation and oxidative stress. We established chromosome numbers by cytogenetics, analyzed DNA copy number changes by means of array Comparative Genomic Hybridization (array CGH), employed the genome-wide chromosome conformation capture technique Hi-C to detect chromosomal translocations, and derived mutational signatures by whole-genome sequencing. We observed that chronic SM exposure eliminated the initially prevailing hypotetraploid cell population in favor of a hyperdiploid one, which contrasts with previous observations that link polyploidization to increased tolerance and adaptability toward genotoxic stress. Furthermore, we observed an accumulation of chromosomal translocations, frequently flanked by DNA copy number changes, which indicates a high rate of DNA double-strand breaks and their misrepair. HaCaT/SM-specific single-nucleotide variants showed enrichment of C > A and T > A transversions and a lower rate of deaminated cytosines in the CpG dinucleotide context. Given the frequent use of HaCaT in toxicology, this study provides a valuable data source with respect to the original genotype of HaCaT and the mutational signatures associated with chronic alkylation and oxidative stress.
The Expression Levels and Cellular Localization of Pigment Epithelium Derived Factor (PEDF) in Mouse Testis: Its Possible Involvement in the Differentiation of Spermatogonial Cells
Authors: Bagdadi Noy , Sawaied Alaa , AbuMadighem Ali , Lunenfeld Eitan , Huleihel Mahmoud
Published: January 2021

Pigment epithelium derived factor (PEDF) is a multifunctional secretory soluble glycoprotein that belongs to the serine protease inhibitor (serpin) family. It was reported to have neurotrophic, anti-angiogenic and anti-tumorigenic activity. Recently, PEDF was found in testicular peritubular cells and it was assumed to be involved in the avascular nature of seminiferous tubules. The aim of this study was to determine the cellular origin, expression levels and target cells of PEDF in testicular tissue of immature and adult mice under physiological conditions, and to explore its possible role in the process of spermatogenesis in vitro. Using immunofluorescence staining, we showed that PEDF was localized in spermatogenic cells at different stages of development as well as in the somatic cells of the testis. Its protein levels in testicular homogenates and Sertoli cells supernatant showed a significant decrease with age. PEDF receptor (PEDF-R) was localized within the seminiferous tubule cells and in the interstitial cells compartment. Its RNA expression levels showed an increase with age until 8 weeks followed by a decrease. RNA levels of PEDF-R showed the opposite trend of the protein. Addition of PEDF to cultures of isolated cells from the seminiferous tubules did not changed their proliferation rate, however, a significant increase was observed in number of meiotic/post meiotic cells at 1000 ng/mL of PEDF; indicating an in vitro differentiation effect. This study may suggest a role for PEDF in the process of spermatogenesis.
Contributions of Flow Cytometry to the Molecular Study of Spermatogenesis in Mammals
Authors: Rodríguez-Casuriaga Rosana , Geisinger Adriana
Published: January 2021

Mammalian testes are very heterogeneous organs, with a high number of different cell types. Testicular heterogeneity, together with the lack of reliable in vitro culture systems of spermatogenic cells, have been an obstacle for the characterization of the molecular bases of the unique events that take place along the different spermatogenic stages. In this context, flow cytometry has become an invaluable tool for the analysis of testicular heterogeneity, and for the purification of stage-specific spermatogenic cell populations, both for basic research and for clinical applications. In this review, we highlight the importance of flow cytometry for the advances on the knowledge of the molecular groundwork of spermatogenesis in mammals. Moreover, we provide examples of different approaches to the study of spermatogenesis that have benefited from flow cytometry, including the characterization of mutant phenotypes, transcriptomics, epigenetic and genome-wide chromatin studies, and the attempts to establish cell culture systems for research and/or clinical aims such as infertility treatment.
Erratum: Chen, Y.-R., et al. Improvement of Impaired Motor Functions by Human Dental Exfoliated Deciduous Teeth Stem Cell-Derived Factors in a Rat Model of Parkinson’s Disease. Int. J. Mol. Sci. 2020, 21, 3807
Authors: Chen Yong-Ren , Lai Pei-Lun , Chien Yueh , Lee Po-Hui , Lai Ying-Hsiu , Ma Hsin-I , Shiau Chia-Yang , Wang Kuo-Chuan
Published: January 2021

The authors regret to have made a mistake in publishing this paper [...]
Protein Engineering Approaches to Enhance Fungal Laccase Production in S. cerevisiae
Authors: Aza Pablo , de Salas Felipe , Molpeceres Gonzalo , Rodríguez-Escribano David , de la Fuente Iñigo , Camarero Susana
Published: January 2021

Laccases secreted by saprotrophic basidiomycete fungi are versatile biocatalysts able to oxidize a wide range of aromatic compounds using oxygen as the sole requirement. Saccharomyces cerevisiae is a preferred host for engineering fungal laccases. To assist the difficult secretion of active enzymes by yeast, the native signal peptide is usually replaced by the preproleader of S. cerevisiae alfa mating factor (MFα1). However, in most cases, only basal enzyme levels are obtained. During directed evolution in S. cerevisiae of laccases fused to the α-factor preproleader, we demonstrated that mutations accumulated in the signal peptide notably raised enzyme secretion. Here we describe different protein engineering approaches carried out to enhance the laccase activity detected in the liquid extracts of S. cerevisiae cultures. We demonstrate the improved secretion of native and engineered laccases by using the fittest mutated α-factor preproleader obtained through successive laccase evolution campaigns in our lab. Special attention is also paid to the role of protein N-glycosylation in laccase production and properties, and to the introduction of conserved amino acids through consensus design enabling the expression of certain laccases otherwise not produced by the yeast. Finally, we revise the contribution of mutations accumulated in laccase coding sequence (CDS) during previous directed evolution campaigns that facilitate enzyme production.
Recent Advances of Microbiome-Associated Metabolomics Profiling in Liver Disease: Principles, Mechanisms, and Applications
Authors: Raja Ganesan , Gupta Haripriya , Gebru Yoseph Asmelash , Youn Gi Soo , Choi Ye Rin , Kim Hyeong Seop , Yoon Sang Jun , Kim Dong Joon , Kim Tae-Jin , Suk Ki Tae
Published: January 2021

Advances in high-throughput screening of metabolic stability in liver and gut microbiota are able to identify and quantify small-molecule metabolites (metabolome) in different cellular microenvironments that are closest to their phenotypes. Metagenomics and metabolomics are largely recognized to be the “-omics” disciplines for clinical therapeutic screening. Here, metabolomics activity screening in liver disease (LD) and gut microbiomes has significantly delivered the integration of metabolomics data (i.e., a set of endogenous metabolites) with metabolic pathways in cellular environments that can be tested for biological functions (i.e., phenotypes). A growing literature in LD and gut microbiomes reports the use of metabolites as therapeutic targets or biomarkers. Although growing evidence connects liver fibrosis, cirrhosis, and hepatocellular carcinoma, the genetic and metabolic factors are still mainly unknown. Herein, we reviewed proof-of-concept mechanisms for metabolomics-based LD and gut microbiotas’ role from several studies (nuclear magnetic resonance, gas/lipid chromatography, spectroscopy coupled with mass spectrometry, and capillary electrophoresis). A deeper understanding of these axes is a prerequisite for optimizing therapeutic strategies to improve liver health.
Analysis of a Preliminary microRNA Expression Signature in a Human Telangiectatic Osteogenic Sarcoma Cancer Cell Line
Authors: Palmini Gaia , Romagnoli Cecilia , Donati Simone , Zonefrati Roberto , Galli Gianna , Marini Francesca , Iantomasi Teresa , Aldinucci Alessandra , Leoncini Gigliola , Franchi Alessandro , Beltrami Giovanni , Campanacci Domenico Andrea , Capanna Rodolfo , Brandi Maria Luisa
Published: January 2021

Telangiectatic osteosarcoma (TOS) is an aggressive variant of osteosarcoma (OS) with distinctive radiographic, gross, microscopic features, and prognostic implications. Despite several studies on OS, we are still far from understanding the molecular mechanisms of TOS. In recent years, many studies have demonstrated not only that microRNAs (miRNAs) are involved in OS tumorigenesis, development, and metastasis, but also that the presence in high-grade types of OS of cancer stem cells (CSCs) plays an important role in tumor progression. Despite these findings, nothing has been described previously about the expression of miRNAs and the presence of CSCs in human TOS. Therefore, we have isolated/characterized a putative CSC cell line from human TOS (TOS-CSCs) and evaluated the expression levels of several miRNAs in TOS-CSCs using real-time quantitative assays. We show, for the first time, the existence of CSCs in human TOS, highlighting the in vitro establishment of this unique stabilized cell line and an identification of a preliminary expression of the miRNA profile, characteristic of TOS-CSCs. These findings represent an important step in the study of the biology of one of the most aggressive variants of OS and the role of miRNAs in TOS-CSC behavior.