bluuebunny/crossref_metadata_2025 huggingface dataset:
Helium–Oxygen Mixture Model for Particle Transport in CT-Based Upper Airways
Authors: Islam Mohammad S. , Gu YuanTong , Farkas Arpad , Paul Gunther , Saha Suvash C.
Published: May 2020

The knowledge of respiratory particle transport in the extra-thoracic pathways is essential for the estimation of lung health-risk and optimization of targeted drug delivery. The published literature reports that a significant fraction of the inhaled aerosol particles are deposited in the upper airways, and available inhalers can deliver only a small amount of drug particles to the deeper airways. To improve the targeted drug delivery efficiency to the lungs, it is important to reduce the drug particle deposition in the upper airways. This study aims to minimize the unwanted aerosol particle deposition in the upper airways by employing a gas mixture model for the aerosol particle transport within the upper airways. A helium–oxygen (heliox) mixture (80% helium and 20% oxygen) model is developed for the airflow and particle transport as the heliox mixture is less dense than air. The mouth–throat and upper airway geometry are extracted from CT-scan images. Finite volume based ANSYS Fluent (19.2) solver is used to simulate the airflow and particle transport in the upper airways. Tecplot software and MATLAB code are employed for the airflow and particle post-processing. The simulation results show that turbulence intensity for heliox breathing is lower than in the case of air-breathing. The less turbulent heliox breathing eventually reduces the deposition efficiency (DE) at the upper airways than the air-breathing. The present study, along with additional patient-specific investigation, could improve the understanding of particle transport in upper airways, which may also increase the efficiency of aerosol drug delivery.
Coverage of Health Information by Different Sources in Communities: Implication for COVID-19 Epidemic Response
Authors: Tran Bach Xuan , Dang Anh Kim , Thai Phong Khanh , Le Huong Thi , Le Xuan Thanh Thi , Do Toan Thanh Thi , Nguyen Tu Huu , Pham Hai Quang , Phan Hai Thanh , Vu Giang Thu , Phung Dung Tri , Nghiem Son Hong , Nguyen Thu Ha , Tran Trung Dinh , Do Khanh Nam , Truong Dat Van , Vu Giap Van , Latkin Carl A. , Ho Roger C.M. , Ho Cyrus S.H.
Published: May 2020

Health personnel and community workers are at the front line of the COVID-19 emergency response and need to be equipped with adequate knowledge related to epidemics for an effective response. This study aimed to identify the coverage of COVID-19 health information via different sources accessed by health workers and community workers in Vietnam. A cross-sectional study using a web-based survey was carried out from January to February 2020 in Vietnam. Respondent-driven sampling (RDS) was used for recruiting participants. We utilized the exploratory factor analysis (EFA) to examine the construct validity of the questionnaire. A higher percentage of participants knew about “Clinical and pathogen characteristics of COVID-19”, compared to “Regulations and policies related to COVID-19”. The percentage of participants accessing the information on “Guidelines and policies on prevention and control of COVID-19” was the lowest, especially among medical students. “Mass media and peer-educators” channels had a higher score of accessing COVID-19 information, compared to “Organizations/ agencies/ associations” sources. Participants consumed most of their COVID-19 information via “Internet, online newspapers, social networks”. Our findings indicate an urgency to re-design training programs and communication activities for a more effective dissemination of information related to the COVID-19 epidemic or epidemics in general.
Analysis of the Dimensions of Quality of Life in Colombian University Students: Structural Equation Analysis
Authors: Arcila-Arango Juan-Cancio , Castro-Sánchez Manuel , Espoz-Lazo Sebastian , Cofre-Bolados Cristian , Zagalaz-Sánchez Maria Luisa , Valdivia-Moral Pedro
Published: May 2020

The aim of the present study was to define and contrast a explicative model of the relationship between the variables of quality of life that make up the KIDSCREEN-52 questionnaire. Methods: A total of 1641 Colombian university students aged between 17 and 18 years (17.69 + 0.490) participated in this research (61.2% males and 38.8% females) analyzing the dimensions of the KIDSCREEN-52 quality of life questionnaire. A model of structural equation was made and adjusted (χ2 = 118.021; DF = 6; p < 0.001; CFI = 0.953; NFI = 0.951; IFI = 0.954; RMSEA = 0.076). Results: The analyzed dimensions of quality of life were related in a positive and direct way, except for the Parent Relationship and Family Life (Family L.) with Social Acceptance (Social A.), which were associated in a negative and indirect manner. Conclusions: The main conclusion of this investigation is that all dimensions of quality of life associate in a positive manner with the exception of Parent Relationship and Family Life (Family L.) which associated with Social Acceptance (Social A.). The qualities improve together, highlighting the idea that working on any of the areas that comprise quality of life will cause development of the remaining areas.
An Unusual Dysphagia for Solids in a 17-Year-Old Girl Due To a Lusoria Artery: A Case Report and Review of the Literature
Authors: Fanelli Umberto , Iannarella Rosanna , Meoli Aniello , Gismondi Pierpacifico , Cella Simone , Vincenzi Francesca , Esposito Susanna
Published: May 2020

Background: Dysphagia is a condition that can have many underlying causes, often different between adults and children and its early diagnosis is crucial especially during childhood and adolescence, given the importance of proper nutritional intake to ensure adequate growth and development. Case report: We described the case of a 17-year-old girl reporting dysphagia for solids for approximately one month. No symptoms were previously referred. Oesophagogastroduodenoscopy was performed, detecting an image of ab extrinseco compression at the level of the mid-cervical oesophagus. An upper gastrointestinal tract radiography confirmed an oesophageal impression above the arch of the aorta suggestive of vascular abnormality. Computed tomography angiography and three-dimensional reconstruction techniques showed the presence of a lusoria artery that originated from the medial margin of the descending aorta and crossed the trachea and oesophagus posteriorly to the distal third. The lusoria artery was transected via a left thoracotomy and re-implanted into the right common carotid artery with complete symptom resolution. Conclusions: Dysphagia lusoria is an impairment of swallowing due to compression from an aberrant right subclavian artery. The diagnosis is always difficult, as the symptoms are often nonspecific. It is imperative to accurately identify and properly manage dysphagia in pediatric age and this is only possible with an anamnestic, clinical and instrumental process that takes into account an adequate differential diagnosis.
Appropriate Employment for Segregated Roma: Mechanisms in a Public–Private Partnership Project
Authors: Bosakova Lucia , Madarasova Geckova Andrea , van Dijk Jitse P. , Reijneveld Sijmen A.
Published: May 2020

Our earlier article showed that increased employability of segregated Roma may improve their well-being and health. To achieve that, appropriate employment based on a public–private partnership could be the key. For optimal design of such a partnership, we need insight into its potential mechanisms. Evidence on this is lacking, however. This paper builds on the previously published article by focusing on mechanisms for achieving better health. Therefore, our aim was to identify the potential mechanisms by which a public–private Roma employment project could increase employability. We investigated a Roma employment project called Equality of Opportunity established by a private company, U.S. Steel Kosice in eastern Slovakia. We conducted a multi-perspective qualitative study to obtain key stakeholders’ perspectives on the potential mechanisms of a public–private Roma employment project in terms of increased employability. We found three types of mechanisms. The first type regarded formal job mechanisms, such as an appropriate employment and salary offer and a bottom-up approach in capacity building. The second type involved sustainability mechanisms, such as the personal profile of project and work-shift coordinators, the continuous offer of training and cooperation with relevant stakeholders (municipalities, community centers, etc.). The third type was cultural mechanisms, such as personal contact with project participants, attention to less-voiced groups like children, the motivation of project participants, a counter-value reciprocity approach and respect for the specifics of Roma history. Our findings imply that policymakers could consider public–private partnerships for increasing the employability of segregated Roma, as they have the potential to address a wider range of social needs simultaneously.
A Brief Intervention for Malnutrition among Older Adults: Stepping Up Your Nutrition
Authors: Smith Matthew Lee , Bergeron Caroline D. , Lachenmayr Sue , Eagle Leigh Ann , Simon Judy R.
Published: May 2020

Despite a multitude of nutritional risk factors among older adults, there is a lack of community-based programs and activities that screen for malnutrition and address modifiable risk among this vulnerable population. Given the known association of protein and fluid consumption with fall-related risk among older adults and the high prevalence of falls among Americans age 65 years and older each year, a brief intervention was created. Stepping Up Your Nutrition (SUYN) is a 2.5 h workshop developed through a public/private partnership to motivate older adults to reduce their malnutrition risk. The purposes of this naturalistic workshop dissemination were to: (1) describe the SUYN brief intervention; (2) identify participant characteristics associated with malnutrition risk; and (3) identify participant characteristics associated with subsequent participation in Stepping On (SO), an evidence-based fall prevention program. Data were analyzed from 429 SUYN participants, of which 38% (n = 163) subsequently attended SO. As measured by the SCREEN II®, high and moderate malnutrition risk scores were reported among approximately 71% and 20% of SUYN participants, respectively. Of the SUYN participants with high malnutrition risk, a significantly larger proportion attended a subsequent SO workshop (79.1%) compared to SUYN participants who did not proceed to SO (65.8%) (χ2 = 8.73, p = 0.013). Findings suggest SUYN may help to identify malnutrition risk among community-dwelling older adults and link them to needed services like evidence-based programs. Efforts are needed to expand the delivery infrastructure of SUYN to reach more at-risk older adults.
Risk of Herpes Zoster in Patients with Adhesive Capsulitis of the Shoulder
Authors: Hsu Chao-Yu , Ke Der-Shin , Lin Cheng-Li , Kao Chia-Hung
Published: May 2020

Background: Physical diseases, such as infection, and emotional distress are associated with herpes zoster (HZ). However, the relationship between adhesive capsulitis of the shoulder (ACoS) and HZ remains unknown. Objective: This study investigated the risk of HZ development in patients with ACoS. Methods: We analyzed the Longitudinal Health Insurance Database, a subset of 1 million beneficiaries from the National Health Insurance Research Database. Patients newly diagnosed with ACoS during the 2000–2012 period were the case group. Each patient with ACoS was matched to a control, according to age and index year, through frequency matching. HZ was the primary event in this study. Results: A total of 60,478 patients were included and each group contained 30,239 patients. The risk of HZ infection in the case cohort was 1.28 times that of the control cohort. ACoS increased the risk of HZ infection in each age group, particularly among patients aged younger than 50 [adjusted hazard ratio (aHR) = 1.52, 95% confidence interval (CI): 1.31–1.75]. Relative to the control group, the hazard ratio of HZ for male patients (aHR = 1.40, 95% CI: 1.26–1.55) in the case group was higher than that for female patients (aHR = 1.22, 95% CI: 1.13–1.32). Conclusion: Patients with ACoS have a higher risk of HZ development, particularly among those aged younger than 50 years. The effect of ACoS on HZ development among young adults requires attention.
Factors Associated with Burnout Syndrome in Primary and Secondary School Teachers in the Republic of Srpska (Bosnia and Herzegovina)
Authors: Marić Nada , Mandić-Rajčević Stefan , Maksimović Nataša , Bulat Petar
Published: May 2020

Objectives: The aim of this study was to estimate the prevalence of burnout syndrome in a large sample of primary and secondary school teachers in the Republic of Srpska (Bosnia and Herzegovina) and identify the factors associated with burnout in this population. Methods: This cross-sectional study was conducted in August and September of 2018, on a sample of 952 teachers. Beside socio-demographic information, Bortner scale, Job Content Questionnaire, and Maslach Burnout Inventory were filled in by the study participants. Results: Only 5.1% of teachers reported high levels of emotional exhaustion, 3.8% reported high levels of depersonalization, and 22.3% reported low levels of personal accomplishment. Behavior type, specifically type-A behavior, was associated with higher levels of emotional exhaustion. The most important factors associated with burnout were work–life characteristics and job-demand-control model of occupational stress. Conclusions: Our study shows a low prevalence of emotional exhaustion and depersonalization in teachers in the Republic of Srpska before the beginning of the new school year. Since similar studies show a high prevalence of burnout at the end of the school year, a potential seasonality of this syndrome should be considered and explored further.
Anticipating Environmental Burdens in Research and Innovation Projects—Application to the Case of Active and Healthy Ageing
Authors: Monsonís-Payá Irene , Gómez-Navarro Tomás , García-Melón Mónica
Published: May 2020

In this paper; for research and innovation projects without environmental goals; a procedure is proposed to operationalize the anticipation and reflexivity of environmental concerns in the initial phases. By using the expert knowledge of specialists; we have first conducted a study to identify the general environmental topics relevant in any kind of research and innovation project not addressing the environment. In a second phase; a strategy is proposed to rank order the topics in terms of environmental relevance by means of the Analytic Hierarchy Process. To illustrate it; the case of Information and Communication Technologies for Active and Healthy Ageing is used because of its increasing importance; and because normal environmental targets are not considered. Results show that; in this case; the most relevant topic to be considered is the primary energy consumption by sources; followed by hazardous solid waste and consumption of non-renewable and scarce materials. According to the experts; these should be the main issues to be considered regarding the environmental sustainability of the outputs of such research and innovation projects. In conclusion; this paper contributes to a better understanding of how to promote a wider integration of environmental sustainability in research and innovation when environmental goals are not initially included.
A Review of Techniques for 3D Reconstruction of Indoor Environments
Authors: Kang Zhizhong , Yang Juntao , Yang Zhou , Cheng Sai
Published: May 2020

Indoor environment model reconstruction has emerged as a significant and challenging task in terms of the provision of a semantically rich and geometrically accurate indoor model. Recently, there has been an increasing amount of research related to indoor environment reconstruction. Therefore, this paper reviews the state-of-the-art techniques for the three-dimensional (3D) reconstruction of indoor environments. First, some of the available benchmark datasets for 3D reconstruction of indoor environments are described and discussed. Then, data collection of 3D indoor spaces is briefly summarized. Furthermore, an overview of the geometric, semantic, and topological reconstruction of the indoor environment is presented, where the existing methodologies, advantages, and disadvantages of these three reconstruction types are analyzed and summarized. Finally, future research directions, including technique challenges and trends, are discussed for the purpose of promoting future research interest. It can be concluded that most of the existing indoor environment reconstruction methods are based on the strong Manhattan assumption, which may not be true in a real indoor environment, hence limiting the effectiveness and robustness of existing indoor environment reconstruction methods. Moreover, based on the hierarchical pyramid structures and the learnable parameters of deep-learning architectures, multi-task collaborative schemes to share parameters and to jointly optimize each other using redundant and complementary information from different perspectives show their potential for the 3D reconstruction of indoor environments. Furthermore, indoor–outdoor space seamless integration to achieve a full representation of both interior and exterior buildings is also heavily in demand.
A GIS-based DRASTIC Model and an Adjusted DRASTIC Model (DRASTICA) for Groundwater Susceptibility Assessment along the China–Pakistan Economic Corridor (CPEC) Route
Authors: Maqsoom Ahsen , Aslam Bilal , Khalil Umer , Ghorbanzadeh Omid , Ashraf Hassan , Faisal Tufail Rana , Farooq Danish , Blaschke Thomas
Published: May 2020

Land use types and anthropogenic activities represent considerable threats to groundwater pollution. To effectively monitor the groundwater quality, it is vital to measure pollution levels before they become severe. In our research area, located in Gilgit Baltistan in northern Pakistan, groundwater supplies are diminishing due to urban sprawl. In this study, we used a GIS-based DRASTIC model (Depth to water, Recharge, Aquifer media, Soil media, Topography, Impact of the vadose zone, Hydraulic conductivity) to analyze the area’s hydrological attributes to assess the groundwater susceptibility to pollution. Considering the importance of anthropogenic activities, this research primarily utilizes an adjusted DRASTIC model called DRASTICA, which incorporates anthropogenic impact as a parameter in the model. The resulting map, which depicts vulnerability to groundwater contamination, reveals that 19% of the study area is classed as having high vulnerability, 42% has moderate vulnerability, 37% has low vulnerability, and 2% has very low vulnerability to groundwater contamination. The adopted validation process (nitrate parameter of water quality) revealed that the suggested DRASTICA model achieved better results than the established DRASTIC model in a built-up environment. We used the nitrate concentration in groundwater to verify the formulated results, and the single parameter sensitivity analysis and map removal sensitivity analysis to analyze the model sensitivity. The sensitivity analysis indicated that the groundwater vulnerability to pollution is largely influenced by anthropogenic impact and depth to the water table, thereby suggesting that anthropogenic impact must be explicitly tackled in such studies. The groundwater zones exposed to anthropogenic pollution can be better classified with the help of the proposed DRASTICA model, particularly in and around built-up environments. The responsible authorities can use this groundwater contamination data as an early warning sign, so they can take practical actions to avoid extra pressure on this vital resource.
Modelling Offset Regions around Static and Mobile Locations on a Discrete Global Grid System: An IoT Case Study
Authors: Bowater David , Wachowicz Monica
Published: May 2020

With the huge volume of location-based point data being generated by Internet of Things (IoT) devices and subsequent rising interest from the Digital Earth community, a need has emerged for spatial operations that are compatible with Digital Earth frameworks, the foundation of which are Discrete Global Grid Systems (DGGSs). Offsetting is a fundamental spatial operation that allows us to determine the region within a given distance of an IoT device location, which is important for visualizing or querying nearby location-based data. Thus, in this paper, we present methods of modelling an offset region around the point location of an IoT device (both static and mobile) that is quantized into a cell of a DGGS. Notably, these methods illustrate how the underlying indexing structure of a DGGS can be utilized to determine the cells in an offset region at different spatial resolutions. For a static IoT device location, we describe a single resolution approach as well as a multiresolution approach that allows us to efficiently determine the cells in an offset region at finer (or coarser) resolutions. For mobile IoT device locations, we describe methods to efficiently determine the cells in successive offset regions at fine and coarse resolutions. Lastly, we present a variety of results that demonstrate the effectiveness of the proposed methods.
Discovery of the Novel Inhibitor Against New Delhi Metallo-β-Lactamase Based on Virtual Screening and Molecular Modelling
Authors: Wang Xiyan , Yang Yanan , Gao Yawen , Niu Xiaodi
Published: May 2020

New Delhi metallo-β-lactamase (NDM-1), one of the metallo-β-lactamases (MBLs), leads to antibiotic resistance in clinical treatments due to the strong ability of hydrolysis to almost all kinds of β-lactam antibiotics. Therefore, there is the urgent need for the research and development of the novel drug-resistant inhibitors targeting NDM-1. In this study, ZINC05683641 was screened as potential NDM-1 inhibitor by virtual screening and the inhibitor mechanism of this compound was explored based on molecular dynamics simulation. The nitrocefin assay showed that the IC50 value of ZINC05683641 was 13.59 ± 0.52 μM, indicating that the hydrolytic activity of NDM-1 can be obviously suppressed by ZINC05683641. Further, the binding mode of ZINC05683641 with NDM-1 was obtained by molecular modeling, binding free energy calculation, mutagenesis assays and fluorescence-quenching assays. As results, ILE-35, MET-67, VAL-73, TRP-93, CYS-208, ASN-220 and HIS-250 played the key roles in the binding of NDM-1 with ZINC05683641. Interestingly, these key residues were exactly located in the catalytic activity region of NDM-1, implying that the inhibitor mechanism of ZINC05683641 against NDM-1 was the competitive inhibition. These findings will provide an available approach to research and develop new drug against NDM-1 and treatment for bacterial resistance.
Breast Cancer Derived Extracellular Vesicles in Bone Metastasis Induction and Their Clinical Implications as Biomarkers
Authors: Taverna Simona , Giusti Ilaria , D’Ascenzo Sandra , Pizzorno Laura , Dolo Vincenza
Published: May 2020

Cancer incidence and mortality are rapidly growing worldwide. The main risk factors for cancer can be associated with aging as well as the growth of the population and socioeconomic condition. Breast cancer, a crucial public health problem, is the second cause of death among women. About 70% of patients with advanced breast cancer have bone metastases. In bone metastasis, cancer cells and osteoclasts form a vicious cycle: cancer cells promote osteoclast differentiation and activation that, in turn, induce cancer cell seeding and proliferation in the bone. Growing evidence shows that extracellular vesicles (EVs) play a key role in carcinogenesis, proliferation, pre-metastatic niche formation, angiogenesis, metastasis, and chemoresistance in several tumors, such as breast, lung, prostate, and liver cancer. Here, we discuss the role of EVs released by breast cancer cells, focusing on bone metastasis induction and their clinical implications as biomarkers.
Cathecol and Naphtol Groups in Salphen-Type Schiff Bases for the Preparation of Polynuclear Complexes
Authors: Gholizadeh Dogaheh Samira , Barbero Sara , Barrientos Joel , Janczak Jan , Soleimannejad Janet , Sañudo E. Carolina
Published: May 2020

In this paper, we show a strategy to modify salphen-type Schiff base ligands with naphtol (SYML1) and pyrocathecol (2,3-dihydroxyphenyl) groups (SYML2), or a combination of both (ASYML). Each of these ligands can be used to obtain polynuclear metal complexes following two different strategies. One relies on using metals that are either too large for the N2O2 cavity or not fond of coordination number 4 and the other one relies on forcing the polynuclear species by adding functional groups to the hydroxybenzaldehayde in order to have extra coordination sites in the ligand. We report and characterize the mononuclear complexes SYML1-Cu and SYML1-Ce, along with the dinuclear complex SYML1-Fe and the tetranuclear species SYML2-Mn. The asymmetric ligand ASYML routinely hydrolyzes into the symmetric ligands in the reaction mixtures. SYML1-Fe displays a nearly linear Fe-O-Fe bridge with very strong antiferromagnetic coupling between the Fe(III) ions.
Correction: Cuenca-Zamora, Ernesto José., et al. Tubulin in Platelets: When the Shape Matter. Int. J. Mol. Sci. 2019, 20, 3484
Authors: Cuenca-Zamora Ernesto José , Ferrer-Marín Francisca , Rivera José , Teruel-Montoya Raúl
Published: May 2020

The authors wish to make the following corrections to this paper [...]
Resveratrol Delivery from Implanted Cyclodextrin Polymers Provides Sustained Antioxidant Effect on Implanted Neural Probes
Authors: Haley Rebecca M. , Zuckerman Sean T. , Dakhlallah Hassan , Capadona Jeffery R. , von Recum Horst A. , Ereifej Evon S.
Published: May 2020

Intracortical microelectrodes are valuable tools used to study and treat neurological diseases. Due in large part to the oxidative stress and inflammatory response occurring after electrode implantation, the signal quality of these electrodes decreases over time. To alleviate this response, resveratrol, a natural antioxidant which elicits neuroprotective effects through reduction of oxidative stress, was utilized. This work compares traditional systemic delivery of resveratrol to the novel cyclodextrin polymer (pCD) local delivery approach presented herein, both in vitro and in vivo. The pCD displayed an extended resveratrol release for 100 days, as well as 60 days of free radical scavenging activity in vitro. In vivo results indicated that our pCD delivery system successfully delivered resveratrol to the brain with a sustained release for the entire short-duration study (up to 7 days). Interestingly, significantly greater concentrations of resveratrol metabolites were found at the intracortical probe implantation site compared to the systemic administration of resveratrol. Together, our pilot results provide support for the possibility of improving the delivery of resveratrol in an attempt to stabilize long-term neural interfacing applications.
Similarity-Based Methods and Machine Learning Approaches for Target Prediction in Early Drug Discovery: Performance and Scope
Authors: Mathai Neann , Kirchmair Johannes
Published: May 2020

Computational methods for predicting the macromolecular targets of drugs and drug-like compounds have evolved as a key technology in drug discovery. However, the established validation protocols leave several key questions regarding the performance and scope of methods unaddressed. For example, prediction success rates are commonly reported as averages over all compounds of a test set and do not consider the structural relationship between the individual test compounds and the training instances. In order to obtain a better understanding of the value of ligand-based methods for target prediction, we benchmarked a similarity-based method and a random forest based machine learning approach (both employing 2D molecular fingerprints) under three testing scenarios: a standard testing scenario with external data, a standard time-split scenario, and a scenario that is designed to most closely resemble real-world conditions. In addition, we deconvoluted the results based on the distances of the individual test molecules from the training data. We found that, surprisingly, the similarity-based approach generally outperformed the machine learning approach in all testing scenarios, even in cases where queries were structurally clearly distinct from the instances in the training (or reference) data, and despite a much higher coverage of the known target space.
APE1 Promotes Pancreatic Cancer Proliferation through GFRα1/Src/ERK Axis-Cascade Signaling in Response to GDNF
Authors: Choi Yoo-Duk , Jung Ji-Yeon , Baek Minwoo , Khan Sheema , Song Peter I. , Ryu Sunhyo , Koo Joo-Yeon , Chauhan Subhash C. , Tsin Andrew , Choi Chan , Kim Won Jae , Kim Mihwa
Published: May 2020

Pancreatic cancer is the worst exocrine gastrointestinal cancer leading to the highest mortality. Recent studies reported that aberrant expression of apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) is involved in uncontrolled cell growth. However, the molecular mechanism of APE1 biological role remains unrevealed in pancreatic cancer progression. Here, we demonstrate that APE1 accelerates pancreatic cancer cell proliferation through glial cell line-derived neurotrophic factor (GDNF)/glial factor receptor α1 (GFRα1)/Src/ERK axis-cascade signaling. The proliferation of endogenous APE1 expressed-MIA PaCa-2, a human pancreatic carcinoma cell line, was increased by treatment with GDNF, a ligand of GFRα1. Either of downregulated APE1 or GFRα1 expression using small interference RNA (siRNA) inhibited GDNF-induced cancer cell proliferation. The MEK-1 inhibitor PD98059 decreased GDNF-induced MIA PaCa-2 cell proliferation. Src inactivation by either its siRNA or Src inhibitor decreased ERK-phosphorylation in response to GDNF in MIA PaCa-2 cells. Overexpression of GFRα1 in APE1-deficient MIA PaCa-2 cells activated the phosphorylation of Src and ERK. The expression of both APE1 and GFRα1 was gradually increased as progressing pancreatic cancer grades. Our results highlight a critical role for APE1 in GDNF-induced pancreatic cancer cell proliferation through APE1/GFRα1/Src/ERK axis-cascade signaling and provide evidence for future potential therapeutic drug targets for the treatment of pancreatic cancer.
Robust Sampling of Defective Pathways in Alzheimer’s Disease. Implications in Drug Repositioning
Authors: Fernández-Martínez Juan Luis , Álvarez-Machancoses Óscar , deAndrés-Galiana Enrique J. , Bea Guillermina , Kloczkowski Andrzej
Published: May 2020

We present the analysis of the defective genetic pathways of the Late-Onset Alzheimer’s Disease (LOAD) compared to the Mild Cognitive Impairment (MCI) and Healthy Controls (HC) using different sampling methodologies. These algorithms sample the uncertainty space that is intrinsic to any kind of highly underdetermined phenotype prediction problem, by looking for the minimum-scale signatures (header genes) corresponding to different random holdouts. The biological pathways can be identified performing posterior analysis of these signatures established via cross-validation holdouts and plugging the set of most frequently sampled genes into different ontological platforms. That way, the effect of helper genes, whose presence might be due to the high degree of under determinacy of these experiments and data noise, is reduced. Our results suggest that common pathways for Alzheimer’s disease and MCI are mainly related to viral mRNA translation, influenza viral RNA transcription and replication, gene expression, mitochondrial translation, and metabolism, with these results being highly consistent regardless of the comparative methods. The cross-validated predictive accuracies achieved for the LOAD and MCI discriminations were 84% and 81.5%, respectively. The difference between LOAD and MCI could not be clearly established (74% accuracy). The most discriminatory genes of the LOAD-MCI discrimination are associated with proteasome mediated degradation and G-protein signaling. Based on these findings we have also performed drug repositioning using Dr. Insight package, proposing the following different typologies of drugs: isoquinoline alkaloids, antitumor antibiotics, phosphoinositide 3-kinase PI3K, autophagy inhibitors, antagonists of the muscarinic acetylcholine receptor and histone deacetylase inhibitors. We believe that the potential clinical relevance of these findings should be further investigated and confirmed with other independent studies.
Placental Microarray Profiling Reveals Common mRNA and lncRNA Expression Patterns in Preeclampsia and Intrauterine Growth Restriction
Authors: Medina-Bastidas Diana , Guzmán-Huerta Mario , Borboa-Olivares Hector , Ruiz-Cruz César , Parra-Hernández Sandra , Flores-Pliego Arturo , Salido-Guadarrama Ivan , Camargo-Marín Lisbeth , Arambula-Meraz Eliakym , Estrada-Gutierrez Guadalupe
Published: May 2020

Preeclampsia (PE) and Intrauterine Growth Restriction (IUGR) are major contributors to perinatal morbidity and mortality. These pregnancy disorders are associated with placental dysfunction and share similar pathophysiological features. The aim of this study was to compare the placental gene expression profiles including mRNA and lncRNAs from pregnant women from four study groups: PE, IUGR, PE-IUGR, and normal pregnancy (NP). Gene expression microarray analysis was performed on placental tissue obtained at delivery and results were validated using RTq-PCR. Differential gene expression analysis revealed that the largest transcript variation was observed in the IUGR samples compared to NP (n = 461; 314 mRNAs: 252 up-regulated and 62 down-regulated; 133 lncRNAs: 36 up-regulated and 98 down-regulated). We also detected a group of differentially expressed transcripts shared between the PE and IUGR samples compared to NP (n = 39), including 9 lncRNAs with a high correlation degree (p < 0.05). Functional enrichment of these shared transcripts showed that cytokine signaling pathways, protein modification, and regulation of JAK-STAT cascade are over-represented in both placental ischemic diseases. These findings contribute to the molecular characterization of placental ischemia showing common epigenetic regulation implicated in the pathophysiology of PE and IUGR.
Zygotic Vsx1 Plays a Key Role in Defining V2a Interneuron Sub-Lineage by Directly Repressing tal1 Transcription in Zebrafish
Authors: Zhang Qi , Xu Haomang , Zhao Wei , Zheng Jianbo , Sun Lei , Luo Chen
Published: May 2020

In the spinal cord, excitatory V2a and inhibitory V2b interneurons are produced together by the final division of common P2 progenitors. During V2a and V2b diversification, Tal1 is necessary and sufficient to promote V2b differentiation and Vsx2 suppresses the expression of motor neuron genes to consolidate V2a interneuron identity. The expression program of Tal1 is triggered by a Foxn4-driven regulatory network in the common P2 progenitors. Why the expression of Tal1 is inhibited in V2a interneurons at the onset of V2a and V2b sub-lineage diversification remains unclear. Since transcription repressor Vsx1 is expressed in the P2 progenitors and newborn V2a cells in zebrafish, we investigated the role of Vsx1 in V2a fate specification during V2a and V2b interneuron diversification in this species by loss and gain-of-function experiments. In vsx1 knockdown embryos or knockout Go chimeric embryos, tal1 was ectopically expressed in the presumptive V2a cells, while the generation of V2a interneurons was significantly suppressed. By contrast, in vsx1 overexpression embryos, normal expression of tal1 in the presumptive V2b cells was suppressed, while the generation of V2a interneuron was expanded. Chromatin immunoprecipitation and electrophoretic mobility shift assays in combination with core consensus sequence mutation analysis further revealed that Vsx1 can directly bind to tal1 promoter and repress tal1 transcription. These results indicate that Vsx1 can directly repress tal1 transcription and plays an essential role in defining V2a interneuron sub-lineage during V2a and V2b sub-lineage diversification in zebrafish.
On-Target CRISPR/Cas9 Activity Can Cause Undesigned Large Deletion in Mouse Zygotes
Authors: Korablev Alexey , Lukyanchikova Varvara , Serova Irina , Battulin Nariman
Published: May 2020

Genome engineering has been tremendously affected by the appearance of the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (CRISPR/Cas9)-based approach. Initially discovered as an adaptive immune system for prokaryotes, the method has rapidly evolved over the last decade, overtaking multiple technical challenges and scientific tasks and becoming one of the most effective, reliable, and easy-to-use technologies for precise genomic manipulations. Despite its undoubtable advantages, CRISPR/Cas9 technology cannot ensure absolute accuracy and predictability of genomic editing results. One of the major concerns, especially for clinical applications, is mutations resulting from error-prone repairs of CRISPR/Cas9-induced double-strand DNA breaks. In some cases, such error-prone repairs can cause unpredicted and unplanned large genomic modifications within the CRISPR/Cas9 on-target site. Here we describe the largest, to the best of our knowledge, undesigned on-target deletion with a size of ~293 kb that occurred after the cytoplasmic injection of CRISPR/Cas9 system components into mouse zygotes and speculate about its origin. We suppose that deletion occurred as a result of the truncation of one of the ends of a double-strand break during the repair.
Plasma Oxalate as a Predictor of Kidney Function Decline in a Primary Hyperoxaluria Cohort
Authors: Shah Ronak Jagdeep , Vaughan Lisa E. , Enders Felicity T. , Milliner Dawn S. , Lieske John C.
Published: May 2020

This retrospective analysis investigated plasma oxalate (POx) as a potential predictor of end-stage kidney disease (ESKD) among primary hyperoxaluria (PH) patients. PH patients with type 1, 2, and 3, age 2 or older, were identified in the Rare Kidney Stone Consortium (RKSC) PH Registry. Since POx increased with falling estimated glomerular filtration rate (eGFR), patients were stratified by chronic kidney disease (CKD) subgroups (stages 1, 2, 3a, and 3b). POx values were categorized into quartiles for analysis. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for risk of ESKD were estimated using the Cox proportional hazards model with a time-dependent covariate. There were 118 patients in the CKD1 group (nine ESKD events during follow-up), 135 in the CKD 2 (29 events), 72 in CKD3a (34 events), and 45 patients in CKD 3b (31 events). During follow-up, POx Q4 was a significant predictor of ESKD compared to Q1 across CKD2 (HR 14.2, 95% CI 1.8–115), 3a (HR 13.7, 95% CI 3.0–62), and 3b stages (HR 5.2, 95% CI 1.1–25), p < 0.05 for all. Within each POx quartile, the ESKD rate was higher in Q4 compared to Q1–Q3. In conclusion, among patients with PH, higher POx concentration was a risk factor for ESKD, particularly in advanced CKD stages.
Multiplatform Investigation of Plasma and Tissue Lipid Signatures of Breast Cancer Using Mass Spectrometry Tools
Authors: Silva Alex Ap. Rosini , Cardoso Marcella R. , Rezende Luciana Montes , Lin John Q. , Guimaraes Fernando , Silva Geisilene R. Paiva , Murgu Michael , Priolli Denise Gonçalves , Eberlin Marcos N. , Tata Alessandra , Eberlin Livia S. , Derchain Sophie F. M. , Porcari Andreia M.
Published: May 2020

Plasma and tissue from breast cancer patients are valuable for diagnostic/prognostic purposes and are accessible by multiple mass spectrometry (MS) tools. Liquid chromatography-mass spectrometry (LC-MS) and ambient mass spectrometry imaging (MSI) were shown to be robust and reproducible technologies for breast cancer diagnosis. Here, we investigated whether there is a correspondence between lipid cancer features observed by desorption electrospray ionization (DESI)-MSI in tissue and those detected by LC-MS in plasma samples. The study included 28 tissues and 20 plasma samples from 24 women with ductal breast carcinomas of both special and no special type (NST) along with 22 plasma samples from healthy women. The comparison of plasma and tissue lipid signatures revealed that each one of the studied matrices (i.e., blood or tumor) has its own specific molecular signature and the full interposition of their discriminant ions is not possible. This comparison also revealed that the molecular indicators of tissue injury, characteristic of the breast cancer tissue profile obtained by DESI-MSI, do not persist as cancer discriminators in peripheral blood even though some of them could be found in plasma samples.
Role and Mechanisms of RAGE-Ligand Complexes and RAGE-Inhibitors in Cancer Progression
Authors: El-Far Ali H. , Sroga Grazyna , Al Jaouni Soad K. , Mousa Shaker A.
Published: May 2020

Interactions of the receptor for advanced glycation end product (RAGE) and its ligands in the context of their role in diabetes mellitus, inflammation, and carcinogenesis have been extensively investigated. This review focuses on the role of RAGE-ligands and anti-RAGE drugs capable of controlling cancer progression. Different studies have demonstrated interaction of RAGE with a diverse range of acidic (negatively charged) ligands such as advanced glycation end products (AGEs), high-mobility group box1 (HMGB1), and S100s, and their importance to cancer progression. Some RAGE-ligands displayed effects on anti- and pro-apoptotic proteins through upregulation of the phosphatidylinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), mitogen-activated protein kinases (MAPKs), matrix metalloproteinases (MMPs), vascular endothelial growth factor (VEGF), and nuclear factor kappa B (NF-κB) pathways, while downregulating p53 in cancer progression. In addition, RAGE may undergo ligand-driven multimodal dimerization or oligomerization mediated through self-association of some of its subunits. We conclude our review by proposing possible future lines of study that could result in control of cancer progression through RAGE inhibition.
Methanol-Essential Growth of Corynebacterium glutamicum: Adaptive Laboratory Evolution Overcomes Limitation due to Methanethiol Assimilation Pathway
Authors: Hennig Guido , Haupka Carsten , Brito Luciana F. , Rückert Christian , Cahoreau Edern , Heux Stéphanie , Wendisch Volker F.
Published: May 2020

Methanol is a sustainable substrate for biotechnology. In addition to natural methylotrophs, metabolic engineering has gained attention for transfer of methylotrophy. Here, we engineered Corynebacterium glutamicum for methanol-dependent growth with a sugar co-substrate. Heterologous expression of genes for methanol dehydrogenase from Bacillus methanolicus and of ribulose monophosphate pathway genes for hexulose phosphate synthase and isomerase from Bacillus subtilis enabled methanol-dependent growth of mutants carrying one of two independent metabolic cut-offs, i.e., either lacking ribose-5-phosphate isomerase or ribulose-5-phosphate epimerase. Whole genome sequencing of strains selected by adaptive laboratory evolution (ALE) for faster methanol-dependent growth was performed. Subsequently, three mutations were identified that caused improved methanol-dependent growth by (1) increased plasmid copy numbers, (2) enhanced riboflavin supply and (3) reduced formation of the methionine-analogue O-methyl-homoserine in the methanethiol pathway. Our findings serve as a foundation for the engineering of C. glutamicum to unleash the full potential of methanol as a carbon source in biotechnological processes.
A Review on Turbine Trailing Edge Flow
Authors: Sieverding Claus , Manna Marcello
Published: May 2020

The paper presents a state-of-the-art review of turbine trailing edge flows, both from an experimental and numerical point of view. With the help of old and recent high-resolution time resolved data, the main advances in the understanding of the essential features of the unsteady wake flow are collected and homogenized. Attention is paid to the energy separation phenomenon occurring in turbine wakes, as well as to the effects of the aerodynamic parameters chiefly influencing the features of the vortex shedding. Achievements in terms of unsteady numerical simulations of turbine wake flow characterized by vigorous vortex shedding are also reviewed. Whenever possible the outcome of a detailed code-to-code and code-to-experiments validation process is presented and discussed, on account of the adopted numerical method and turbulence closure.
Multi-Vehicle Simulation in Urban Automated Driving: Technical Implementation and Added Benefit
Authors: Feierle Alexander , Rettenmaier Michael , Zeitlmeir Florian , Bengler Klaus
Published: May 2020

This article investigates the simultaneous interaction between an automated vehicle (AV) and its passenger, and between the same AV and a human driver of another vehicle. For this purpose, we have implemented a multi-vehicle simulation consisting of two driving simulators, one for the AV and one for the manual vehicle. The considered scenario is a road bottleneck with a double-parked vehicle either on one side of the road or on both sides of the road where an AV and a simultaneously oncoming human driver negotiate the right of way. The AV communicates to its passenger via the internal automation human–machine interface (HMI) and it concurrently displays the right of way to the human driver via an external HMI. In addition to the regular encounters, this paper analyzes the effect of an automation failure, where the AV first communicates to yield the right of way and then changes its strategy and passes through the bottleneck first despite oncoming traffic. The research questions the study aims to answer are what methods should be used for the implementation of multi-vehicle simulations with one AV, and if there is an added benefit of this multi-vehicle simulation compared to single-driver simulator studies. The results show an acceptable synchronicity for using traffic lights as basic synchronization and a distance control as the detail synchronization method. The participants had similar passing times in the multi-vehicle simulation compared to a previously conducted single-driver simulation. Moreover, there was a lower crash rate in the multi-vehicle simulation during the automation failure. Concluding the results, the proposed method seems to be an appropriate solution to implement multi-vehicle simulation with one AV. Additionally, multi-vehicle simulation offers a benefit if more than one human affects the interaction within a scenario.