bluuebunny/crossref_metadata_2025 huggingface dataset:
A Countrywide Survey in Saudi Arabia Regarding the Knowledge and Attitude of Health Care Professionals about Coronavirus Disease (COVID-19)
Authors: Alduraywish Abdulrahman A. , Srivastava Kumar Chandan , Shrivastava Deepti , Sghaireen Mohammed Ghazi , Alsharari Abdalkarem F. , Al-Johani Khalid , Alam Mohammad Khursheed
Published: October 2020

Coronavirus disease (COVID-19) has emerged as a pandemic. The updated knowledge and a positive attitude of health care professionals (HCPs) towards fighting any pandemic is the key to success. Thus, the present study aims to assess the knowledge and attitude of HCPs towards COVID-19 in the Kingdom of Saudi Arabia (KSA). A cross-sectional study was conducted across the KSA, covering its five geographical regions with a non-probability quota sample. Twenty-nine, close-ended questions evaluating the knowledge and attitude domain were included in the questionnaire. It was developed with the help of Qualtrics software and circulated among the HCPs through the electronic mode. We analyzed data from about 1040 HCPs using the statistical package of social sciences (SPSS) v.21. All variables were presented in number and percentages. Univariate and multivariate logistic regression was performed to explore the odds ratio (OR) and adjusted odds ratio (aOR) of independent variables for inadequate knowledge and attitude. Considering the “good” level of the respective domain, the HCPs have displayed better knowledge (48.2%) over attitude (33.8%). Female (aOR: 1.55; 95% CI: 1.15–2.09; p = 0.004), Diploma degree (aOR: 2.51; 95% CI: 1.64–3.83; p < 0.001), 7–10 years’ experience (aOR: 1.47; 95% CI: 1.01–2.15; p = 0.045) were at higher risk of having inadequate knowledge compared to their contemporaries. Among the sources, the Ministry of Health (MOH) website was the most popular source of information (76%). The knowledge and attitude of HCPs regarding COVID-19 was similar across all the regions of KSA. However, the continuing education program is warranted to fill the potential gap in knowledge for HCPs in higher-risk groups.
Effect of Income Level and Perception of Susceptibility and Severity of COVID-19 on Stay-at-Home Preventive Behavior in a Group of Older Adults in Mexico City
Authors: Irigoyen-Camacho Maria Esther , Velazquez-Alva Maria Consuelo , Zepeda-Zepeda Marco Antonio , Cabrer-Rosales Maria Fernanda , Lazarevich Irina , Castaño-Seiquer Antonio
Published: October 2020

Early information on public health behaviors adopted to prevent the spread of coronavirus (COVID-19) may be useful in controlling the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) transmission. The objective of this study was to assess the role of income level (IL) and the perception of older adults, regarding COVID-19 susceptibility and severity, on adopting stay-at-home preventive behavior during the first week of the outbreak in Mexico. Participants in this cross-sectional study were urban community dwellers, aged ≥ 65 years from Mexico City. A total of 380 interviews were conducted over the phone. The mean respondent age was 72.9 years, and 76.1% were women. Over half (54.2%) of the participants perceived their susceptibility to COVID-19 as very low or low. Similarly, 33.4% perceived COVID-19 severity as being very low or low, and 57.6% had decided to stay at home: this behavior was associated with IL (β = 1.05, p < 0.001), and its total effect was partially mediated (15.1%) by perceived severity. Educational attainment was also associated with staying at home (β = 0.10, p = 0.018) and its total effect was partially mediated (15.0%) by perceived susceptibility. Interventions aimed at low income and less educated older adults should be developed to improve preventive behaviors in this vulnerable group during the COVID-19 pandemic.
Recognizing Emotions through Facial Expressions: A Largescale Experimental Study
Authors: Dores Artemisa R. , Barbosa Fernando , Queirós Cristina , Carvalho Irene P. , Griffiths Mark D.
Published: October 2020

Experimental research examining emotional processes is typically based on the observation of images with affective content, including facial expressions. Future studies will benefit from databases with emotion-inducing stimuli in which characteristics of the stimuli potentially influencing results can be controlled. This study presents Portuguese normative data for the identification of seven facial expressions of emotions (plus a neutral face), on the Radboud Faces Database (RaFD). The effect of participants’ gender and models’ sex on emotion recognition was also examined. Participants (N = 1249) were exposed to 312 pictures of white adults displaying emotional and neutral faces with a frontal gaze. Recognition agreement between the displayed and participants’ chosen expressions ranged from 69% (for anger) to 97% (for happiness). Recognition levels were significantly higher among women than among men only for anger and contempt. The emotion recognition was higher either in female models or in male models depending on the emotion. Overall, the results show high recognition levels of the facial expressions presented, indicating that the RaFD provides adequate stimuli for studies examining the recognition of facial expressions of emotion among college students. Participants’ gender had a limited influence on emotion recognition, but the sex of the model requires additional consideration.
Adolescent Tobacco Exposure in 31 Latin American Cities before and after the Framework Convention for Tobacco Control
Authors: Prado-Galbarro Francisco-Javier , Auchincloss Amy H. , Pérez-Ferrer Carolina , Sanchez-Franco Sharon , Barrientos-Gutierrez Tonatiuh
Published: October 2020

Our objective was to describe the prevalence and changes in tobacco use and tobacco control policies in Latin American countries and cities before and after ratification of the 2003 Framework Convention on Tobacco Control (FCTC). Country-level tobacco policy data came from reports on the global tobacco epidemic (World Health Organization, 2007–2014). Global Youth Tobacco Survey data, 2000–2011, came from six countries (Argentina, Brazil, Chile, Colombia, Mexico, Peru), 31 cities and 132,065 students. Pre- and post-FCTC prevalence and relative changes were estimated. All countries showed improvements in tobacco control policies but Mexico and Peru showed the smallest improvements. In general, adolescents reduced their tobacco use, reported less exposure to smoking at home, more tobacco education, and more retailer refusals to sell them cigarettes. Adolescents reported smaller reductions in secondhand smoke exposure outside the home and no change in exposure to tobacco media/promotions. Pre-FCTC prevalence and relative changes during the post-FCTC period were more heterogeneous across cities than across countries. Despite overall improvements in tobacco policies and the decline in exposure to tobacco, policies related to media/promotions and secondhand smoke need strengthening. There was wide variation in adolescent exposure to tobacco between cities (within countries), which suggested major heterogeneity of policy implementation at the local level.
Menstrual Problems and Lifestyle among Spanish University Women
Authors: Fernández-Martínez Elia , Fernández-Villa Tania , Amezcua-Prieto Carmen , Suárez-Varela María Morales , Mateos-Campos Ramona , Ayán-Pérez Carlos , Molina de la Torre Antonio José , Ortíz-Moncada Rocío , Almaraz Ana , Blázquez Abellán Gemma , Delgado-Rodríguez Miguel , Alonso-Molero Jéssica , Martínez-Ruíz Virginia , Llopis-Morales Agustín , Valero Juan Luis Félix , Cancela Carral José Mª , Martín-Peláez Sandra , Alguacil Juan
Published: October 2020

Menstrual problems affect many young women worldwide, conditioning both their academic performance and quality of life. This study sought to analyse the prevalence of menstrual problems and their possible relationship with lifestyle among Spanish university women, as part of a research project (UniHcos Project) involving a cohort of 11 Spanish universities with 7208 university students. A descriptive analysis was performed using the bivariate chi-square test and the Student’s t-test together with a binary logistic regression, in which the dependent variable was ‘suffering from menstrual problems’. Menstrual problems were identified in 23.8% of the students, representing women who paid more visits to the doctor and to emergency rooms, and who consumed more painkillers and contraceptives. In relation to dietary preferences, menstrual problems were 1.39 (CI 95% 1.22–1.61; p = 0.000) times more likely among women classified as high-risk alcohol users according to the AUDIT questionnaire, and 1.187 (CI 95% 1.029–1.370; p = 0.019) times greater among those who consumed sweets daily, 1.592 (CI 95% 1.113–2.276; p = 0.011) times more frequent among those who eat fish daily, and 1.199 (CI 95% 1.004–1.432; p = 0.045) times greater among those who were dieting. Menstrual problems affect many college students and potentially modifiable lifestyle variables exist which may influence their prevalence. It would be interesting to develop programmes to promote women’s health in the university context.
Swiss University Students’ Risk Perception and General Anxiety during the COVID-19 Pandemic
Authors: Dratva Julia , Zysset Annina , Schlatter Nadine , von Wyl Agnes , Huber Marion , Volken Thomas
Published: October 2020

University students were confronted with abrupt changes to their daily lives by the COVID-19 lock-down. We investigated Generalized Anxiety Disorder Scale-7 (GAD-7) and anxiety levels, and the association between perceived impact on well-being, studies, and daily lives and anxiety levels, adjusted for gender, age, social class and affiliation. Early in the lock-down all students of the Zurich University of Applied Sciences (N = 12,429) were invited to a voluntary longitudinal health survey. Participation rate was 20% (n = 2437): 70% females, median age 25 yrs. (IQR 23–28). A total of 10% reported a deterioration of well-being compared to pre-Corona. LCA yielded three classes varying in perceived COVID-19 impact: 1 (low, n = 675), 2 (moderate, n = 1098), and 3 (strong, n = 656). Adjusted proportion of moderate to severe anxiety by class were 45% (95% CI: 28.0–62.0), 15.5% (95% CI: 13.1–17.9), and 5.1% (95% CI: 4.7–5.6), respectively. Multivariate regression analyses yielded an OR for moderate to severe anxiety of 3.88 (95% CI: 2.5–6.0, class 2) and 22.43 (95% CI: 14.5–34.6, class 3) compared to class-1. The investigated association implies that containment measures have a selective effect on anxiety in students. The diversity of students’ perception and associated anxiety should be monitored and considered in future response to pandemics.
Work-Related Psychosocial Stress in Small and Medium-Sized Enterprises: An Integrative Review
Authors: Schreibauer Elena Christina , Hippler Melina , Burgess Stephanie , Rieger Monika A. , Rind Esther
Published: October 2020

Background: Work-related psychosocial stress can cause mental and physical illnesses resulting in high costs for the individual, the economy and society. Small and medium-sized enterprises (SMEs) employ the majority of the world’s workforce and often have fewer financial and human resources compared to larger businesses. The aim of this review is to summarize current knowledge on work-related stress in SMEs according to well-established guidelines categorizing psychosocial factors at work. Methods: A systematic database search was carried out in PubMed, PsycINFO, PSYNDEX and Business Source Premiere from March to June 2019, updated in January 2020. Data of included studies were analyzed and mapped into five themes: “work content and task”, “organization of work”, “social relations”, “working environment” and “new forms of work”. Results: After full-text screening, 45 out of 116 studies were included for data extraction. Studies were very heterogeneous and of varying quality, mostly applying a cross-sectional study design. Psychosocial factors in SMEs have been researched with a focus on the work patterns “work organization” and “work content and task”. Conclusions: This review underlines the need for more and better quality research of psychosocial factors in SMEs, particularly in relation to ongoing and new challenges in the workplace, including stressors related to the process of digitalization or the development of safe working conditions during the emerge of new infectious diseases.
Prevalence and Credibility of Nutrition and Health Claims: Policy Implications from a Case Study of Mongolian Food Labels
Authors: Chimedtseren Nyamragchaa , Kelly Bridget , McMahon Anne-Therese , Yeatman Heather
Published: October 2020

Nutrition and health claims should be truthful and not misleading. We aimed to determine the use of nutrition and health claims in packaged foods sold in Mongolia and examine their credibility. A cross-sectional study examined the label information of 1723 products sold in marketplaces in Ulaanbaatar, Mongolia. The claim data were analysed descriptively. In the absence of national regulations, the credibility of the nutrition claims was examined by using the Codex Alimentarius guidelines, while the credibility of the health claims was assessed by using the European Union (EU) Regulations (EC) No 1924/2006. Nutritional quality of products bearing claims was determined by nutrient profiling. Approximately 10% (n = 175) of products carried at least one health claim and 9% (n = 149) carried nutrition claims. The credibility of nutrition and health claims was very low. One-third of nutrition claims (33.7%, n = 97) were deemed credible, by having complete and accurate information on the content of the claimed nutrient/s. Only a few claims would be permitted in the EU countries by complying with the EU regulations. Approximately half of the products with nutrition claims and 40% of products with health claims were classified as less healthy products. The majority of nutrition and health claims on food products sold in Mongolia were judged as non-credible, and many of these claims were on unhealthy products. Rigorous and clear regulations are needed to prevent negative impacts of claims on food choices and consumption, and nutrition transition in Mongolia.
Predictors of Delirium in Octogenarian Patients Hospitalized for a Hip Fracture
Authors: Plaza-Carmona María , Requena-Hernández Carmen , Jiménez-Mola Sonia
Published: October 2020

Introduction: Since delirium is a major complication that can arise after a patient with a hip fracture has been hospitalized, it is considered to be one of the most common geriatric conditions. Therefore, its prevention and early detection are essential for reducing both the length of the patient’s stay in the hospital and complications during the hospitalization process. Objective: To identify and analyze the predictors for developing delirium in octogenarians who were admitted to hospital for a hip fracture. Methodology: A prospective study conducted with a sample of 287 patients aged 80 years and older (mean age 87.2 ± 3.2 years; 215 women, 72 men), recruited from the Trauma Unit of the University Hospital of León (Spain). Further, 71.1% of the patients lived in a family member’s home, while the other 28.9% lived in a nursing home. After observing each patient’s interactions with their doctor in a clinical setting, the data for this study were obtained by reviewing the selected patients’ charts. The variables analyzed were sociodemographic information (age, sex, and place of residence), medical information (type of hip break and surgical intervention), cognitive impairment (MMSE score), functional level (Barthel Index score), and clinical information (pharmacological, comorbidities, complications, and the diagnosis and assessment of the severity of delirium in a patient). The univariate and multivariate logistic regression analysis showed a significant relationship between acute confusional state and the following variables: anemia, American Society of Anesthesiologists (ASA) III and IV patients, state of cognitive frailty and functional level, a urinary tract infection, changes in the visual field, renal arterial occlusion, and the type and dosage of drugs administered (this variable was identified in the multivariate model). The inverse relationship between anemia and acute confusional state is surprising. Conclusion: This research shows that clinical observation of acute confusional state is necessary but not sufficient for addressing this condition early and adequately in older adults who have been hospitalized for a hip fracture.
Do Analysts’ Cash Flow Forecasts Improve Firm Value?
Authors: Oh Hyun Min , Park Sam Bock , Kim Jong Hyun
Published: October 2020

We examine whether analysts’ cash flow forecasts improve firm value. First, we analyze whether the joint issuance of financial analysts’ earnings and cash flow forecasts improve firm value. Second, we analyze whether the quality of analysts’ cash flow forecasts improve firm value. The empirical results of our study are as follows. First, the joint issuance of analysts’ earnings and cash flow forecasts has a significantly positive effect on firm value; providing cash flow forecasts reduces information asymmetry and increases earnings quality, thereby increasing corporate value. Second, the quality of analysts’ cash flow forecasts has a significantly positive effect on firm value; the more accurate cash flow forecasts are, the higher firm value is. Our study provides empirical evidence for that the conclusion that cash flow forecasting information produced by financial analysts provides useful information for capital market participants in economic decision making.
Differences in Mitochondrial Membrane Potential Identify Distinct Populations of Human Cardiac Mesenchymal Progenitor Cells
Authors: Gambini Elisa , Martinelli Ilenia , Stadiotti Ilaria , Vinci Maria Cristina , Scopece Alessandro , Eramo Luana , Sommariva Elena , Resta Jessica , Benaouadi Sabrina , Cogliati Elisa , Paolin Adolfo , Parini Angelo , Pompilio Giulio , Savagner Frederique
Published: October 2020

Adult human cardiac mesenchymal progenitor cells (hCmPC) are multipotent resident populations involved in cardiac homeostasis and heart repair. Even if the mechanisms have not yet been fully elucidated, the stem cell differentiation is guided by the mitochondrial metabolism; however, mitochondrial approaches to identify hCmPC with enhanced stemness and/or differentiation capability for cellular therapy are not established. Here we demonstrated that hCmPCs sorted for low and high mitochondrial membrane potential (using a lipophilic cationic dye tetramethylrhodamine methyl ester, TMRM), presented differences in energy metabolism from preferential glycolysis to oxidative rates. TMRM-high cells are highly efficient in terms of oxygen consumption rate, basal and maximal respiration, and spare respiratory capacity compared to TMRM-low cells. TMRM-high cells showed characteristics of pre-committed cells and were associated with higher in vitro differentiation capacity through endothelial, cardiac-like, and, to a lesser extent, adipogenic and chondro/osteogenic cell lineage, when compared with TMRM-low cells. Conversely, TMRM-low showed higher self-renewal potential. To conclude, we identified two hCmPC populations with different metabolic profile, stemness maturity, and differentiation potential. Our findings suggest that metabolic sorting can isolate cells with higher regenerative capacity and/or long-term survival. This metabolism-based strategy to select cells may be broadly applicable to therapies.
Early Pro-Inflammatory Remodeling of HDL Proteome in a Model of Diet-Induced Obesity: 2H2O-Metabolic Labeling-Based Kinetic Approach
Authors: Sadana Prabodh , Lin Li , Aghayev Mirjavid , Ilchenko Serguei , Kasumov Takhar
Published: October 2020

Mice fed a high-fat diet for 12 weeks or longer develop hyperglycemia, insulin resistance, dyslipidemia, and fatty liver. Additionally, a high-fat diet induces inflammation that remodels and affects the anti-inflammatory and antiatherogenic property of the high-density lipoprotein (HDL). However, the precise time course of metabolic disease progression and HDL remodeling remains unclear. Short-term (four weeks) high-fat feeding (60% fat calories) was performed in wild-type male C57BL/6J mice to gain insights into the early metabolic disease processes in conjunction with a HDL proteome dynamics analysis using a heavy water metabolic labeling approach. The high-fat diet-fed mice developed hyperglycemia, impaired glucose tolerance, hypercholesterolemia without hypertriglyceridemia or hepatic steatosis. A plasma HDL proteome dynamics analysis revealed increased turnover rates (and reduced half-lives) of several acute-phase response proteins involved in innate immunity, including complement C3 (12.77 ± 0.81 vs. 9.98 ± 1.20 h, p < 0.005), complement factor B (12.71 ± 1.01 vs. 10.85 ± 1.04 h, p < 0.05), complement Factor H (19.60 ± 1.84 vs. 16.80 ± 1.58 h, p < 0.05), and complement factor I (25.25 ± 1.29 vs. 19.88 ± 1.50 h, p < 0.005). Our findings suggest that an early immune response-induced inflammatory remodeling of the plasma HDL proteome precedes the diet-induced steatosis and dyslipidemia.
Solid-Phase Synthesis and In-Silico Analysis of Iron-Binding Catecholato Chelators
Authors: Gacesa Ranko , Tripodi Andrea A. P. , Cilibrizzi Agostino , Leggio Antonella , Hider Robert , Abbate Vincenzo
Published: October 2020

Siderophores are iron-complexing compounds synthesized by bacteria and fungi. They are low molecular weight compounds (500-1500 Daltons) possessing high affinity for iron(III). Since 1970 a large number of siderophores have been characterized, the majority using hydroxamate or catecholate as functional groups. The biosynthesis of siderophores is typically regulated by the iron levels of the environment where the organism is located. Because of their exclusive affinity and specificity for iron(III), natural siderophores and their synthetic derivatives have been exploited in the treatment of human iron-overload diseases, as both diagnostic and therapeutic agents. Here, solid-phase approach for the preparation of hexadentate, peptide-based tricatecholato containing peptides is described. The versatility of the synthetic method allows for the design of a common scaffolding structure whereby diverse ligands can be conjugated. With so many possibilities, a computational approach has been developed which will facilitate the identification of those peptides which are capable of providing a high affinity iron(III) binding site. This study reports an integrated computational/synthetic approach towards a rational development of peptide-based siderophores.
All-Atomic Molecular Dynamic Studies of Human and Drosophila CDK8: Insights into Their Kinase Domains, the LXXLL Motifs, and Drug Binding Site
Authors: Xu Wu , Xie Xiao-Jun , Faust Ali K. , Liu Mengmeng , Li Xiao , Chen Feng , Naquin Ashlin A. , Walton Avery C. , Kishbaugh Peter W. , Ji Jun-Yuan
Published: October 2020

Cyclin-dependent kinase 8 (CDK8) and its regulatory partner Cyclin C (CycC) play conserved roles in modulating RNA polymerase II (Pol II)-dependent gene expression. To understand the structure and function relations of CDK8, we analyzed the structures of human and Drosophila CDK8 proteins using molecular dynamics simulations, combined with functional analyses in Drosophila. Specifically, we evaluated the structural differences between hCDK8 and dCDK8 to predict the effects of the LXXLL motif mutation (AQKAA), the P154L mutations, and drug binding on local structures of the CDK8 proteins. First, we have observed that both the LXXLL motif and the kinase activity of CDK8 are required for the normal larval-to-pupal transition in Drosophila. Second, our molecular dynamic analyses have revealed that hCDK8 has higher hydrogen bond occupation of His149-Asp151 and Asp151-Asn156 than dCDK8. Third, the substructure of Asp282, Phe283, Arg285, Thr287 and Cys291 can distinguish human and Drosophila CDK8 structures. In addition, there are two hydrogen bonds in the LXXLL motif: a lower occupation between L312 and L315, and a relatively higher occupation between L312 and L316. Human CDK8 has higher hydrogen bond occupation between L312 and L316 than dCDK8. Moreover, L312, L315 and L316 in the LXXLL motif of CDK8 have the specific pattern of hydrogen bonds and geometries, which could be crucial for the binding to nuclear receptors. Furthermore, the P154L mutation dramatically decreases the hydrogen bond between L312 and L315 in hCDK8, but not in dCDK8. The mutations of P154L and AQKAA modestly alter the local structures around residues 154. Finally, we identified the inhibitor-induced conformational changes of hCDK8, and our results suggest a structural difference in the drug-binding site between hCDK8 and dCDK8. Taken together, these results provide the structural insights into the roles of the LXXLL motif and the kinase activity of CDK8 in vivo.
GPR4 Knockout Improves the Neurotoxin-Induced, Caspase-Dependent Mitochondrial Apoptosis
of the Dopaminergic Neuronal Cell
Authors: Haque Md Ezazul , Akther Mahbuba , Azam Shofiul , Choi Dong-Kug , Kim In-Su
Published: October 2020

In Parkinson’s disease, mitochondrial oxidative stress-mediated apoptosis is a major cause of dopaminergic neuronal loss in the substantia nigra (SN). G protein-coupled receptor 4 (GPR4), previously recognised as an orphan G protein coupled-receptor (GPCR), has recently been claimed as a member of the group of proton-activated GPCRs. Its activity in neuronal apoptosis, however, remains undefined. In this study, we investigated the role of GPR4 in the 1-methyl-4-phenylpyridinium ion (MPP+) and hydrogen peroxide (H2O2)-treated apoptotic cell death of stably GPR4-overexpressing and stably GPR4-knockout human neuroblastoma SH-SY5Y cells. In GPR4-OE cells, MPP+ and H2O2 were found to significantly increase the expression levels of both mRNA and proteins of the pro-apoptotic Bcl-2-associated X protein (Bax) genes, while they decreased the anti-apoptotic B-cell lymphoma 2 (Bcl-2) genes. In addition, MPP+ treatment activated Caspase-3, leading to the cleavage of poly (ADP-ribose) polymerase (PARP) and decreasing the mitochondrial membrane potential (ΔΨm) in GPR4-OE cells. In contrast, H2O2 treatment significantly increased the intracellular calcium ions (Ca2+) and reactive oxygen species (ROS) in GPR4-OE cells. Further, chemical inhibition by NE52-QQ57, a selective antagonist of GPR4, and knockout of GPR4 by clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 decreased the Bax/Bcl-2 ratio and ROS generation, and stabilised the ΔΨm, thus protecting the SH-SY5Y cells from MPP+- or H2O2-induced apoptotic cell death. Moreover, the knockout of GPR4 decreased the proteolytic degradation of phosphatidylinositol biphosphate (PIP2) and subsequent release of the endoplasmic reticulum (ER)-stored Ca2+ in the cytosol. Our results suggest that the pharmacological inhibition or genetic deletion of GPR4 improves the neurotoxin-induced caspase-dependent mitochondrial apoptotic pathway, possibly through the modulation of PIP2 degradation-mediated calcium signalling. Therefore, GPR4 presents a potential therapeutic target for neurodegenerative disorders such as Parkinson’s disease.
Targeted Amino Acid Substitutions in a Trichoderma Peptaibol Confer Activity against Fungal Plant Pathogens and Protect Host Tissues from Botrytis cinerea Infection
Authors: De Zotti Marta , Sella Luca , Bolzonello Angela , Gabbatore Laura , Peggion Cristina , Bortolotto Alessandro , Elmaghraby Ibrahim , Tundo Silvio , Favaron Francesco
Published: October 2020

Fungal species belonging to the Trichoderma genus are commonly used as biocontrol agents against several crop pathogens. Among their secondary metabolites, peptaibols are helical, antimicrobial peptides, which are structurally stable even under extreme pH and temperature conditions. The promise of peptaibols as agrochemicals is, however, hampered by poor water solubility, which inhibits efficient delivery for practical use in crop protection. Using a versatile synthetic strategy, based on green chemistry procedures, we produced water-soluble analogs of the short-length peptaibol trichogin. Although natural trichogin was inactive against the tested fungal plant pathogens (Botrytis cinerea, Bipolaris sorokiniana, Fusarium graminearum, and Penicillium expansum), three analogs completely inhibited fungal growth at low micromolar concentrations. The most effective peptides significantly reduced disease symptoms by B. cinerea on common bean and grapevine leaves and ripe grape berries without visible phytotoxic effects. An in-depth conformational analysis featuring a 3D-structure–activity relationship study indicated that the relative spatial position of cationic residues is crucial for increasing peptide fungicidal activity.
Macrophage-Derived Iron-Bound Lipocalin-2 Correlates with Renal Recovery Markers Following Sepsis-Induced Kidney Damage
Authors: Mertens Christina , Kuchler Laura , Sola Anna , Guiteras Roser , Grein Stephan , Brüne Bernhard , von Knethen Andreas , Jung Michaela
Published: October 2020

During the course of sepsis in critically ill patients, kidney dysfunction and damage are among the first events of a complex scenario toward multi-organ failure and patient death. Acute kidney injury triggers the release of lipocalin-2 (Lcn-2), which is involved in both renal injury and recovery. Taking into account that Lcn-2 binds and transports iron with high affinity, we aimed at clarifying if Lcn-2 fulfills different biological functions according to its iron-loading status and its cellular source during sepsis-induced kidney failure. We assessed Lcn-2 levels both in serum and in the supernatant of short-term cultured renal macrophages (MΦ) as well as renal tubular epithelial cells (TEC) isolated from either Sham-operated or cecal ligation and puncture (CLP)-treated septic mice. Total kidney iron content was analyzed by Perls’ staining, while Lcn-2-bound iron in the supernatants of short-term cultured cells was determined by atomic absorption spectroscopy. Lcn-2 protein in serum was rapidly up-regulated at 6 h after sepsis induction and subsequently increased up to 48 h. Lcn-2-levels in the supernatant of TEC peaked at 24 h and were low at 48 h with no change in its iron-loading. In contrast, in renal MΦ Lcn-2 was low at 24 h, but increased at 48 h, where it mainly appeared in its iron-bound form. Whereas TEC-secreted, iron-free Lcn-2 was associated with renal injury, increased MΦ-released iron-bound Lcn-2 was linked to renal recovery. Therefore, we hypothesized that both the cellular source of Lcn-2 as well as its iron-load crucially adds to its biological function during sepsis-induced renal injury.
Activation of the VEGF-A/ERK/PLA2 Axis Mediates Early Retinal Endothelial Cell Damage Induced by High Glucose: New Insight from an In Vitro Model of Diabetic Retinopathy
Authors: Giurdanella Giovanni , Lupo Gabriella , Gennuso Florinda , Conti Federica , Furno Debora Lo , Mannino Giuliana , Anfuso Carmelina Daniela , Drago Filippo , Salomone Salvatore , Bucolo Claudio
Published: October 2020

Early blood retinal barrier (BRB) dysfunction induced by hyperglycemia was related to increased pro-inflammatory activity of phospholipase A2 (PLA2) and the upregulation of vascular endothelial growth factor A (VEGF-A). Here, we tested the role of VEGF-A in high glucose (HG)-induced damage of human retinal endothelial cells (HRECs) mediated by Ca++-dependent (cPLA2) and Ca++-independent (iPLA2) PLA2s. HRECs were treated with normal glucose (5 mM, NG) or high glucose (25 mM, HG) for 48 h with or without the VEGF-trap Aflibercept (Afl, 40 µg/mL), the cPLA2 inhibitor arachidonoyl trifluoromethyl ketone (AACOCF3; 15 µM), the iPLA2 inhibitor bromoenol lactone (BEL; 5 µM), or VEGF-A (80 ng/mL). Both Afl and AACOCF3 prevented HG-induced damage (MTT and LDH release), impairment of angiogenic potential (tube-formation), and expression of VEGF-A mRNA. Furthermore, Afl counteracted HG-induced increase of phospho-ERK and phospho-cPLA2 (immunoblot). VEGF-A in HG-medium increased glucose toxicity, through upregulation of phospho-ERK, phospho-cPLA2, and iPLA2 (about 55%, 45%, and 50%, respectively); immunocytochemistry confirmed the activation of these proteins. cPLA2 knockdown by siRNA entirely prevented cell damage induced by HG or by HG plus VEGF-A, while iPLA2 knockdown produced a milder protective effect. These data indicate that VEGF-A mediates the early glucose-induced damage in retinal endothelium through the involvement of ERK1/2/PLA2 axis activation.
Isolinderalactone Induces Cell Death via Mitochondrial Superoxide- and STAT3-Mediated Pathways in Human Ovarian Cancer Cells
Authors: Rajina Shakya , Kim Woo Jean , Shim Jung-Hyun , Chun Kyung-Soo , Joo Sang Hoon , Shin Hwa Kyoung , Lee Seo-Yeon , Choi Joon-Seok
Published: October 2020

The mortality rate of ovarian cancer (OC) worldwide increases with age. OC is an often fatal cancer with a curative rate of only 20–30%, as symptoms often appear after disease progression. Studies have reported that isolinderalactone (ILL), a furanosesquiterpene derivative extracted from the dried root of Lindera aggregata, can inhibit several cancer cell lines’ growth. However, the molecular mechanisms underlying ILL activities in human OC cells remain unexplored. This study investigated the antitumor activities of ILL in human OC cells by inducing mitochondrial superoxide (mtSO) and JAK-signal transducer and activator of transcription 3 (STAT3)-dependent cell death. ILL caused cell death in SKOV-3 and OVCAR-3 cells and increased the cell proportion in the subG1 phase. Additionally, ILL significantly induced mtSO production and reduced ROS production. Moreover, ILL downregulated mitochondrial membrane potential and the expression levels of anti-apoptotic Bcl-2 family proteins and superoxide dismutase (SOD)2. Results showed that ILL decreased phosphorylation of serine 727 and tyrosine 705 of STAT3 and expression of survivin, a STAT3-regulated gene. Furthermore, ILL-induced cell death was reversed by pretreatment of Mito-TEMPO, a mitochondria-specific antioxidant. These results suggest that ILL induces cell death by upregulation of mtSO, downregulation of mitochondrial SOD2, and inactivation of the STAT3-mediated pathway.
Multifaceted Roles of TRIM Proteins in Colorectal Carcinoma
Authors: Eberhardt Wolfgang , Haeussler Kristina , Nasrullah Usman , Pfeilschifter Josef
Published: October 2020

Colorectal cancer (CRC) is one of the most frequently diagnosed tumor in humans and one of the most common causes of cancer-related death worldwide. The pathogenesis of CRC follows a multistage process which together with somatic gene mutations is mainly attributed to the dysregulation of signaling pathways critically involved in the maintenance of homeostasis of epithelial integrity in the intestine. A growing number of studies has highlighted the critical impact of members of the tripartite motif (TRIM) protein family on most types of human malignancies including CRC. In accordance, abundant expression of many TRIM proteins has been observed in CRC tissues and is frequently correlating with poor survival of patients. Notably, some TRIM members can act as tumor suppressors depending on the context and the type of cancer which has been assessed. Mechanistically, most cancer-related TRIMs have a critical impact on cell cycle control, apoptosis, epithelial–mesenchymal transition (EMT), metastasis, and inflammation mainly through directly interfering with diverse oncogenic signaling pathways. In addition, some recent publications have emphasized the emerging role of some TRIM members to act as transcription factors and RNA-stabilizing factors thus adding a further level of complexity to the pleiotropic biological activities of TRIM proteins. The current review focuses on oncogenic signaling processes targeted by different TRIMs and their particular role in the development of CRC. A better understanding of the crosstalk of TRIMs with these signaling pathways relevant for CRC development is an important prerequisite for the validation of TRIM proteins as novel biomarkers and as potential targets of future therapies for CRC.
MiR-302 Regulates Glycolysis to Control Cell-Cycle during Neural Tube Closure
Authors: Keuls Rachel A. , Kojima Karin , Lozzi Brittney , Steele John W. , Chen Qiuying , Gross Steven S. , Finnell Richard H. , Parchem Ronald J.
Published: October 2020

Neural tube closure is a critical early step in central nervous system development that requires precise control of metabolism to ensure proper cellular proliferation and differentiation. Dysregulation of glucose metabolism during pregnancy has been associated with neural tube closure defects (NTDs) in humans suggesting that the developing neuroepithelium is particularly sensitive to metabolic changes. However, it remains unclear how metabolic pathways are regulated during neurulation. Here, we used single-cell mRNA-sequencing to analyze expression of genes involved in metabolism of carbon, fats, vitamins, and antioxidants during neurulation in mice and identify a coupling of glycolysis and cellular proliferation to ensure proper neural tube closure. Using loss of miR-302 as a genetic model of cranial NTD, we identify misregulated metabolic pathways and find a significant upregulation of glycolysis genes in embryos with NTD. These findings were validated using mass spectrometry-based metabolite profiling, which identified increased glycolytic and decreased lipid metabolites, consistent with a rewiring of central carbon traffic following loss of miR-302. Predicted miR-302 targets Pfkp, Pfkfb3, and Hk1 are significantly upregulated upon NTD resulting in increased glycolytic flux, a shortened cell cycle, and increased proliferation. Our findings establish a critical role for miR-302 in coordinating the metabolic landscape of neural tube closure.
Sphingosine-1-Phosphate Receptor Modulators and Oligodendroglial Cells: Beyond Immunomodulation
Authors: Roggeri Alessandra , Schepers Melissa , Tiane Assia , Rombaut Ben , van Veggel Lieve , Hellings Niels , Prickaerts Jos , Pittaluga Anna , Vanmierlo Tim
Published: October 2020

Multiple sclerosis (MS) is an autoimmune inflammatory disease characterized by demyelination, axonal loss, and synaptic impairment in the central nervous system (CNS). The available therapies aim to reduce the severity of the pathology during the early inflammatory stages, but they are not effective in the chronic stage of the disease. In this phase, failure in endogenous remyelination is associated with the impairment of oligodendrocytes progenitor cells (OPCs) to migrate and differentiate into mature myelinating oligodendrocytes. Therefore, stimulating differentiation of OPCs into myelinating oligodendrocytes has become one of the main goals of new therapeutic approaches for MS. Different disease-modifying therapies targeting sphingosine-1-phosphate receptors (S1PRs) have been approved or are being developed to treat MS. Besides their immunomodulatory effects, growing evidence suggests that targeting S1PRs modulates mechanisms beyond immunomodulation, such as remyelination. In this context, this review focuses on the current understanding of S1PR modulators and their direct effect on OPCs and oligodendrocytes.
How Periodontal Disease and Presence of Nitric Oxide Reducing Oral Bacteria Can Affect Blood Pressure
Authors: Pignatelli Pamela , Fabietti Giulia , Ricci Annalisa , Piattelli Adriano , Curia Maria Cristina
Published: October 2020

Nitric oxide (NO), a small gaseous and multifunctional signaling molecule, is involved in the maintenance of metabolic and cardiovascular homeostasis. It is endogenously produced in the vascular endothelium by specific enzymes known as NO synthases (NOSs). Subsequently, NO is readily oxidized to nitrite and nitrate. Nitrite is also derived from exogenous inorganic nitrate (NO3) contained in meat, vegetables, and drinking water, resulting in greater plasma NO2 concentration and major reduction in systemic blood pressure (BP). The recycling process of nitrate and nitrite to NO (nitrate-nitrite-NO pathway), known as the enterosalivary cycle of nitrate, is dependent upon oral commensal nitrate-reducing bacteria of the dorsal tongue. Veillonella, Actinomyces, Haemophilus, and Neisseria are the most copious among the nitrate-reducing bacteria. The use of chlorhexidine mouthwashes and tongue cleaning can mitigate the bacterial nitrate-related BP lowering effects. Imbalances in the oral reducing microbiota have been associated with a decrease of NO, promoting endothelial dysfunction, and increased cardiovascular risk. Although there is a relationship between periodontitis and hypertension (HT), the correlation between nitrate-reducing bacteria and HT has been poorly studied. Restoring the oral flora and NO activity by probiotics may be considered a potential therapeutic strategy to treat HT.
Surface-Modified Poly(l-lactide-co-glycolide) Scaffolds for the Treatment of Osteochondral Critical Size Defects—In Vivo Studies on Rabbits
Authors: Krok-Borkowicz Małgorzata , Reczyńska Katarzyna , Rumian Łucja , Menaszek Elżbieta , Orzelski Maciej , Malisz Piotr , Silmanowicz Piotr , Dobrzyński Piotr , Pamuła Elżbieta
Published: October 2020

Poly(l-lactide-co-glycolide) (PLGA) porous scaffolds were modified with collagen type I (PLGA/coll) or hydroxyapatite (PLGA/HAp) and implanted in rabbits osteochondral defects to check their biocompatibility and bone tissue regeneration potential. The scaffolds were fabricated using solvent casting/particulate leaching method. Their total porosity was 85% and the pore size was in the range of 250–320 µm. The physico-chemical properties of the scaffolds were evaluated using scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX), X-ray diffractometry (XRD), X-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy (FTIR), sessile drop, and compression tests. Three types of the scaffolds (unmodified PLGA, PLGA/coll, and PLGA/HAp) were implanted into the defects created in New Zealand rabbit femoral trochlears; empty defect acted as control. Samples were extracted after 1, 4, 12, and 26 weeks from the implantation, evaluated using micro-computed tomography (µCT), and stained by Masson–Goldner and hematoxylin-eosin. The results showed that the proposed method is suitable for fabrication of highly porous PLGA scaffolds. Effective deposition of both coll and HAp was confirmed on all surfaces of the pores through the entire scaffold volume. In the in vivo model, PLGA and PLGA/HAp scaffolds enhanced tissue ingrowth as shown by histological and morphometric analyses. Bone formation was the highest for PLGA/HAp scaffolds as evidenced by µCT. Neo-tissue formation in the defect site was well correlated with degradation kinetics of the scaffold material. Interestingly, around PLGA/coll extensive inflammation and inhibited tissue healing were detected, presumably due to immunological response of the host towards collagen of bovine origin. To summarize, PLGA scaffolds modified with HAp are the most promising materials for bone tissue regeneration.
Chemerin-156 is the Active Isoform in Human Hepatic Stellate Cells
Authors: Spirk Marlen , Zimny Sebastian , Neumann Maximilian , McMullen Nichole , Sinal Christopher J. , Buechler Christa
Published: October 2020

The chemokine chemerin exists as C-terminally processed isoforms whose biological functions are mostly unknown. A highly active human chemerin variant (huChem-157) was protective in experimental hepatocellular carcinoma (HCC) models. Hepatic stellate cells (HSCs) are central mediators of hepatic fibrogenesis and carcinogenesis and express the chemerin receptors chemokine-like receptor 1 (CMKLR1) and G protein-coupled receptor 1 (GPR1). Here we aimed to analyse the effect of chemerin isoforms on the viability, proliferation and secretome of the human HSC cell line LX-2. Therefore, huChem-157, 156 and 155 were over-expressed in LX-2 cells, which have low endogenous chemerin levels. HuChem-157 produced in LX-2 cells activated CMKLR1 and GPR1, and huChem-156 modestly induced GPR1 signaling. HuChem-155 is an inactive chemerin variant. Chemerin isoforms had no effect on cell viability and proliferation. Cellular expression of the fibrotic proteins galectin-3 and alpha-smooth muscle actin was not regulated by any chemerin isoform. HuChem-156 increased IL-6, IL-8 and galectin-3 in cell media. HuChem-157 was ineffective, and accordingly, did not enhance levels of these proteins in media of primary human hepatic stellate cells when added exogenously. These analyses provide evidence that huChem-156 is the biologic active chemerin variant in hepatic stellate cells and acts as a pro-inflammatory factor.
CCN3 (NOV) Drives Degradative Changes in Aging Articular Cartilage
Authors: Kuwahara Miho , Kadoya Koichi , Kondo Sei , Fu Shanqi , Miyake Yoshiko , Ogo Ayako , Ono Mitsuaki , Furumatsu Takayuki , Nakata Eiji , Sasaki Takako , Minagi Shogo , Takigawa Masaharu , Kubota Satoshi , Hattori Takako
Published: October 2020

Aging is a major risk factor of osteoarthritis, which is characterized by the degeneration of articular cartilage. CCN3, a member of the CCN family, is expressed in cartilage and has various physiological functions during chondrocyte development, differentiation, and regeneration. Here, we examine the role of CCN3 in cartilage maintenance. During aging, the expression of Ccn3 mRNA in mouse primary chondrocytes from knee cartilage increased and showed a positive correlation with p21 and p53 mRNA. Increased accumulation of CCN3 protein was confirmed. To analyze the effects of CCN3 in vitro, either primary cultured human articular chondrocytes or rat chondrosarcoma cell line (RCS) were used. Artificial senescence induced by H2O2 caused a dose-dependent increase in Ccn3 gene and CCN3 protein expression, along with enhanced expression of p21 and p53 mRNA and proteins, as well as SA-β gal activity. Overexpression of CCN3 also enhanced p21 promoter activity via p53. Accordingly, the addition of recombinant CCN3 protein to the culture increased the expression of p21 and p53 mRNAs. We have produced cartilage-specific CCN3-overexpressing transgenic mice, and found degradative changes in knee joints within two months. Inflammatory gene expression was found even in the rib chondrocytes of three-month-old transgenic mice. Similar results were observed in human knee articular chondrocytes from patients at both mRNA and protein levels. These results indicate that CCN3 is a new senescence marker of chondrocytes, and the overexpression of CCN3 in cartilage may in part promote chondrocyte senescence, leading to the degeneration of articular cartilage through the induction of p53 and p21.
Characterization of Asparagine Deamidation in Immunodominant Myelin Oligodendrocyte Glycoprotein Peptide Potential Immunotherapy for the Treatment of Multiple Sclerosis
Authors: Androutsou Maria-Eleni , Nteli Agathi , Gkika Areti , Avloniti Maria , Dagkonaki Anastasia , Probert Lesley , Tselios Theodore , Golič Grdadolnik Simona
Published: October 2020

Mannan (polysaccharide) conjugated with a myelin oligodendrocyte glycoprotein (MOG) peptide, namely (KG)5MOG35–55, represents a potent and promising new approach for the immunotherapy of Multiple Sclerosis (MS). The MOG35–55 epitope conjugated with the oxidized form of mannan (poly-mannose) via a (KG)5 linker was found to inhibit the symptoms of MOG35–55-induced experimental autoimmune encephalomyelitis (EAE) in mice using prophylactic and therapeutic vaccinated protocols. Deamidation is a common modification in peptide and protein sequences, especially for Gln and Asn residues. In this study, the structural solution motif of deaminated peptides and their functional effects in an animal model for MS were explored. Several peptides based on the MOG35–55 epitope have been synthesized in which the Asn53 was replaced with Ala, Asp, or isoAsp. Our results demonstrate that the synthesized MOG peptides were formed to the deaminated products in basic conditions, and the Asn53 was mainly modified to Asp. Moreover, both peptides (wild type and deaminated derivative) conjugated with mannan (from Saccharomyces cerevisiae) independently inhibited the development of neurological symptoms and inflammatory demyelinating spinal cord lesions in MOG35–55-induced EAE. To conclude, mannan conjugated with a deamidated product did not affect the efficacy of the parent peptide.