bluuebunny/crossref_metadata_2025 huggingface dataset:
How Fear of COVID-19 Can Affect Treatment Choices for Anaplastic Large Cell Lymphomas ALK+ Therapy: A Case Report
Authors: Sica Antonello , Sagnelli Caterina , Casale Beniamino , Svanera Gino , Creta Massimiliano , Calogero Armando , Franco Renato , Sagnelli Evangelista , Ronchi Andrea
Published: February 2021

Background: The t (2; 5) chromosomal rearrangement of the ALK gene with nucleophosmin 1 gene (NPM1), resulting in an NPM1–ALK fusion, was first demonstrated in 1994 in anaplastic large cell lymphoma, (ALCL), a T-cell lymphoma responsive to cyclophosphamide, abriblastine, vincristine and prednisone in approximately 80% of cases; refractory cases usually respond favorably to brentuximab vedotin. These treatments are regarded as a bridge to allogeneic hematopoietic stem cell transplantation (allo-SCT). Nowadays, transplant procedures and the monitoring of chemotherapy patients proceed very slowly because the SARS-CoV-2 pandemic has heavily clogged the hospitals in all countries. Results: A 40-year-old Caucasian woman was first seen at our clinical center in June 2020. She had ALCL ALK+, a history of failure to two previous therapeutic lines and was in complete remission after 12 courses of brentuximab, still pending allo-SCT after two failed donor selections. Facing a new therapeutic failure, we requested and obtained authorization from the Italian drug regulatory agency to administer 250 mg of crizotinib twice a day, a drug incomprehensibly not registered for ALCL ALK +. Conclusions: The response to crizotinib was optimal since no adverse event occurred, and CT-PET scans persisted negative; this drug has proved to be a valid bridge to allo-SCT.
Short-Term Impact of Video-Assisted Thoracoscopic Surgery on Lung Function, Physical Function, and Quality of Life
Authors: Akezaki Yoshiteru , Nakata Eiji , Tominaga Ritsuko , Iwata Orie , Kawakami Juichi , Tsuji Tetsuya , Ueno Tsuyoshi , Yamashita Motohiro , Sugihara Shinsuke
Published: February 2021

Background: Video-assisted thoracoscopic surgery (VATS) has been increasingly used as an approach for lung lobectomy. However, the recovery of respiratory and physical function may be insufficient at discharge because the average length of hospital stay is decreasing after surgery. In this study, we investigated the changes in physical function, lung function, and quality of life (QOL) of lung cancer patients after VATS, and factors for QOL were also evaluated. Methods: The subjects of this study were 41 consecutive patients who underwent video-assisted lung lobectomy for lung cancer. Rehabilitation was performed both before and after surgery. Lung function testing, physical function testing (timed up and go test (TUG) and the 30-s chair-stand test (CS-30)), and QOL (EORTC QLQ-C30) were measured before and 1 week after surgery. Results: Postoperative VC recovered to 76.3% ± 15.6% 1 week after surgery. TUG, CS-30, and QOL were significantly worse after surgery (p < 0.05). Lung function and physical function were found to affect QOL. Postoperative complications included pneumonia in 1 patient. There were no patients who discontinued rehabilitation. Conclusion: Our rehabilitation program was safe and useful for patients after VATS.
Addiction Problems, Aggression, and Quality of Life in People with Different Occupations in South Korea
Authors: Wee Hwee , Kang Gweon-Young
Published: February 2021

Addiction is related to aggression and quality of life. This study examined the relationship between these three factors according to occupation group in a mixed urban/rural area to better understand adult addiction problems. This study was a secondary data analysis of cross-sectional data collected by a 2017 regional survey of adults living in Gunsan City, South Korea. The survey included 500 people split into the unemployed (Group1), full-time homemakers (Group2), and primary (Group3), secondary (Group4), and tertiary (Group5) industry workers. Addiction problems and aggression were positively correlated (p < 0.01). Aggression and alcohol use disorder were correlated in Group3 (r = 0.31), Group4 (r = 0.34), and Group5 (r = 0.32), and aggression and smartphone addiction were correlated in Group2 (r = 0.39) and Group4 (r = 0.31). Problem gambling was correlated with aggression in Group5 (r = 0.39). A negative relationship between quality of life and alcohol use disorder occurred in Group1 (r = −0.36). According to the occupation group, the relationships between addiction problems, aggression, and quality of life were different. These findings suggest that addiction management for adults should be implemented in consideration of occupation groups.
Scaling up of Eco-Bio-Social Strategy to Control Aedes aegypti in Highly Vulnerable Areas in Fortaleza, Brazil: A Cluster, Non-Randomized Controlled Trial Protocol
Authors: Macêdo Suyanne Freire de , Silva Kellyanne Abreu , Vasconcelos Renata Borges de , Sousa Izautina Vasconcelos de , Mesquita Lyvia Patrícia Soares , Barakat Roberta Duarte Maia , Fernandes Hélida Melo Conrado , Queiroz Ana Carolina Melo , Santos Gerarlene Ponte Guimarães , Filho Valter Cordeiro Barbosa , Carrasquilla Gabriel , Caprara Andrea , de Oliveira Lima José Wellington
Published: February 2021

Aedes aegypti is a cosmopolitan vector for arboviruses dengue, Zika and chikungunya, disseminated in all Brazilian states. The Eco-Bio-Social (EBS) strategy is vital in Aedes aegypti control as it mobilizes stakeholders (government, professionals, society, and academics) to promote healthy environments. This paper describes the rationale and methods of expanding the EBS strategy for Aedes aegypti control in Fortaleza, Northeast Brazil. A cluster, non-randomized controlled clinical trial was developed to analyze the strategy’s effectiveness in vulnerable territories (high incidence of dengue and violent deaths; low HDI; substandard urban infrastructure, high population density, and water scarcity). We selected two intervention and two control groups, resulting in a sample of approximately 16,000 properties. The intervention consisted of environmental management by sealing large elevated water tanks, introduction of beta fish in waterholes, elimination of potential breeding sites, and mobilization and training of schoolchildren, endemic disease workers, health workers, social mobilizers, and community leaders; community surveillance of arboviruses; construction and validation of a booklet for the prevention of arboviruses in pregnant women. We analyzed the costs of arboviruses to government and households, the intervention cost-effectiveness, chikungunya’s chronicity, and acceptance, sustainability, and governance of vector control actions. The primary outcome (infestation) was analyzed using the house, container, and Breteau indices. We hope that this study will help us understand how to scale up strategies to fight Aedes aegypti in vulnerable areas.
Applying Spatial Video Geonarratives and Physiological Measurements to Explore Perceived Safety in Baton Rouge, Louisiana
Authors: Ristea Alina , Leitner Michael , Resch Bernd , Stratmann Judith
Published: February 2021

Spatial crime analysis, together with perceived (crime) safety analysis have tremendously benefitted from Geographic Information Science (GISc) and the application of geospatial technology. This research study discusses a novel methodological approach to document the use of emerging geospatial technologies to explore perceived urban safety from the lenses of fear of crime or crime perception in the city of Baton Rouge, USA. The mixed techniques include a survey, spatial video geonarrative (SVG) in the field with study participants, and the extraction of moments of stress (MOS) from biosensing wristbands. This study enrolled 46 participants who completed geonarratives and MOS detection. A subset of 10 of these geonarratives are presented here. Each participant was driven in a car equipped with audio recording and spatial video along a predefined route while wearing the Empatica E4 wristbands to measure three physiological variables, all of them linked by timestamp. The results show differences in the participants’ sentiments (positive or negative) and MOS in the field based on gender. These mixed-methods are encouraging for finding relationships between actual crime occurrences and the community perceived fear of crime in urban areas.
Increased Alopecia Areata Risk in Children with Attention-Deficit/Hyperactivity Disorder and the Impact of Methylphenidate Use: A Nationwide Population-Based Cohort Study
Authors: Ho Hsing-Ying , Wong Chih-Kai , Wu Szu-Yuan , Hsiao Ray C. , Chen Yi-Lung , Yen Cheng-Fang
Published: February 2021

Alopecia areata (AA) is an autoimmune disease that causes sudden hair loss. Although few studies have reported the association between AA and attention-deficit/hyperactivity disorder (ADHD), the impact of methylphenidate (MPH) on AA has not been examined. This study examined whether AA risk is higher in children with ADHD than in those without ADHD as well as the impact of MPH use on AA risk in children with ADHD. From the Taiwan Maternal and Child Health Database, we enrolled all 1,750,456 newborns from 2004 to 2017 in Taiwan. Of them, 90,016 children received a diagnosis of ADHD whereas the remaining 1,660,440 did not. To compare AA risk in ADHD and the impact of MPH treatment on it, multiple Cox regression with adjustments for covariates (i.e., age, sex, and psychiatric comorbidities) was performed. The results indicated that 88 (0.098%) children with ADHD and 1191 (0.072%) children without ADHD had AA. Nevertheless, after adjustment for the covariates, AA risk was higher in children with ADHD than in those without ADHD (adjusted hazard ratio [aHR]: 1.30, 95% confidence interval [CI]: 1.04–1.64). Our data indicated a considerable reduction in AA risk (aHR: 0.64) among children with ADHD who received MPH than among those who did not receive MPH; however, this difference was nonsignificant, indicated by a wide 95% CI (0.32–1.25). In conclusion, ADHD and AA may share some underlying mechanisms.
Systematic Review of Intervention Studies Aiming at Reducing Inequality in Dental Caries among Children
Authors: Shen Anqi , Bernabé Eduardo , Sabbah Wael
Published: February 2021

(1) Background: The objective is to systematically review the evidence on intervention programs aiming at reducing inequality in dental caries among children. (2) Methods: Two independent investigators searched MEDLINE, Cochrane library, and Ovid up to December 2020 to identify intervention studies assessing the impact on socioeconomic inequalities in dental caries among children. The interventions included any health promotion/preventive intervention aiming at reducing caries among children across different socioeconomic groups. Comparison groups included children with alternative or no intervention. Cochrane criteria were used to assess interventional studies for risk of bias. (3) Results: After removal of duplicate studies, 1235 articles were retained. Out of 43 relevant papers, 13 articles were identified and used in qualitative synthesis, and reported quantifiable outcomes. The included studies varied in measurements of interventions, sample size, age groups, and follow-up time. Five studies assessed oral health promotion or health-education, four assessed topical fluorides, and four assessed water fluoridation. Interventions targeting the whole population showed a consistent reduction of socioeconomic inequalities in dental caries among children. (4) Conclusion: The quality of included papers was moderate. High heterogeneity did not allow aggregation of the findings. The overall findings suggest that whole population interventions such as water fluoridation are more likely to reduce inequalities in children’s caries than target population and individual interventions.
Accessibility of Rural Life Space on the Jianghan Plain, China: The Role of Livelihood
Authors: Zhuo Rongrong , Rosenberg Mark , Yu Bin , Guo Xinwei , Wang Mingjie
Published: February 2021

This article aims to contribute to the relationship between accessibility of rural life space and rural livelihood capital and transitions in rural central China. Employing data produced from a household survey, we developed a composite index for accessibility of rural life space incorporating spatial and temporal attributes of a household’s daily activities and then explored the mediation effect of rural livelihood capital and transitions on accessibility. Results revealed a pattern of diversification in terms of life space accessibility undertaken for daily activities across households. Both livelihood capital and transitions had significant mediation effects on the relationship between socio-economic characteristics of rural households and accessibility of rural life space. The effects of livelihood capital on livelihood transitions also influenced the path on rural households’ accessibility of rural life space. One of the implications of this article is to link rural transformation to the context of urbanization and rural access issues from a perspective of daily activity, and then to figure out the best method for rural development policy and service planning.
Do Dietary Supplements Improve Perceived Health Well-Being? Evidence from Korea
Authors: Kim Donghoon , Ji Inbae , Ng’ombe John N. , Han Kwideok , Vitale Jeffrey
Published: February 2021

This study analyzes the self-reported intake of dietary supplements (DS) and their effects on perceived health well-being from a survey with 1210 adult respondents in Korea. To account for selectivity bias from observable confounders, we use a propensity score matching (PSM) model. Our findings show that demographics, health concerns, family history of disease, frequency of hospital visits, and regular exercise are positively associated with intake of DS among consumers. Results from PSM show that the intake of DS leads to significant improvements in perceived health well-being among DS takers relative to DS non-takers regardless of gender, urban residence, having self-reported diseases or not. The paper concludes with implications for policies that promote intake of DS in Korea.
The Role of Betting on Digital Credit Repayment, Coping Mechanisms and Welfare Outcomes: Evidence from Kenya
Authors: Chamboko Richard , Guvuriro Sevias
Published: February 2021

Digital financial services and more importantly, mobile money, have become an important financial innovation to advance financial inclusion in developing and emerging economies. While digital financial services have improved the lives of many Kenyans, to the growing betting segment of the Kenyan population, these innovations have also brought great convenience to betting. The innovations have allowed easy access to digital credit which can be used for betting. Despite betting or gambling being a widely studied area, particularly in developed countries, little is known about its interaction with financial innovations such as digital financial services in developing and emerging economies. Using data from a 2017 digital credit survey in Kenya, this study investigates if bettors are more likely than non-bettors to be financially distressed or engage in welfare-undermining coping strategies and potentially experience inferior welfare outcomes. The study uses a representative sample of 1040 digital borrowers, of which 304 were digital bettors. Using multivariate logistic regressions, the study found that, after controlling for socio-economic and demographic factors, bettors are significantly more likely than non-bettors to be financially distressed, engage in welfare undermining coping strategies, and have inferior welfare outcomes.
Diabetes Induces a Transcriptional Signature in Bone Marrow–Derived CD34+ Hematopoietic Stem Cells Predictive of Their Progeny Dysfunction
Authors: D’Alessandra Yuri , Chiesa Mattia , Vigorelli Vera , Ricci Veronica , Rurali Erica , Raucci Angela , Colombo Gualtiero Ivanoe , Pompilio Giulio , Vinci Maria Cristina
Published: February 2021

Hematopoietic stem/progenitor cells (HSPCs) participate in cardiovascular (CV) homeostasis and generate different types of blood cells including lymphoid and myeloid cells. Diabetes mellitus (DM) is characterized by chronic increase of pro-inflammatory mediators, which play an important role in the development of CV disease, and increased susceptibility to infections. Here, we aimed to evaluate the impact of DM on the transcriptional profile of HSPCs derived from bone marrow (BM). Total RNA of BM-derived CD34+ stem cells purified from sternal biopsies of patients undergoing coronary bypass surgery with or without DM (CAD and CAD-DM patients) was sequenced. The results evidenced 10566 expressed genes whose 79% were protein-coding genes, and 21% non-coding RNA. We identified 139 differentially expressed genes (p-value < 0.05 and |log2 FC| > 0.5) between the two comparing groups of CAD and CAD-DM patients. Gene Set Enrichment Analysis (GSEA), based on Gene Ontology biological processes (GO-BP) terms, led to the identification of fourteen overrepresented biological categories in CAD-DM samples. Most of the biological processes were related to lymphocyte activation, chemotaxis, peptidase activity, and innate immune response. Specifically, HSPCs from CAD-DM patients displayed reduced expression of genes coding for proteins regulating antibacterial and antivirus host defense as well as macrophage differentiation and lymphocyte emigration, proliferation, and differentiation. However, within the same biological processes, a consistent number of inflammatory genes coding for chemokines and cytokines were up-regulated. Our findings suggest that DM induces transcriptional alterations in HSPCs, which are potentially responsible of progeny dysfunction.
The Role of miRNAs, miRNA Clusters, and isomiRs in Development of Cancer Stem Cell Populations in Colorectal Cancer
Authors: Stark Victoria A. , Facey Caroline O. B. , Viswanathan Vignesh , Boman Bruce M.
Published: February 2021

MicroRNAs (miRNAs or miRs) have a critical role in regulating stem cells (SCs) during development and altered expression can cause developmental defects and/or disease. Indeed, aberrant miRNA expression leads to wide-spread transcriptional dysregulation which has been linked to many cancers. Mounting evidence also indicates a role for miRNAs in the development of the cancer SC (CSC) phenotype. Our goal herein is to provide a review of: (i) current research on miRNAs and their targets in colorectal cancer (CRC), and (ii) miRNAs that are differentially expressed in colon CSCs. MicroRNAs can work in clusters or alone when targeting different SC genes to influence CSC phenotype. Accordingly, we discuss the specific miRNA cluster classifications and isomiRs that are predicted to target the ALDH1, CD166, BMI1, LRIG1, and LGR5 SC genes. miR-23b and miR-92A are of particular interest because our previously reported studies on miRNA expression in isolated normal versus malignant human colonic SCs showed that miR-23b and miR-92a are regulators of the LGR5 and LRIG1 SC genes, respectively. We also identify additional miRNAs whose expression inversely correlated with mRNA levels of their target genes and associated with CRC patient survival. Altogether, our deliberation on miRNAs, their clusters, and isomiRs in regulation of SC genes could provide insight into how dysregulation of miRNAs leads to the emergence of different CSC populations and SC overpopulation in CRC.
Programmed Death-Ligand 2 Deficiency Exacerbates Experimental Autoimmune Myocarditis in Mice
Authors: Li Siqi , Tajiri Kazuko , Murakoshi Nobuyuki , Xu DongZhu , Yonebayashi Saori , Okabe Yuta , Yuan Zixun , Feng Duo , Inoue Keiko , Aonuma Kazuhiro , Shimoda Yuzuno , Song Zoughu , Mori Haruka , Huang Honglan , Aonuma Kazutaka , Ieda Masaki
Published: February 2021

Programmed death ligand 2 (PD-L2) is the second ligand of programmed death 1 (PD-1) protein. In autoimmune myocarditis, the protective roles of PD-1 and its first ligand programmed death ligand 1 (PD-L1) have been well documented; however, the role of PD-L2 remains unknown. In this study, we report that PD-L2 deficiency exacerbates myocardial inflammation in mice with experimental autoimmune myocarditis (EAM). EAM was established in wild-type (WT) and PD-L2-deficient mice by immunization with murine cardiac myosin peptide. We found that PD-L2-deficient mice had more serious inflammatory infiltration in the heart and a significantly higher myocarditis severity score than WT mice. PD-L2-deficient dendritic cells (DCs) enhanced CD4+ T cell proliferation in the presence of T cell receptor and CD28 signaling. These data suggest that PD-L2 on DCs protects against autoreactive CD4+ T cell expansion and severe inflammation in mice with EAM.
Changes in the Expression of TBP-2 in Response to Histone Deacetylase Inhibitor Treatment in Human Endometrial Cells
Authors: Kim Hye In , Seo Seok Kyo , Chon Seung Joo , Kim Ga Hee , Lee Inha , Yun Bo Hyon
Published: February 2021

Histone deacetylase inhibitors (HDACi) induce apoptosis preferentially in cancer cells by caspase pathway activation and reactive oxygen species (ROS) accumulation. Suberoylanilide hydroxamic acid (SAHA), a HDACi, increases apoptosis via altering intracellular oxidative stress through thioredoxin (TRX) and TRX binding protein-2 (TBP-2). Because ROS accumulation, as well as the redox status determined by TBP-2 and TRX, are suggested as possible mechanisms for endometriosis, we queried whether SAHA induces apoptosis of human endometrial cells via the TRX–TBP-2 system in endometriosis. Eutopic endometrium from participants without endometriosis, and ectopic endometrium from patients with endometriosis, was obtained surgically. Human endometrial stromal cells (HESCs) and Ishikawa cells were treated with SAHA and cell proliferation was assessed using the CCK-8 assay. Real-time PCR and Western blotting were used to quantify TRX and TBP-2 mRNA and protein expression. After inducing oxidative stress, SAHA was applied. Short-interfering TRX (SiTRX) transfection was performed to see the changes after TRX inhibition. The mRNA and protein expression of TBP-2 was increased with SAHA concentrations in HESCs significantly. The mRNA TBP-2 expression was decreased after oxidative stress, upregulated by adding 2.5 μM of SAHA. The TRX/TBP-2 ratio decreased, apoptosis increased significantly, and SiTRX transfection decreased with SAHA. In conclusion, SAHA induces apoptosis by modulating the TRX/TBP-2 system, suggesting its potential as a therapeutic agent for endometriosis.
Ancient Evolutionary Origin and Properties of Universally Produced Natural Exosomes Contribute to Their Therapeutic Superiority Compared to Artificial Nanoparticles
Authors: Askenase Phillip W.
Published: February 2021

Extracellular vesicles (EVs), such as exosomes, are newly recognized fundamental, universally produced natural nanoparticles of life that are seemingly involved in all biologic processes and clinical diseases. Due to their universal involvements, understanding the nature and also the potential therapeutic uses of these nanovesicles requires innovative experimental approaches in virtually every field. Of the EV group, exosome nanovesicles and larger companion micro vesicles can mediate completely new biologic and clinical processes dependent on the intercellular transfer of proteins and most importantly selected RNAs, particularly miRNAs between donor and targeted cells to elicit epigenetic alterations inducing functional cellular changes. These recipient acceptor cells are nearby (paracrine transfers) or far away after distribution via the circulation (endocrine transfers). The major properties of such vesicles seem to have been conserved over eons, suggesting that they may have ancient evolutionary origins arising perhaps even before cells in the primordial soup from which life evolved. Their potential ancient evolutionary attributes may be responsible for the ability of some modern-day exosomes to withstand unusually harsh conditions, perhaps due to unique membrane lipid compositions. This is exemplified by ability of the maternal milk exosomes to survive passing the neonatal acid/enzyme rich stomach. It is postulated that this resistance also applies to their durable presence in phagolysosomes, thus suggesting a unique intracellular release of their contained miRNAs. A major discussed issue is the generally poorly realized superiority of these naturally evolved nanovesicles for therapies when compared to human-engineered artificial nanoparticles, e.g., for the treatment of diseases like cancers.
Influence of Antiplatelet Agents on the Lipid Composition of Platelet Plasma Membrane: A Lipidomics Approach with Ticagrelor and Its Active Metabolite
Authors: Lagoutte-Renosi Jennifer , Allemand Florentin , Ramseyer Christophe , Rabani Vahideh , Davani Siamak
Published: February 2021

Lipids contained in the plasma membrane of platelets play an important role in platelet function. Modifications in the lipid composition can fluidify or rigidify the environment around embedded receptors, in order to facilitate the access of the receptor by the drug. However, data concerning the lipid composition of platelet plasma membrane need to be updated. In addition, data on the impact of drugs on plasma membrane composition, in particular antiplatelet agents, remain sparse. After isolation of platelet plasma membrane, we assessed, using lipidomics, the effect of ticagrelor, a P2Y12 antagonist, and its active metabolite on the lipid composition of these plasma membranes. We describe the exact lipid composition of plasma membrane, including all sub-species. Ticagrelor and its active metabolite significantly increased cholesterol and phosphatidylcholine ether with short saturated acyl chains 16:0/16:0, and decreased phosphatidylcholine, suggesting overall rigidification of the membrane. Furthermore, ticagrelor and its active metabolite decreased some arachidonylated plasmalogens, suggesting a decrease in availability of arachidonic acid from the membrane phospholipids for synthesis of biologically active mediators. To conclude, ticagrelor and its active metabolite seem to influence the lipid environment of receptors embedded in the lipid bilayer and modify the behavior of the plasma membrane.
Mesenchymal Stem Cell-Derived Exosomes as New Remedy for the Treatment of Neurocognitive Disorders
Authors: Harrell Carl Randall , Volarevic Ana , Djonov Valentin , Volarevic Vladislav
Published: February 2021

Mesenchymal stem cell (MSC)-derived exosomes (MSC-Exo) are nano-sized extracellular vesicles enriched with MSC-sourced neuroprotective and immunomodulatory microRNAs, neural growth factors, and anti-inflammatory cytokines, which attenuate neuro-inflammation, promote neo-vascularization, induce neurogenesis, and reduce apoptotic loss of neural cells. Accordingly, a large number of experimental studies demonstrated MSC-Exo-dependent improvement of cognitive impairment in experimental animals. In this review article, we summarized current knowledge about molecular and cellular mechanisms that were responsible for MSC-Exo-based restoration of cognitive function, emphasizing therapeutic potential of MSC-Exos in the treatment of neurocognitive disorders.
The Contribution of the Urokinase Plasminogen Activator and the Urokinase Receptor to Pleural and Parenchymal Lung Injury and Repair: A Narrative Review
Authors: Tucker Torry A. , Idell Steven
Published: February 2021

Pleural and parenchymal lung injury have long been characterized by acute inflammation and pathologic tissue reorganization, when severe. Although transitional matrix deposition is a normal part of the injury response, unresolved fibrin deposition can lead to pleural loculation and scarification of affected areas. Within this review, we present a brief discussion of the fibrinolytic pathway, its components, and their contribution to injury progression. We review how local derangements of fibrinolysis, resulting from increased coagulation and reduced plasminogen activator activity, promote extravascular fibrin deposition. Further, we describe how pleural mesothelial cells contribute to lung scarring via the acquisition of a profibrotic phenotype. We also discuss soluble uPAR, a recently identified biomarker of pleural injury, and its diagnostic value in the grading of pleural effusions. Finally, we provide an in-depth discussion on the clinical importance of single-chain urokinase plasminogen activator (uPA) for the treatment of loculated pleural collections.
A Bioassay Using a Pentadecanal Derivative to Measure S1P Lyase Activity
Authors: Shin Kyong-Oh , Shamshiddinova Maftuna , Lee Jung-No , Lee Kwang-Sik , Lee Yong-Moon
Published: February 2021

Sphingosine-1-phosphate (S1P) is a unique lipid ligand binding to S1P receptors to transduce various cell survival or proliferation signals via small G proteins. S1P lyase (S1PL) is the specific enzyme that degrades S1P to phosphoethanolamine and (2E)-hexadecenal and therefore regulates S1P levels. S1PL also degrades dihydrosphingosine-1-phosphate (Sa1P), with a higher affinity to produce hexadecanal. Here, we developed a newly designed assay using a C17-Sa1P substrate that degrades into pentadecanal and phosphoethanolamine. For higher sensitivity in pentadecanal analysis, we developed a quantitative protocol as well as a 5,5-dimethyl cyclohexanedione (5,5-dimethyl CHD) derivatization method. The derivatization conditions were optimized for the reaction time, temperature, and concentrations of the 5,5-dimethyl CHD reagent, acetic acid, and ammonium acetate. The S1PL reaction in the cell lysate after spiking 20 µM of C17-Sa1P for 20 min was linear to the total protein concentrations of 50 µg. The S1PL levels (4 pmol/mg/min) were readily detected in this HPLC with fluorescence detection (λex = 366 nm, λem = 455 nm). The S1PL-catalyzed reaction was linear over 30 min and yielded a Km value of 2.68 μM for C17-Sa1P. This new method was validated to measure the S1PL activity of mouse embryonal carcinoma cell lines of the standard cell (F9-0), S1PL knockdown cells (F9-2), and S1PL-overexpressed cells (F9-4). Furthermore, we treated F9-4 cells with different S1PL inhibitors such as FTY720, 4-deoxypyridoxine (DOP), and the deletion of pyridoxal-5-phosphate (P5P), an essential cofactor for S1PL activity, and observed a significant decrease in pentadecanal relative to the untreated cells. In conclusion, we developed a highly sensitive S1PL assay using a C17-Sa1P substrate for pentadecanal quantification for application in the characterization of S1PL activity in vitro.
NMR Characterization of Angiogenin Variants and tRNAAla Products Impacting Aberrant Protein Oligomerization
Authors: Fagagnini Andrea , Garavís Miguel , Gómez-Pinto Irene , Fasoli Sabrina , Gotte Giovanni , Laurents Douglas V.
Published: February 2021

Protein oligomerization is key to countless physiological processes, but also to abnormal amyloid conformations implicated in over 25 mortal human diseases. Human Angiogenin (h-ANG), a ribonuclease A family member, produces RNA fragments that regulate ribosome formation, the creation of new blood vessels and stress granule function. Too little h-ANG activity leads to abnormal protein oligomerization, resulting in Amyotrophic Lateral Sclerosis (ALS) or Parkinson’s disease. While a score of disease linked h-ANG mutants has been studied by X-ray diffraction, some elude crystallization. There is also a debate regarding the structure that RNA fragments adopt after cleavage by h-ANG. Here, to better understand the beginning of the process that leads to aberrant protein oligomerization, the solution secondary structure and residue-level dynamics of WT h-ANG and two mutants i.e., H13A and R121C, are characterized by multidimensional heteronuclear NMR spectroscopy under near-physiological conditions. All three variants are found to adopt well folded and highly rigid structures in the solution, although the elements of secondary structure are somewhat shorter than those observed in crystallography studies. R121C alters the environment of nearby residues only. By contrast, the mutation H13A affects local residues as well as nearby active site residues K40 and H114. The conformation characterization by CD and 1D 1H NMR spectroscopies of tRNAAla before and after h-ANG cleavage reveals a retention of the duplex structure and little or no G-quadruplex formation.
Immune Actions on the Peripheral Nervous System in Pain
Authors: Liu Jessica Aijia , Yu Jing , Cheung Chi Wai
Published: February 2021

Pain can be induced by tissue injuries, diseases and infections. The interactions between the peripheral nervous system (PNS) and immune system are primary actions in pain sensitizations. In response to stimuli, nociceptors release various mediators from their terminals that potently activate and recruit immune cells, whereas infiltrated immune cells further promote sensitization of nociceptors and the transition from acute to chronic pain by producing cytokines, chemokines, lipid mediators and growth factors. Immune cells not only play roles in pain production but also contribute to PNS repair and pain resolution by secreting anti-inflammatory or analgesic effectors. Here, we discuss the distinct roles of four major types of immune cells (monocyte/macrophage, neutrophil, mast cell, and T cell) acting on the PNS during pain process. Integration of this current knowledge will enhance our understanding of cellular changes and molecular mechanisms underlying pain pathogenies, providing insights for developing new therapeutic strategies.
Phosphatidic Acid Stimulates Myoblast Proliferation through Interaction with LPA1 and LPA2 Receptors
Authors: Gomez-Larrauri Ana , Gangoiti Patricia , Presa Natalia , Dominguez-Herrera Asier , Donati Chiara , Bruni Paola , Trueba Miguel , Gomez-Muñoz Antonio , Ouro Alberto
Published: February 2021

Phosphatidic acid (PA) is a bioactive phospholipid capable of regulating key biological functions, including neutrophil respiratory burst, chemotaxis, or cell growth and differentiation. However, the mechanisms whereby PA exerts these actions are not completely understood. In this work, we show that PA stimulates myoblast proliferation, as determined by measuring the incorporation of [3H]thymidine into DNA and by staining the cells with crystal violet. PA induced the rapid phosphorylation of Akt and ERK1/2, and pretreatment of the cells with specific small interferin RNA (siRNA) to silence the genes encoding these kinases, or with selective pharmacologic inhibitors, blocked PA-stimulated myoblast proliferation. The mitogenic effects of PA were abolished by the preincubation of the myoblasts with pertussis toxin, a Gi protein inhibitor, suggesting the implication of Gi protein-coupled receptors in this action. Although some of the effects of PA have been associated with its possible conversion to lysoPA (LPA), treatment of the myoblasts with PA for up to 60 min did not produce any significant amount of LPA in these cells. Of interest, pharmacological blockade of the LPA receptors 1 and 2, or specific siRNA to silence the genes encoding these receptors, abolished PA-stimulated myoblast proliferation. Moreover, PA was able to compete with LPA for binding to LPA receptors, suggesting that PA can act as a ligand of LPA receptors. It can be concluded that PA stimulates myoblast proliferation through interaction with LPA1 and LPA2 receptors and the subsequent activation of the PI3K/Akt and MEK/ERK1-2 pathways, independently of LPA formation.
Resveratrol Supplementation Attenuates Cognitive and Molecular Alterations under Maternal High-Fat Diet Intake: Epigenetic Inheritance over Generations
Authors: Izquierdo Vanesa , Palomera-Ávalos Verónica , Pallàs Mercè , Griñán-Ferré Christian
Published: February 2021

Environmental factors such as maternal high-fat diet (HFD) intake can increase the risk of age-related cognitive decline in adult offspring. Epigenetic mechanisms are a possible link between diet effect and neurodegeneration across generations. Here, we found a significant decrease in triglyceride levels in a high-fat diet with resveratrol (RSV) HFD + RSV group and the offspring. Firstly, we obtained better cognitive performance in HFD+RSV groups and their offspring. Molecularly, a significant increase in DNA methylation (5-mC) levels, as well as increased gene expression of DNA methyltransferase 1 (Dnmt1) and Dnmt3a in HFD + RSV F1 group, were found. Furthermore, a significant increase of N6-Methyladenosine methylation (m6A) levels in HFD+RSV F1, as well as changes in gene expression of its enzymes Methyltransferase like 3 (Mettl3) and FTO alpha-ketoglutarate dependent dioxygenase (Fto) were found. Moreover, we found a decrease in gene expression levels of pro-inflammatory markers such as Interleukin 1β (Il1-β), Interleukin 6 (Il-6), Tumor necrosis factor-α (Tnf-α), C-X-C motifchemokine ligand 10 (Cxcl-10), the pro-inflammatory factors monocyte chemoattractant protein 1 (Mcp-1) and Tumor growth factor-β1 (Tgf-β1) in HFD+RSV and HFD+RSV F1 groups. Moreover, there was increased gene expression of neurotrophins such as Neural growth factor (Ngf), Neurotrophin-3 (Nt3), and its receptors Tropomyosin receptor kinase TrkA and TrkB. Likewise, an increase in protein levels of brain-derived neurotrophic factor (BDNF) and phospho-protein kinase B (p-Akt) in HFD+RSV F1 was found. These results suggest that maternal RSV supplementation under HFD intake prevents cognitive decline in senescence-accelerated mice prone 8 (SAMP8) adult offspring, promoting a reduction in triglycerides and leptin plasma levels, changes in the pro-inflammatory profile, and restoring the epigenetic landscape as well as synaptic plasticity.
Combination of Entecavir or Tenofovir with Pegylated Interferon-α for Long-Term Reduction in Hepatitis B Surface Antigen Levels: Simultaneous, Sequential, or Add-on Combination Therapy
Authors: Yoshida Kanako , Enomoto Masaru , Tamori Akihiro , Nishiguchi Shuhei , Kawada Norifumi
Published: February 2021

Seroclearance of hepatitis B surface antigen (HBsAg) (“functional cure”) is the optimal endpoint of antiviral therapy for chronic hepatitis B virus (HBV) infection. Currently available anti-HBV therapy includes nucleoside/nucleotide analogs (NAs) and peginterferon-α (Peg-IFNα). Combination of NAs and Peg-IFNα, each with different mechanisms of action, is an attractive approach for treating chronic HBV infection. In earlier studies, compared with monotherapy using IFNα, combination therapy showed greater on-treatment HBV DNA suppression but no difference in the sustained response. However, responses to the combination of non-pegylated IFNα with lamivudine or adefovir were not assessed based on HBsAg quantification but were defined by normal alanine aminotransferase levels, testing negative for hepatitis B e-antigen, and low HBV DNA load over a short term. Here, we reviewed previous reports regarding the effects of combination therapy of entecavir or tenofovir with Peg-IFNα, focusing on long-term reduction in HBsAg levels. Regimens of combination therapy were classified into “simultaneous” combination (“de novo” strategy); “sequential” combination, which involved starting with one therapy followed by the other (“switch-to” strategy); “add-on” combination, which involved adding Peg-IFNα to an ongoing NAs. Some studies have shown promising results, but there is no robust evidence that combination therapy is superior to monotherapy. Large studies are needed to assess the safety and efficacy of combination therapies to increase the rates of HBsAg seroclearance over the long term.
Intricacies of GABAA Receptor Function: The Critical Role of the β3 Subunit in Norm and Pathology
Authors: Menzikov Sergey A. , Morozov Sergey G. , Kubatiev Aslan A.
Published: February 2021

Neuronal intracellular chloride ([Cl−]i) is a key determinant in γ-aminobutyric acid type A (GABA)ergic signaling. γ-Aminobutyric acid type A receptors (GABAARs) mediate both inhibitory and excitatory neurotransmission, as the passive fluxes of Cl− and HCO3− via pores can be reversed by changes in the transmembrane concentration gradient of Cl−. The cation–chloride co-transporters (CCCs) are the primary systems for maintaining [Cl−]i homeostasis. However, despite extensive electrophysiological data obtained in vitro that are supported by a wide range of molecular biological studies on the expression patterns and properties of CCCs, the presence of ontogenetic changes in [Cl−]i—along with the consequent shift in GABA reversal potential—remain a subject of debate. Recent studies showed that the β3 subunit possesses properties of the P-type ATPase that participates in the ATP-consuming movement of Cl− via the receptor. Moreover, row studies have demonstrated that the β3 subunit is a key player in GABAAR performance and in the appearance of serious neurological disorders. In this review, we discuss the properties and driving forces of CCCs and Cl−, HCO3−ATPase in the maintenance of [Cl−]i homeostasis after changes in upcoming GABAAR function. Moreover, we discuss the contribution of the β3 subunit in the manifestation of epilepsy, autism, and other syndromes.
Dynamic Planning of Construction Site for Linear Projects
Authors: Petroutsatou Kleopatra , Apostolidis Nikolaos , Zarkada Athanasia , Ntokou Aneta
Published: February 2021

The area of dynamic planning of construction sites is unexplored. Although there is a large amount of scientific interest in the literature in dynamic planning of construction site layouts, with different methodologies developed, studies on construction site relocation do not exist. The purpose of this study is to cover this gap in the literature and contribute to the body of knowledge by presenting for the first time a dynamic planning of a construction site and its importance in linear construction projects and to validate this methodology through real case studies. The decisive variables that determine the appropriate site locations and the costs that arise from these choices are analyzed. The choice that maximizes the production rate of the construction site and thus minimizes the costs is further investigated. An algorithm has also been developed that estimates the cost of transportation of the equipment used in the project and thus enables the investigation of the “ideal” location that minimizes this cost. The “ideal” site location is examined according to the time schedule of the project at time intervals that are determined by the work progress. The optimization algorithm aims to minimize the cost that derives from non-productive activities. The validity of the proposed model is tested in four motorway projects. A sensitivity analysis concerning different sequences in the construction methods reveals remarkable changes in cost fluctuations depending on project size. The outcomes show that for the second, third, and fourth projects, dynamic planning is demanded, and the profit gained ranges from 1 to 1.5% of total budget cost. Financing expenses could be covered by this profit. The case studies presented are derived from linear infrastructure projects that are more sensitive to this approach because of their size and their budget that both affect the results.
Copper(II) Complexes with Tetradentate Piperazine-Based Ligands: DNA Cleavage and Cytotoxicity
Authors: Doniz Kettenmann Sebastian , Nossol Yvonne , Louka Febee R. , Legrande Julia R. , Marine Elise , Fischer Roland C. , Mautner Franz A. , Hergl Vinja , Kulak Nora , Massoud Salah S.
Published: February 2021

Five-coordinate Cu(II) complexes, [Cu(Ln)X]ClO4/PF6, where Ln = piperazine ligands bearing two pyridyl arms and X = ClO4− for Ln = L1 (1-ClO4), L2 (2-ClO4), L3 (3-ClO4), and L6 (6-ClO4) as well as [Cu(Ln)Cl]PF6 for Ln = L1 (1-Cl), L4 (4-Cl), and L5 (5-Cl) have been synthesized and characterized by spectroscopic techniques. The molecular structures of the last two complexes were determined by X-ray crystallography. In aqueous acetonitrile solutions, molar conductivity measurements and UV-VIS spectrophotometric titrations of the complexes revealed the hydrolysis of the complexes to [Cu(Ln)(H2O)]2+ species. The biological activity of the Cu(II) complexes with respect to DNA cleavage and cytotoxicity was investigated. At micromolar concentration within 2 h and pH 7.4, DNA cleavage rate decreased in the order: 1-Cl ≈ 1-ClO4 > 3-ClO4 ≥ 2-ClO4 with cleavage enhancements of up to 23 million. Complexes 4-Cl, 5-Cl, and 6-ClO4 were inactive. In order to elucidate the cleavage mechanism, the cleavage of bis(4-nitrophenyl)phosphate (BNPP) and reactive oxygen species (ROS) quenching studies were conducted. The mechanistic pathway of DNA cleavage depends on the ligand’s skeleton: while an oxidative pathway was preferable for 1-Cl/1-ClO4, DNA cleavage by 2-ClO4 and 3-ClO4 predominantly proceeds via a hydrolytic mechanism. Complexes 1-ClO4, 3-ClO4, and 5-Cl were found to be cytotoxic against A2780 cells (IC50 30–40 µM). In fibroblasts, the IC50 value was much higher for 3-ClO4 with no toxic effect.
Non-Covalent Interactions of the Lewis Acids Cu–X, Ag–X, and Au–X (X = F and Cl) with Nine Simple Lewis Bases B: A Systematic Investigation of Coinage–Metal Bonds by Ab Initio Calculations
Authors: Alkorta Ibon , Walker Nicholas R. , Legon Anthony C.
Published: February 2021

The equilibrium geometry and two measures (the equilibrium dissociation energy in the complete basis set limit, De(CBS) and the intermolecular stretching force constant kσ) of the strength of the non-covalent interaction of each of six Lewis acids M–X (M = Cu, Ag, Au) with each of nine simple Lewis bases B (B = N2, CO, HCCH, CH2CH2, H2S, PH3, HCN, H2O, and NH3) have been calculated at the CCSD(T)/aug-cc-pVTZ level of theory in a systematic investigation of the coinage–metal bond. Unlike the corresponding series of hydrogen-bonded B⋯HX and halogen-bonded B⋯XY complexes (and other series involving non-covalent interactions), De is not directly proportional to kσ. Nevertheless, as for the other series, it has been possible to express De in terms of the equation De = cNB.EMX, where NB and EMX are the nucleophilicities of the Lewis bases B and the electrophilicities of the Lewis acids M–X, respectively. The order of the EMX is determined to be EAuF > EAuCl > ECuF > ECuCl > EAgF ≈ EAgCl. A reduced electrophilicity defined as (EMX/σmax) is introduced, where σmax is the maximum positive value of the molecular electrostatic surface potential on the 0.001 e/bohr3 iso-surface. This quantity is, in good approximation, independent of whether F or Cl is attached to M.
Discrete Seed Feeder Designing for Mobile Apparatus: Early Results for Pinus sylvestris L. Species
Authors: Bacherikov Ivan , Novikov Arthur , Petrishchev Evgeniy
Published: February 2021

Discrete feeding of forest seeds is an urgent task for accurate detection of seeds during grading and reducing the seeding rate. The study used Pinus sylvestris L. seeds from cones collected in a natural stand of the Lisinsky educational-and-experimental forestry farm, Leningrad region, Russia, in 2017. Well-known methods for determining the properties of bulk materials were used; the results were processed by mathematical statistics using the MS Excel program. The physical and mechanical properties of uncalibrated seeds as a bulk material were determined. The angle of repose of Pinus sylvestris L. seeds, determined using a hollow cylinder by calculation, is 24.92°. The angle of repose of Pinus sylvestris L. seeds, determined using a hollow cylinder and a goniometer, is 32.7°. The significant discrepancy (~8°) in the values obtained by these methods is explained by the seeds shape. The flowability of Pinus sylvestris L. seeds corresponds to an excellent (free) category. The study will enable correct seed treatment protocols for sustainable forest management. However, some questions remained unresolved: how to orient a single seed in the right direction? How does seed-size calibration affect the angle of repose?