bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Contamination by Heavy Metals and Metalloids on Chromosomes, Serum Biochemistry and Histopathology of the Bonylip Barb Fish Near Sepon Gold-Copper Mine, Lao PDR
Authors: Soulivongsa Latsamy , Tengjaroenkul Bundit , Neeratanaphan Lamyai
Published: December 2020

The objectives of the present study were to determine the concentrations of heavy metals and metalloids in water, sediment and Osteochilus vittatus fish, and to assess chromosome aberrations, serum biochemical changes and histopathological alterations in O. vittatus from the Nam Kok river near the Sepon gold-copper mine, Lao People’s Democratic Republic compared with the reference area. The results showed that Fe, Mn and Ni in water, As and Cd in sediment as well as As, Cd, Cr, Mn and Ni in O. vittatus muscle samples near the gold-copper mine exceeded standard values. Furthermore, the chromosome assessment in O. vittatus revealed seven types of chromosome aberrations, and the highest total number of chromosome aberrations was a centromere gap. The total number of chromosome aberrations, cell number with chromosome aberrations and percentage of chromosome aberrations in O. vittatus as well as serum liver enzymes between the studied areas were significantly different (p < 0.05). The liver histopathological alterations of the fish near the gold-copper mine revealed atypical cellular structures as nuclear membrane degeneration, rough endoplasmic reticulum disintegration and abnormal cytoplasmic mitochondria. The results of this study suggested that heavy metal and metalloid contaminations from the Sepon gold-copper mine area negatively affect O. vittatus fish in terms of chromosomal defects, serum biochemical changes and liver histopathological appearances.
Heart Rate Variability in Women with Systemic Lupus Erythematosus: Association with Health-Related Parameters and Effects of Aerobic Exercise
Authors: Martínez-Rosales Elena , Sola-Rodríguez Sergio , Vargas-Hitos José Antonio , Gavilán-Carrera Blanca , Rosales-Castillo Antonio , Hernández-Martínez Alba , Artero Enrique G. , Sabio José Mario , Soriano-Maldonado Alberto
Published: December 2020

Abnormal heart rate variability (HRV) has been observed in patients with systemic lupus erythematosus (SLE). In a combined cross-sectional and interventional study approach, we investigated the association of HRV with inflammation and oxidative stress markers, patient-reported outcomes, and the effect of 12 weeks of aerobic exercise in HRV. Fifty-five women with SLE (mean age 43.5 ± 14.0 years) were assigned to either aerobic exercise (n = 26) or usual care (n = 29) in a non-randomized trial. HRV was assessed using a heart rate monitor during 10 min, inflammatory and oxidative stress markers were obtained, psychological stress (Perceived Stress Scale), sleep quality (Pittsburg Sleep Quality Index), fatigue (Multidimensional Fatigue Inventory), depressive symptoms (Beck Depression Inventory), and quality of life (36-item Short-Form Health Survey) were also assessed. Low frequency to high frequency power (LFHF) ratio was associated with physical fatigue (p = 0.019). Sample entropy was inversely associated with high-sensitivity C-reactive protein (p = 0.014) and myeloperoxidase (p = 0.007). There were no significant between-group differences in the changes in HRV derived parameters after the exercise intervention. High-sensitivity C-reactive protein and myeloperoxidase were negatively related to sample entropy and physical fatigue was positively related to LFHF ratio. However, an exercise intervention of 12 weeks of aerobic training did not produce any changes in HRV derived parameters in women with SLE in comparison to a control group.
Enterococcus mundtii Isolated from Slovak Raw Goat Milk and Its Bacteriocinogenic Potential
Authors: Lauková Andrea , Focková Valentína , Pogány Simonová Monika
Published: December 2020

Enterococci are lactic acid bacteria. Most of them can adapt well to the food system due to their salt and acid-tolerance. Moreover, many enterococcal species have been found to produce antimicrobial substances of proteinaceous character, i.e., bacteriocins/enterocins. In this study, Enterococcus mundtii EM ML2/2 with bacteriocinogenic potential was identified in Slovak raw goat milk. This strain demonstrated inhibition activity against up to 36% of Gram-positive indicator bacteria, and in concentrated form the bacteriocin substance (pH 6.3) showed the highest inhibition activity (1600 AU/mL) against the principal indicator strain E. avium EA5. Semi-purified substance (SPS) EM ML2/2 produced inhibition activity up to 3200 AU/mL. Concentrated bacteriocin substance and SPS maintained active (inhibition activity up to 100 AU/mL) for three months under −20 °C storage conditions. The strain showed susceptible antibiotic profile, and it did not form biofilm. No production of damaging enzymes was noted. It was nonhemolytic, as well as DNase, and gelatinase-negative. It grew well in skim milk, and it was salt and acid-tolerant. The bacteriocin potential of E. mundtii species isolated from Slovak raw goat milk has not previously been detected, so this is an original contribution which may stimulate addtitional research and application studies.
Deep-Learning-Based Prediction of High-Risk Taxi Drivers Using Wellness Data
Authors: Lee Seolyoung , Kim Jae Hun , Park Jiwon , Oh Cheol , Lee Gunwoo
Published: December 2020

Background: Factors related to the wellness of taxi drivers are important for identifying high-risk drivers based on human factors. The purpose of this study is to predict high-risk taxi drivers based on a deep learning method by identifying the wellness of a driver, which reflects the personal characteristics of the driver. Methods: In-depth interviews with taxi drivers are conducted to collect wellness data. The priorities of factors affecting the severity of accidents are derived through a random forest model. In addition, based on the derived priority of variables, various combinations of inputs are set as scenarios and optimal artificial neural network models are derived for each scenario. Finally, the model with the best performance for predicting high-risk taxi drivers is selected based on three criteria. Results: A model with variables up to the 16th priority as inputs is selected as the best model; this has a classification accuracy of 86% and an F1-score of 0.77. Conclusions: The wellness-based model for predicting high-risk taxi drivers presented in this study can be used for developing a taxi driver management system. In addition, it is expected to be useful when establishing customized traffic safety improvement measures for commercial vehicle drivers.
COVID-19 Policy Differences across US States: Shutdowns, Reopening, and Mask Mandates
Authors: Zhang Xue , Warner Mildred E.
Published: December 2020

This work used event study to examine the impact of three policies (shutdowns, reopening, and mask mandates) on changes in the daily COVID-19 infection growth rate at the state level in the US (February through August 2020). The results show the importance of early intervention: shutdowns and mask mandates reduced the COVID-19 infection growth rate immediately after being imposed statewide. Over the longer term, mask mandates had a larger effect on flattening the curve than shutdowns. The increase in the daily infection growth rate pushed state governments to shut down, but reopening led to significant increases in new cases 21 days afterward. The results suggest a dynamic social distancing approach: a shutdown for a short period followed by reopening, combined with universal mask wearing. We also found that the COVID-19 growth rate increased in states with higher percentages of essential workers (during reopening) and higher percentages of minorities (during the mask mandate period). Health insurance access for low-income workers (via Medicaid expansion) helped to reduce COVID-19 cases in the reopening model. The implications for public health show the importance of access to health insurance and mask mandates to protect low-income essential workers, but minority groups still face a higher risk of infection during the pandemic.
The Utility of Novel Renal Biomarkers in Assessment of Chronic Kidney Disease of Unknown Etiology (CKDu): A Review
Authors: Gunasekara T.D.K.S.C. , De Silva P. Mangala C.S. , Herath Chula , Siribaddana Sisira , Siribaddana Nipuna , Jayasumana Channa , Jayasinghe Sudheera , Cardenas-Gonzalez Maria , Jayasundara Nishad
Published: December 2020

Chronic Kidney Disease (CKD) is a globally prevalent non-communicable disease with significant mortality and morbidity. It is typically associated with diabetes and hypertension; however, over the last two decades, an emergence of CKD of unknown etiology (CKDu) has claimed thousands of lives in several tropical agricultural communities. CKDu is associated with gradual loss of renal function without initial symptoms until reaching complete kidney failure and eventually death. The most impacted are young adult males of lower socio-economic strata. Since the disease progression can be successfully attenuated through early detection, the development of superior screening and management measures is of utmost importance. In contrast to the conventional biomarkers, novel biomarkers with improved sensitivity and specificity are being discussed as promising tools for early diagnosis of the disease. This review summarizes emerging novel biomarkers used in assessing CKD and discusses the current utility and diagnostic potential of such biomarkers for CKDu screening in clinical settings of different communities impacted by CKDu. Our goal is to provide a framework for practitioners in CKDu impacted regions to consider the use of these novel biomarkers through this synthesis. The increased use of these biomarkers will not only help to validate their diagnostic power further and establish potential prognostic value but may also provide critical insights into sites and mechanisms of renal damage.
Titration of SF3B1 Activity Reveals Distinct Effects on the Transcriptome and Cell Physiology
Authors: Kim Guisbert Karen S. , Mossiah Isiah , Guisbert Eric
Published: December 2020

SF3B1 is a core component of the U2 spliceosome that is frequently mutated in cancer. We have previously shown that titrating the activity of SF3B1, using the inhibitor pladienolide B (PB), affects distinct steps of the heat shock response (HSR). Here, we identify other genes that are sensitive to different levels of SF3B1 (5 vs. 100 nM PB) using RNA sequencing. Significant changes to mRNA splicing were identified at both low PB and high PB concentrations. Changes in expression were also identified in the absence of alternative splicing, suggesting that SF3B1 influences other gene expression pathways. Surprisingly, gene expression changes identified in low PB are not predictive of changes in high PB. Specific pathways were identified with differential sensitivity to PB concentration, including nonsense-mediated decay and protein-folding homeostasis, both of which were validated using independent reporter constructs. Strikingly, cells exposed to low PB displayed enhanced protein-folding capacity relative to untreated cells. These data reveal that the transcriptome is exquisitely sensitive to SF3B1 and suggests that the activity of SF3B1 is finely regulated to coordinate mRNA splicing, gene expression and cellular physiology.
Application of Safirinium N-Hydroxysuccinimide Esters to Derivatization of Peptides for High-Resolution Mass Spectrometry, Tandem Mass Spectrometry, and Fluorescent Labeling of Bacterial Cells
Authors: Fedorowicz Joanna , Wierzbicka Magdalena , Cebrat Marek , Wiśniewska Paulina , Piątek Rafał , Zalewska-Piątek Beata , Szewczuk Zbigniew , Sączewski Jarosław
Published: December 2020

Mass spectrometry methods are commonly used in the identification of peptides and biomarkers. Due to a relatively low abundance of proteins in biological samples, there is a need for the development of novel derivatization methods that would improve MS detection limits. Hence, novel fluorescent N–hydroxysuccinimide esters of dihydro-[1,2,4]triazolo[4,3-a]pyridin-2-ium carboxylates (Safirinium P dyes) have been synthesized. The obtained compounds, which incorporate quaternary ammonium salt moieties, easily react with aliphatic amine groups of peptides, both in solution and on the solid support; thus, they can be applied for derivatization as ionization enhancers. Safirinium tagging experiments with ubiquitin hydrolysate revealed that the sequence coverage level was high (ca. 80%), and intensities of signals were enhanced up to 8-fold, which proves the applicability of the proposed tags in the bottom–up approach. The obtained results confirmed that the novel compounds enable the detection of trace amounts of peptides, and fixed positive charge within the tags results in high ionization efficiency. Moreover, Safirinium NHS esters have been utilized as imaging agents for fluorescent labeling and the microscopic visualization of living cells such as E. coli Top10 bacterial strain.
Gangliosides in Podocyte Biology and Disease
Authors: Savas Berkan , Astarita Giuseppe , Aureli Massimo , Sahali Dil , Ollero Mario
Published: December 2020

Gangliosides constitute a subgroup of glycosphingolipids characterized by the presence of sialic acid residues in their structure. As constituents of cellular membranes, in particular of raft microdomains, they exert multiple functions, some of them capital in cell homeostasis. Their presence in cells is tightly regulated by a balanced expression and function of the enzymes responsible for their biosynthesis, ganglioside synthases, and their degradation, glycosidases. The dysregulation of their abundance results in rare and common diseases. In this review, we make a point on the relevance of gangliosides and some of their metabolic precursors, such as ceramides, in the function of podocytes, the main cellular component of the glomerular filtration barrier, as well as their implications in podocytopathies. The results presented in this review suggest the pertinence of clinical lipidomic studies targeting these metabolites.
Intergenerational Metabolomic Analysis of Mothers with a History of Gestational Diabetes Mellitus and Their Offspring
Authors: Ott Raffael , Pawlow Xenia , Weiß Andreas , Hofelich Anna , Herbst Melanie , Hummel Nadine , Prehn Cornelia , Adamski Jerzy , Römisch-Margl Werner , Kastenmüller Gabi , Ziegler Anette-G. , Hummel Sandra
Published: December 2020

Shared metabolomic patterns at delivery have been suggested to underlie the mother-to-child transmission of adverse metabolic health. This study aimed to investigate whether mothers with gestational diabetes mellitus (GDM) and their offspring show similar metabolomic patterns several years postpartum. Targeted metabolomics (including 137 metabolites) was performed in plasma samples obtained during an oral glucose tolerance test from 48 mothers with GDM and their offspring at a cross-sectional study visit 8 years after delivery. Partial Pearson’s correlations between the area under the curve (AUC) of maternal and offspring metabolites were calculated, yielding so-called Gaussian graphical models. Spearman’s correlations were applied to investigate correlations of body mass index (BMI), Matsuda insulin sensitivity index (ISI-M), dietary intake, and physical activity between generations, and correlations of metabolite AUCs with lifestyle variables. This study revealed that BMI, ISI-M, and the AUC of six metabolites (carnitine, taurine, proline, SM(-OH) C14:1, creatinine, and PC ae C34:3) were significantly correlated between mothers and offspring several years postpartum. Intergenerational metabolite correlations were independent of shared BMI, ISI-M, age, sex, and all other metabolites. Furthermore, creatinine was correlated with physical activity in mothers. This study suggests that there is long-term metabolic programming in the offspring of mothers with GDM and informs us about targets that could be addressed by future intervention studies.
PharmFrag: An Easy and Fast Multiplex Pharmacogenetics Assay to Simultaneously Analyze 9 Genetic Polymorphisms Involved in Response Variability of Anticancer Drugs
Authors: Bouvet Régis , Verdier Marie-Clémence , El Baroudi Yahya , Galibert Marie-Dominique , David Véronique , Schutz Sacha , Tron Camille
Published: December 2020

Regarding several cytotoxic agents, it was evidenced that genetic polymorphisms in genes encoding enzymes involved in their metabolism are associated with higher risk of toxicity. Genotyping these genes before treatment is a valuable strategy to prevent side effects and to predict individual response to drug therapy. This pharmacogenetic approach is recommended for chemotherapies such as thiopurines (azathioprine, 6-mercaptopurine, thioguanine), irinotecan, and fluoropyrimidines (capecitabine and 5-fluorouracil). In this study, we aimed at developing and validating a fast, cost-effective, and easily implementable multiplex genotyping method suitable for analyzing a panel of nine variants involved in the pharmacogenetics of widely prescribed anticancer drugs. We designed a multiplex-specific PCR assay where fragments were labeled by two different fluorescent dye markers (HEX/FAM) identifiable by fragment analysis. These two labels were used to discriminate bi-allelic variants, while the size of the fragment allowed the identification of a particular polymorphism location. Variants of interest were TPMT (rs1800462, rs1142345, rs1800460), NUDT15 (rs116855232), DPYD (rs55886062, rs3918290, rs67376798, rs75017182), and UGT1A1 (rs8175347). The assay was repeatable, and genotypes could be determined when DNA sample amounts ranged from 25 to 100 ng. Primers and dye remained stable in a ready-to-use mixture solution after five freeze–thaw cycles. Accuracy was evidenced by the consistency of 187 genotyping results obtained with our multiplex assay and a reference method. The developed method is fast and cost-effective in simultaneously identifying nine variants involved in the pharmacological response of anticancer drugs. This assay can be easily implemented in laboratories for widespread access to pharmacogenetics in clinical practice.
Oxidative DNA Damage, Inflammatory Signature, and Altered Erythrocytes Properties in Diamond-Blackfan Anemia
Authors: Kapralova Katarina , Jahoda Ondrej , Koralkova Pavla , Gursky Jan , Lanikova Lucie , Pospisilova Dagmar , Divoky Vladimir , Horvathova Monika
Published: December 2020

Molecular pathophysiology of Diamond-Blackfan anemia (DBA) involves disrupted erythroid-lineage proliferation, differentiation and apoptosis; with the activation of p53 considered as a key component. Recently, oxidative stress was proposed to play an important role in DBA pathophysiology as well. CRISPR/Cas9-created Rpl5- and Rps19-deficient murine erythroleukemia (MEL) cells and DBA patients’ samples were used to evaluate proinflammatory cytokines, oxidative stress, DNA damage and DNA damage response. We demonstrated that the antioxidant defense capacity of Rp-mutant cells is insufficient to meet the greater reactive oxygen species (ROS) production which leads to oxidative DNA damage, cellular senescence and activation of DNA damage response signaling in the developing erythroblasts and altered characteristics of mature erythrocytes. We also showed that the disturbed balance between ROS formation and antioxidant defense is accompanied by the upregulation of proinflammatory cytokines. Finally, the alterations detected in the membrane of DBA erythrocytes may cause their enhanced recognition and destruction by reticuloendothelial macrophages, especially during infections. We propose that the extent of oxidative stress and the ability to activate antioxidant defense systems may contribute to high heterogeneity of clinical symptoms and response to therapy observed in DBA patients.
Chitosan and Cellulose-Based Hydrogels for Wound Management
Authors: Alven Sibusiso , Aderibigbe Blessing Atim
Published: December 2020

Wound management remains a challenge worldwide, although there are several developed wound dressing materials for the management of acute and chronic wounds. The wound dressings that are currently used include hydrogels, films, wafers, nanofibers, foams, topical formulations, transdermal patches, sponges, and bandages. Hydrogels exhibit unique features which make them suitable wound dressings such as providing a moist environment for wound healing, exhibiting high moisture content, or creating a barrier against bacterial infections, and are suitable for the management of exuding and granulating wounds. Biopolymers have been utilized for their development due to their non-toxic, biodegradable, and biocompatible properties. Hydrogels have been prepared from biopolymers such as cellulose and chitosan by crosslinking with selected synthetic polymers resulting in improved mechanical, biological, and physicochemical properties. They were useful by accelerating wound re-epithelialization and also mimic skin structure, inducing skin regeneration. Loading antibacterial agents into them prevented bacterial invasion of wounds. This review article is focused on hydrogels formulated from two biopolymers—chitosan and cellulose—for improved wound management.
Dimethyl Fumarate Attenuates Lung Inflammation and Oxidative Stress Induced by Chronic Exposure to Diesel Exhaust Particles in Mice
Authors: Cattani-Cavalieri Isabella , da Maia Valença Helber , Moraes João Alfredo , Brito-Gitirana Lycia , Romana-Souza Bruna , Schmidt Martina , Valença Samuel Santos
Published: December 2020

Air pollution is mainly caused by burning of fossil fuels, such as diesel, and is associated with increased morbidity and mortality due to adverse health effects induced by inflammation and oxidative stress. Dimethyl fumarate (DMF) is a fumaric acid ester and acts as an antioxidant and anti-inflammatory agent. We investigated the potential therapeutic effects of DMF on pulmonary damage caused by chronic exposure to diesel exhaust particles (DEPs). Mice were challenged with DEPs (30 μg per mice) by intranasal instillation for 60 consecutive days. After the first 30 days, the animals were treated daily with 30 mg/kg of DMF by gavage for the remainder of the experimental period. We demonstrated a reduction in total inflammatory cell number in the bronchoalveolar lavage (BAL) of mice subjected to DEP + DMF as compared to those exposed to DEPs alone. Importantly, DMF treatment was able to reduce lung injury caused by DEP exposure. Intracellular total reactive oxygen species (ROS), peroxynitrite (OONO), and nitric oxide (NO) levels were significantly lower in the DEP + DMF than in the DEP group. In addition, DMF treatment reduced the protein expression of kelch-like ECH-associated protein 1 (Keap-1) in lung lysates from DEP-exposed mice, whereas total nuclear factor κB (NF-κB) p65 expression was decreased below baseline in the DEP + DMF group compared to both the control and DEP groups. Lastly, DMF markedly reduced DEP-induced expression of nitrotyrosine, glutathione peroxidase-1/2 (Gpx-1/2), and catalase in mouse lungs. In summary, DMF treatment effectively reduced lung injury, inflammation, and oxidative and nitrosative stress induced by chronic DEP exposure. Consequently, it may lead to new therapies to diminish lung injury caused by air pollutants.
Melatonin Protects Cholangiocytes from Oxidative Stress-Induced Proapoptotic and Proinflammatory Stimuli via miR-132 and miR-34
Authors: Ostrycharz Ewa , Wasik Urszula , Kempinska-Podhorodecka Agnieszka , Banales Jesus M. , Milkiewicz Piotr , Milkiewicz Malgorzata
Published: December 2020

Biosynthesis of melatonin by cholangiocytes is essential for maintaining the function of biliary epithelium. However, this cytoprotective mechanism appears to be impaired in primary biliary cholangitis (PBC). MiR-132 has emerged as a mediator of inflammation in chronic liver diseases. The effect of melatonin on oxidative stress and bile acid-induced apoptosis was also examined in cholangiocyes overexpressing miR506, as a PBC-like cellular model. In PBC patients the serum levels of melatonin were found increased in comparison to healthy controls. Whereas, in cholangiocytes within cirrhotic PBC livers the melatonin biosynthetic pathway was substantially suppressed even though the expressions of melatonin rate-limiting enzyme aralkylamine N-acetyltransferase (AANAT), and CK-19 (marker of cholangiocytes) were enhanced. In cholangiocytes exposed to mitochondrial oxidative stress melatonin decreased the expression of proapoptotic stimuli (PTEN, Bax, miR-34), which was accompanied by the inhibition of a pivotal mediator of inflammatory response Nf-κB-p65 and the activation of antiapoptotic signaling (miR-132, Bcl2). Similarly, melatonin reduced bile acid-induced proapoptotic caspase 3 and Bim levels. In summary, the insufficient hepatic expression of melatonin in PBC patients may predispose cholangiocytes to oxidative stress-related damage. Melatonin, via epigenetic modulation, was able to suppress NF-κB signaling activation and protect against biliary cells apoptotic signaling.
iPSC-Derived Microglia for Modeling Human-Specific DAMP and PAMP Responses in the Context of Alzheimer’s Disease
Authors: Ihnatovych Ivanna , Birkaya Barbara , Notari Emily , Szigeti Kinga
Published: December 2020

Neuroinflammation in Alzheimer’s disease (AD) has been the focus for identifying targetable pathways for drug development. The role of amyloid beta (Aβ), a prototype of damage-associated molecular patterns (DAMPs), has been implicated in triggering an inflammatory response. As alpha7 nicotinic acetylcholine receptor (α7 nAChR) binds Aβ with high affinity, α7 nAChR may play a role in Aβ-induced neuroinflammation. The conundrum of how α7 nAChR as the mediator of the cholinergic anti-inflammatory response may trigger an inflammatory response has not been resolved. CHRFAM7A, the uniquely human fusion gene between ULK4 and CHRNA7, is a negative regulator of α7 nAChR ionotropic function. To provide the human context, isogenic induced pluripotent stem cell (iPSC) lines were developed from CHRFAM7A null and carrier individuals by genome-editing the null line using TALENs to knock-in CHRFAM7A. In iPSC-derived microglia-like cells, CHRFAM7A mitigated Aβ uptake through the α7 nAChR. Despite the lower Aβ uptake, the presence of CHRFAM7A was associated with an innate immune response that was characterized by NF-κB activation and NF-κB target transcription (TNFA, IL6, and IL1B). LPS, a prototype PAMP, induced a heightened immune response in CHRFAM7A carriers. CHRFAM7A modified the dynamics of NF-κB translocation by prolonging its nuclear presence. CHRFAM7A modified the α7 nAChR metabotropic function, resulting in a human-specific innate immune response. This iPSC model provided an opportunity to elucidate the mechanism and establish high throughput screens.
From miRNA Target Gene Network to miRNA Function: miR-375 Might Regulate Apoptosis and Actin Dynamics in the Heart Muscle via Rho-GTPases-Dependent Pathways
Authors: Osmak German , Kiselev Ivan , Baulina Natalia , Favorova Olga
Published: December 2020

MicroRNAs (miRNAs) are short, single-stranded, non-coding ribonucleic acid (RNA) molecules, which are involved in the regulation of main biological processes, such as apoptosis or cell proliferation and differentiation, through sequence-specific interaction with target mRNAs. In this study, we propose a workflow for predicting miRNAs function by analyzing the structure of the network of their target genes. This workflow was applied to study the functional role of miR-375 in the heart muscle (myocardium), since this miRNA was previously shown to be associated with heart diseases, and data on its function in the myocardium are mostly unclear. We identified PIK3CA, RHOA, MAPK3, PAFAH1B1, CTNNB1, MYC, PRKCA, ERBB2, and CDC42 as key genes in the miR-375 regulated network and predicted the possible function of miR-375 in the heart muscle, consisting mainly in the regulation of the Rho-GTPases-dependent signaling pathways. We implemented our algorithm for miRNA function prediction into a Python module, which is available at GitHub.
Circulating Insulin-Like Growth Factor I is Involved in the Effect of High Fat Diet on Peripheral Amyloid β Clearance
Authors: Herrero-Labrador Raquel , Trueba-Saiz Angel , Martinez-Rachadell Laura , Fernandez de Sevilla Mᵃ Estrella , Zegarra-Valdivia Jonathan A. , Pignatelli Jaime , Diaz-Pacheco Sonia , Fernandez Ana M. , Torres Aleman Ignacio
Published: December 2020

Obesity is a risk factor for Alzheimer’s disease (AD), but underlying mechanisms are not clear. We analyzed peripheral clearance of amyloid β (Aβ) in overweight mice because its systemic elimination may impact brain Aβ load, a major landmark of AD pathology. We also analyzed whether circulating insulin-like growth factor I (IGF-I) intervenes in the effects of overweight as this growth factor modulates brain Aβ clearance and is increased in the serum of overweight mice. Overweight mice showed increased Aβ accumulation by the liver, the major site of elimination of systemic Aβ, but unaltered brain Aβ levels. We also found that Aβ accumulation by hepatocytes is stimulated by IGF-I, and that mice with low serum IGF-I levels show reduced liver Aβ accumulation—ameliorated by IGF-I administration, and unchanged brain Aβ levels. In the brain, IGF-I favored the association of its receptor (IGF-IR) with the Aβ precursor protein (APP), and at the same time, stimulated non-amyloidogenic processing of APP in astrocytes, as indicated by an increased sAPPα/sAPPβ ratio after IGF-I treatment. Since serum IGF-I enters into the brain in an activity-dependent manner, we analyzed in overweight mice the effect of brain activation by environmental enrichment (EE) on brain IGF-IR phosphorylation and its association to APP, as a readout of IGF-I activity. After EE, significantly reduced brain IGF-IR phosphorylation and APP/IGF-IR association were found in overweight mice as compared to lean controls. Collectively, these results indicate that a high-fat diet influences peripheral clearance of Aβ without affecting brain Aβ load. Increased serum IGF-I likely contributes to enhanced peripheral Aβ clearance in overweight mice, without affecting brain Aβ load probably because its brain entrance is reduced.
c-Jun N-Terminal Kinase Inhibitors as Potential Leads for New Therapeutics for Alzheimer’s Diseases
Authors: Hepp Rehfeldt Stephanie Cristine , Majolo Fernanda , Goettert Márcia Inês , Laufer Stefan
Published: December 2020

Alzheimer’s Disease (AD) is becoming more prevalent as the population lives longer. For individuals over 60 years of age, the prevalence of AD is estimated at 40.19% across the world. Regarding the cognitive decline caused by the disease, mitogen-activated protein kinases (MAPK) pathways such as the c-Jun N-terminal kinase (JNK) pathway are involved in the progressive loss of neurons and synapses, brain atrophy, and augmentation of the brain ventricles, being activated by synaptic dysfunction, oxidative stress, and excitotoxicity. Nowadays, AD symptoms are manageable, but the disease itself remains incurable, thus the inhibition of JNK3 has been explored as a possible therapeutic target, considering that JNK is best known for its involvement in propagating pro-apoptotic signals. This review aims to present biological aspects of JNK, focusing on JNK3 and how it relates to AD. It was also explored the recent development of inhibitors that could be used in AD treatment since several drugs/compounds in phase III clinical trials failed. General aspects of the MAPK family, therapeutic targets, and experimental treatment in models are described and discussed throughout this review.
Prognostic and Predictive Cross-Roads of Microsatellite Instability and Immune Response to Colon Cancer
Authors: Laghi Luigi , Negri Francesca , Gaiani Federica , Cavalleri Tommaso , Grizzi Fabio , de’ Angelis Gian Luigi , Malesci Alberto
Published: December 2020

Understanding molecular features of colon cancer has shed light on its pathogenesis and progression. Over time, some of these features acquired clinical dignity and were incorporated in decision making. Namely, microsatellite instability (MSI) due to mismatch repair of defects, which primarily was adopted for the diagnosis of Lynch syndrome, became recognized as the biomarker of a different disease type, showing a less aggressive behavior. MSI tumors harbor high amounts of tumor infiltrating lymphocytes (TILs) due to their peculiar load in neoantigens. However, microsatellite stable colon cancer may also show high amounts of TILs, and this feature is as well associated with better outcomes. High TIL loads are in general associated with a favorable prognosis, especially in stage II colon cancer, and therein identifies a patient subset with the lowest probability of relapse. With respect to post-surgical adjuvant treatment, particularly in stage III, TILs predictive ability seems to weaken along with the progression of the disease, being less evident in high risk patients. Moving from cohort studies to the analysis of a series from clinical trials contributed to increase the robustness of TILs as a biomarker. The employment of high TIL densities as an indicator of good prognosis in early-stage colon cancers is strongly advisable, while in late-stage colon cancers the employment as an indicator of good responsiveness to post-surgical therapy requires refinement. It remains to be clarified whether TILs could help in identifying those patients with node-positive cancers to whom adjuvant treatment could be spared, at least in low-risk groups as defined by the TNM staging system.
Novel 1,3,4-Oxadiazole Derivatives of Pyrrolo[3,4-d]pyridazinone Exert Antinociceptive Activity in the Tail-Flick and Formalin Test in Rodents and Reveal Reduced Gastrotoxicity
Authors: Szandruk-Bender Marta , Wiatrak Benita , Szczukowski Łukasz , Świątek Piotr , Rutkowska Maria , Dzimira Stanisław , Merwid-Ląd Anna , Danielewski Maciej , Szeląg Adam
Published: December 2020

Despite the availability of the current drug arsenal for pain management, there is still a clinical need to identify new, more effective, and safer analgesics. Based on our earlier study, newly synthesized 1,3,4-oxadiazole derivatives of pyrrolo[3,4-d]pyridazinone, especially 10b and 13b, seem to be promising as potential analgesics. The current study was designed to investigate whether novel derivatives attenuate nociceptive response in animals subjected to thermal or chemical noxious stimulus, and to compare this effect to reference drugs. The antinociceptive effect of novel compounds was studied using the tail-flick and formalin test. Pretreatment with novel compounds at all studied doses increased the latency time in the tail-flick test and decreased the licking time during the early phase of the formalin test. New derivatives given at the medium and high doses also reduced the late phase of the formalin test. The achieved results indicate that new derivatives dose-dependently attenuate nociceptive response in both models of pain and exert a lack of gastrotoxicity. Both studied compounds act more efficiently than indomethacin, but not morphine. Compound 13b at the high dose exerts the greatest antinociceptive effect. It may be due to the reduction of nociceptor sensitization via prostaglandin E2 and myeloperoxidase levels decrease.
Effect of Acrylamide Supplementation on the Population of Vasoactive Intestinal Peptide (VIP)-Like Immunoreactive Neurons in the Porcine Small Intestine
Authors: Palus Katarzyna , Bulc Michał , Całka Jarosław
Published: December 2020

Acrylamide is one of the harmful substances present in food. The present study aimed to establish the effect of acrylamide supplementation in tolerable daily intake (TDI) dose (0.5 µg/kg b.w./day) and a dose ten times higher than TDI (5 µg/kg b.w./day) on the population of vasoactive intestinal peptide-like immunoreactive (VIP-LI) neurons in the porcine small intestine and the degree of the co-localization of VIP with other neuroactive substances (neuronal nitric oxide synthase (nNOS), substance P (SP), and cocaine- and amphetamine-regulated transcript peptide (CART)). In our work, 15 Danish landrace gilts (5 in each experimental group) received capsules (empty or with low or high doses of acrylamide) for a period of 28 days with their morning feeding. Using double immunofluorescence staining, we established that acrylamide supplementation increased the number of neurons showing immunoreactivity towards VIP in all types of enteric nervous system (ENS) plexuses and fragments of the small intestine studied. Moreover, both doses of acrylamide led to changes in the degree of co-localization of VIP with nNOS, SP, and CART in intramural neurons. The observed changes may be the adaptation of neurons to local inflammation, oxidative stress, or the direct toxic effects of acrylamide on intestinal neurons, also referred to as neuronal plasticity.
A2B Adenosine Receptors: When Outsiders May Become an Attractive Target to Treat Brain Ischemia or Demyelination
Authors: Coppi Elisabetta , Dettori Ilaria , Cherchi Federica , Bulli Irene , Venturini Martina , Lana Daniele , Giovannini Maria Grazia , Pedata Felicita , Pugliese Anna Maria
Published: December 2020

Adenosine is a signaling molecule, which, by activating its receptors, acts as an important player after cerebral ischemia. Here, we review data in the literature describing A2BR-mediated effects in models of cerebral ischemia obtained in vivo by the occlusion of the middle cerebral artery (MCAo) or in vitro by oxygen-glucose deprivation (OGD) in hippocampal slices. Adenosine plays an apparently contradictory role in this receptor subtype depending on whether it is activated on neuro-glial cells or peripheral blood vessels and/or inflammatory cells after ischemia. Indeed, A2BRs participate in the early glutamate-mediated excitotoxicity responsible for neuronal and synaptic loss in the CA1 hippocampus. On the contrary, later after ischemia, the same receptors have a protective role in tissue damage and functional impairments, reducing inflammatory cell infiltration and neuroinflammation by central and/or peripheral mechanisms. Of note, demyelination following brain ischemia, or autoimmune neuroinflammatory reactions, are also profoundly affected by A2BRs since they are expressed by oligodendroglia where their activation inhibits cell maturation and expression of myelin-related proteins. In conclusion, data in the literature indicate the A2BRs as putative therapeutic targets for the still unmet treatment of stroke or demyelinating diseases.
Evidence for Divergent Selection on Immune Genes between the African Malaria Vectors, Anopheles coluzzii and A. gambiae
Authors: Lee Yoosook , Souvannaseng Lattha , Collier Travis C. , Main Bradley J. , Norris Laura C. , Fofana Abdarahamane , Traoré Sekou F. , Cornel Anthony J. , Luckhart Shirley , Lanzaro Gregory C.
Published: December 2020

During their life cycles, microbes infecting mosquitoes encounter components of the mosquito anti-microbial innate immune defenses. Many of these immune responses also mediate susceptibility to malaria parasite infection. In West Africa, the primary malaria vectors are Anopheles coluzzii and A. gambiae sensu stricto, which is subdivided into the Bamako and Savanna sub-taxa. Here, we performed whole genome comparisons of the three taxa as well as genotyping of 333 putatively functional SNPs located in 58 immune signaling genes. Genome data support significantly higher differentiation in immune genes compared with a randomly selected set of non-immune genes among the three taxa (permutation test p < 0.001). Among the 58 genes studied, the majority had one or more segregating mutations (72.9%) that were significantly diverged among the three taxa. Genes detected to be under selection include MAP2K4 and Raf. Despite the genome-wide distribution of immune genes, a high level of linkage disequilibrium (r2 > 0.8) was detected in over 27% of SNP pairs. We discuss the potential role of immune gene divergence as adaptations to the different larval habitats associated with A. gambiae taxa and as a potential force driving ecological speciation in this group of mosquitoes.
Flea Communities on Small Rodents in Eastern Poland
Authors: Zając Zbigniew , Kulisz Joanna , Woźniak Aneta
Published: December 2020

Fleas are hematophagous insects infesting mainly small mammals and, less frequently, birds. With their wide range of potential hosts, fleas play a significant role in the circulation of pathogens in nature. Depending on the species, they can be vectors for viruses, bacteria, rickettsiae, and protozoa and a host for some larval forms of tapeworm species. The aim of this study was to determine the species composition of fleas and their small rodent host preferences in eastern Poland. Animals were captured in traps in various types of ecological habitats (a site covered by grassland vegetation within city limits, an unused agricultural meadow, and a fallow land near a mixed forest). The following rodent species were caught: Apodemus agrarius, Apodemus flavicollis, Microtus arvalis, and Myodesglareolus. Additionally, Ctenophthalmus agyrtes, Ctenophthalmus assimilis, Hystrichopsylla talpae, and Nosopsyllus fasciatus flea species were identified. The peak of the flea activity was noted in summer months. C. agyrtes was found to be the most abundant flea species in eastern Poland, while the greatest numbers of fleas were collected from the rodent species A. agrarius.
Glasgow-Blatchford Score Predicts Post-Discharge Gastrointestinal Bleeding in Hospitalized Patients with Heart Failure
Authors: Hotsuki Yu , Sato Yu , Yoshihisa Akiomi , Watanabe Koichiro , Kimishima Yusuke , Kiko Takatoyo , Yokokawa Tetsuro , Misaka Tomofumi , Sato Takamasa , Kaneshiro Takashi , Oikawa Masayoshi , Kobayashi Atsushi , Yamaki Takayoshi , Kunii Hiroyuki , Nakazato Kazuhiko , Takeishi Yasuchika
Published: December 2020

Background: The Glasgow-Blatchford Score (GBS) is one of the most widely used scoring systems for predicting clinical outcomes for gastrointestinal bleeding (GIB). However, the clinical significance of the GBS in predicting GIB in patients with heart failure (HF) remains unclear. Methods and Results: We conducted a prospective observational study in which we collected the clinical data of a total of 2236 patients (1130 men, median 70 years old) who were admitted to Fukushima Medical University Hospital for acute decompensated HF. During the post-discharge follow-up period of a median of 1235 days, seventy-eight (3.5%) patients experienced GIB. The GBS was calculated based on blood urea nitrogen, hemoglobin, systolic blood pressure, heart rate, and history of hepatic disease. The survival classification and regression tree analysis revealed that the accurate cut-off point of the GBS in predicting post-discharge GIB was six points. The patients were divided into two groups: the high GBS group (GBS > 6, n = 702, 31.4%) and the low GBS group (GBS ≤ 6, n = 1534, 68.6%). The Kaplan–Meier analysis showed that GIB rates were higher in the high GBS group than in the low GBS group. Multivariate Cox proportional hazards analysis adjusted for age, malignant tumor, and albumin indicated that a high GBS was an independent predictor of GIB (hazards ratio 2.258, 95% confidence interval 1.326–3.845, p = 0.003). Conclusions: A high GBS is an independent predictor and useful risk stratification score of post-discharge GIB in patients with HF.
Aqueous Two-Phase System Extraction of Polyketide-Based Fungal Pigments Using Ammonium- or Imidazolium-Based Ionic Liquids for Detection Purpose: A Case Study
Authors: Lebeau Juliana , Petit Thomas , Fouillaud Mireille , Dufossé Laurent , Caro Yanis
Published: December 2020

Demand for microbial colorants is now becoming a competitive research topic for food, cosmetics and pharmaceutics industries. In most applications, the pigments of interest such as polyketide-based red pigments from fungal submerged cultures are extracted by conventional liquid–liquid extraction methods requiring large volumes of various organic solvents and time. To address this question from a different angle, we proposed, here, to investigate the use of three different aqueous two-phase extraction systems using either ammonium- or imidazolium-based ionic liquids. We applied these to four fermentation broths of Talaromyces albobiverticillius (deep red pigment producer), Emericella purpurea (red pigment producer), Paecilomyces marquandii (yellow pigment producer) and Trichoderma harzianum (yellow-brown pigment producer) to investigate their selective extraction abilities towards the detection of polyketide-based pigments. Our findings led us to conclude that (i) these alternative extraction systems using ionic liquids as greener extractant means worked well for this extraction of colored molecules from the fermentation broths of the filamentous fungi investigated here; (ii) tetrabutylammonium bromide, [N4444]Br-, showed the best pigment extraction ability, with a higher putative affinity for azaphilone red pigments; (iii) the back extraction and recovery of the fungal pigments from ionic liquid phases remained the limiting point of the method under our selected conditions for potential industrial applications. Nevertheless, these alternative extraction procedures appeared to be promising ways for the detection of polyketide-based colorants in the submerged cultures of filamentous fungi.
Gene Expression Analysis of Non-Clinical Strain of Aspergillus fumigatus (LMB-35Aa): Does Biofilm Affect Virulence?
Authors: Rebaza Teresa D. , Ludeña Yvette , Samolski Ilanit , Villena Gretty K.
Published: December 2020

Aspergillus fumigatus LMB-35Aa, a saprophytic fungus, was used for cellulase production through biofilms cultures. Since biofilms usually favor virulence in clinical strains, the expression of the related genes of the LMB 35-Aa strain was analyzed by qPCR from the biomass of planktonic cultures and biofilms developed on polyester cloth and polystyrene microplates. For this, virulence-related genes reported for the clinical strain Af293 were searched in A. fumigatus LMB 35-Aa genome, and 15 genes were identified including those for the synthesis of cell wall components, hydrophobins, invasins, efflux transporters, mycotoxins and regulators. When compared with planktonic cultures at 37 °C, invasin gene calA was upregulated in both types of biofilm and efflux transporter genes mdr4 and atrF were predominantly upregulated in biofilms on polystyrene, while aspHs and ftmA were upregulated only in biofilms formed on polyester. Regarding the transcription regulators, laeA was downregulated in biofilms, and medA did not show a significant change. The effect of temperature was also evaluated by comparing the biofilms grown on polyester at 37 vs. 28 °C. Non-significant changes at the expression level were found for most genes evaluated, except for atrF, gliZ and medA, which were significantly downregulated at 37 °C. According to these results, virulence appears to depend on the interaction of several factors in addition to biofilms and growth temperature.