bluuebunny/crossref_metadata_2025 huggingface dataset:
Ambient Air Pollution and Respiratory Health in Sub-Saharan African Children: A Cross-Sectional Analysis
Authors: Cai Yutong Samuel , Gibson Harry , Ramakrishnan Rema , Mamouei Mohammad , Rahimi Kazem
Published: September 2021

Ambient air pollution is projected to become a major environmental risk in sub-Saharan Africa (SSA). Research into its health impacts is hindered by limited data. We aimed to investigate the cross-sectional relationship between particulate matter with a diameter ≤ 2.5 μm (PM2.5) and prevalence of cough or acute lower respiratory infection (ALRI) among children under five in SSA. Data were collected from 31 Demographic and Health Surveys (DHS) in 21 SSA countries between 2005–2018. Prior-month average PM2.5 preceding the survey date was assessed based on satellite measurements and a chemical transport model. Cough and ALRI in the past two weeks were derived from questionnaires. Associations were analysed using conditional logistic regression within each survey cluster, adjusting for child’s age, sex, birth size, household wealth, maternal education, maternal age and month of the interview. Survey-specific odds ratios (ORs) were pooled using random-effect meta-analysis. Included were 368,366 and 109,664 children for the analysis of cough and ALRI, respectively. On average, 20.5% children had reported a cough, 6.4% reported ALRI, and 32% of children lived in urban areas. Prior-month average PM2.5 ranged from 8.9 to 64.6 μg/m3. Pooling all surveys, no associations were observed with either outcome in the overall populations. Among countries with medium-to-high Human Development Index, positive associations were observed with both cough (pooled OR: 1.022, 95%CI: 0.982–1.064) and ALRI (pooled OR: 1.018, 95%CI: 0.975–1.064) for 1 μg/m3 higher of PM2.5. This explorative study found no associations between short-term ambient PM2.5 and respiratory health among young SSA children, necessitating future analyses using better-defined exposure and health metrics to study this important link.
The Association between Dietary Habits, Substance Use, and Mental Distress among Adults in Southern Norway: A Cross-Sectional Study among 28,047 Adults from the General Population
Authors: Stea Tonje Holte , Alvsvåg Linn , Kleppang Annette Løvheim
Published: September 2021

The aim of the present study was to examine associations between dietary habits, substance use, and mental distress among adults. This cross-sectional study was conducted in 2019 using an online questionnaire and included 28,047 adults (≥18 years) from Southern Norway. Multivariable logistic regression models stratified by gender were used to examine the associations between different lifestyle behaviors and mental distress. The results showed increased odds of mental distress among males and females with low consumption of vegetables (OR:1.26; 95% CI:1.08–1.47 and 1.14; 1.02–1.28) and fish (1.28; 1.12–1.46 and 1.36; 1.22–1.52), and among females, but not males, with high consumption of sugar-sweetened beverages (1.25; 1.06–1.48) compared to those with a healthier consumption of these foods and beverages. The results also showed increased odds of mental distress among male and female smokers (1.38; 1.19–1.60 and 1.44; 1.26–1.64), and among females, but not males, reporting current use of smokeless tobacco (1.20; 1.03–1.40), compared to male and female non-smokers and female non-users of smokeless tobacco. Overall, unhealthy dietary habits, smoking and the use of smokeless tobacco was associated with increased odds of mental distress, but the relationship varied according to gender. Future studies are needed to confirm any possible causal relationships.
Ecological Study of Variability in the Relationship between Liver Cancer Mortality and Racial Residential Segregation
Authors: Bemanian Amin , Cassidy Laura D. , Fraser Raphael , Laud Purushottam W. , Saeian Kia , Beyer Kirsten M. M.
Published: September 2021

Racial segregation has been identified as a predictor for the burden of cancer in several different metropolitan areas across the United States. This ecological study tested relationships between racial segregation and liver cancer mortality across several different metropolitan statistical areas in Wisconsin. Tract-level liver cancer mortality rates were calculated using cases from 2003–2012. Hotspot analysis was conducted and segregation scores in high, low, and baseline mortality tracts were compared using ANOVA. Spatial regression analysis was done, controlling for socioeconomic advantage and rurality. Black isolation scores were significantly higher in high-mortality tracts compared to baseline and low-mortality tracts, but stratification by metropolitan areas found this relationship was driven by two of the five metropolitan areas. Hispanic isolation was predictive for higher mortality in regression analysis, but this effect was not found across all metropolitan areas. This study showed associations between liver cancer mortality and racial segregation but also found that this relationship was not generalizable to all metropolitan areas in the study area.
The Predictive Ability of Quarterly Financial Statements
Authors: Zhou Hui , Maneesoonthorn Worapree Ole , Chen Xiangjin Bruce
Published: September 2021

A fundamental role of financial reporting is to provide information useful in forecasting future cash flows. Applying up-to-date time series modelling techniques, this study provides direct evidence on the usefulness of quarterly data in predicting future operating cash flows. Moreover, we show that the predictive gain from using quarterly data is larger for asset-heavy industries and industries with higher levels of earnings smoothness. This study contributes to the accounting literature by examining the usefulness of quarterly financial statements in predicting the realization of future cash flows. Our results help fill the gap in knowledge on quarterly financial statements and provide new insights on why the frequency of financial reporting matters. In addition, our findings have important policy implications for the ongoing debate over interim reporting requirements in multiple jurisdictions around the world.
Improved Indoor Fingerprinting Localization Method Using Clustering Algorithm and Dynamic Compensation
Authors: Bi Jingxue , Huang Lu , Cao Hongji , Yao Guobiao , Sang Wengang , Zhen Jie , Liu Yuying
Published: September 2021

Many indoor fingerprinting localization methods are based on signal-domain distances with large localization error and low stability. An improved fingerprinting localization method using a clustering algorithm and dynamic compensation was proposed. In the offline stage, the fingerprint database was built and clustered based on offline hybrid distance and an affinity propagation clustering algorithm. Furthermore, clusters were adjusted using transition regions and a given radius, as well as updating the corresponding position and fingerprint of the cluster centroid. In the online stage, the lost received signal strength (RSS) in the reference fingerprint would be dynamically compensated by using a minimum RSS value, rather than a fixed one. Online signal-domain distance was calculated for cluster identification based on RSS readings and compensated reference fingerprint. Then, K reference points with minimum online signal-domain distances were selected, and affinity propagation clustering was reused by position-domain distances to choose the position-concentrated sub-cluster for location estimation. Experimental results show that the proposed method outperforms state-of-the-art fingerprinting methods, with the mean error of 2.328 m, the root mean square error of 1.865 m and the maximum error of 10.722 m in a testbed of 3200 square meters. The improvement rates, in terms of accuracy and stability, are more than 21% and 13%, respectively.
Papain Ameliorates Lipid Accumulation and Inflammation in High-Fat Diet-Induced Obesity Mice and 3T3-L1 Adipocytes via AMPK Activation
Authors: Kang Yun-Mi , Kang Hyun-Ae , Cominguez Divina C. , Kim Su-Hyun , An Hyo-Jin
Published: September 2021

Papain is a proteolytic enzyme present in the leaves, fruits, roots, and latex of the Carica papaya (papaya) plant. Although it exhibits a wide range of activities, there are no reports on the anti-obesity effects of papain. This study examined the anti-obesity effect and obesity-involved anti-inflammatory mechanism of papain in in vivo and in vitro models using high-fat diet (HFD)-induced obese mice and 3T3-L1 preadipocytes. Oral administration of papain reduced HFD-induced weight of the body, liver, and adipose tissues of mice. Papain also reduced hepatic lipid accumulation and adipocyte size. Moreover, serum total cholesterol and triglyceride levels were markedly reduced in papain-treated mice. In addition, papain inhibited the differentiation of preadipocytes and oil accumulation in 3T3-L1 preadipocytes and rat primary preadipocytes. Mechanistically, papain significantly downregulated the protein levels of key adipogenesis regulators and reversed the expression of pro-inflammatory cytokines and adipokines in HFD-induced obese mice and 3T3-L1 preadipocytes. Papain also markedly enhanced activation of the AMP-activated protein kinase pathway in both models. Collectively, these results suggest that papain exerts anti-obesity effects in HFD-induced mice and 3T3-L1 preadipocytes by regulating levels of adipogenic factors involved in lipid metabolism and inflammation; thus, it could be useful in the prevention and treatment of obesity.
Effects of Growth Hormone Receptor Ablation in Corticotropin-Releasing Hormone Cells
Authors: dos Santos Willian O. , Gusmao Daniela O. , Wasinski Frederick , List Edward O. , Kopchick John J. , Donato Jr. Jose
Published: September 2021

Corticotropin-releasing hormone (CRH) cells are the dominant neuronal population responsive to the growth hormone (GH) in the paraventricular nucleus of the hypothalamus (PVH). However, the physiological importance of GH receptor (GHR) signaling in CRH neurons is currently unknown. Thus, the main objective of the present study was to investigate the consequences of GHR ablation in CRH-expressing cells of male and female mice. GHR ablation in CRH cells did not cause significant changes in body weight, body composition, food intake, substrate oxidation, locomotor activity, glucose tolerance, insulin sensitivity, counterregulatory response to 2-deoxy-D-glucose and ghrelin-induced food intake. However, reduced energy expenditure was observed in female mice carrying GHR ablation in CRH cells. The absence of GHR in CRH cells did not affect anxiety, circadian glucocorticoid levels or restraint-stress-induced corticosterone secretion and activation of PVH neurons in both male and female mice. In summary, GHR ablation, specifically in CRH-expressing neurons, does not lead to major alterations in metabolism, hypothalamic–pituitary–adrenal axis, acute stress response or anxiety in mice. Considering the previous studies showing that central GHR signaling regulates homeostasis in situations of metabolic stress, future studies are still necessary to identify the potential physiological importance of GH action on CRH neurons.
C5a Activates a Pro-Inflammatory Gene Expression Profile in Human Gaucher iPSC-Derived Macrophages
Authors: Serfecz Jacquelyn C. , Saadin Afsoon , Santiago Clayton P. , Zhang Yuji , Bentzen Søren M. , Vogel Stefanie N. , Feldman Ricardo A.
Published: September 2021

Gaucher disease (GD) is an autosomal recessive disorder caused by bi-allelic GBA1 mutations that reduce the activity of the lysosomal enzyme β-glucocerebrosidase (GCase). GCase catalyzes the conversion of glucosylceramide (GluCer), a ubiquitous glycosphingolipid, to glucose and ceramide. GCase deficiency causes the accumulation of GluCer and its metabolite glucosylsphingosine (GluSph) in a number of tissues and organs. In the immune system, GCase deficiency deregulates signal transduction events, resulting in an inflammatory environment. It is known that the complement system promotes inflammation, and complement inhibitors are currently being considered as a novel therapy for GD; however, the mechanism by which complement drives systemic macrophage-mediated inflammation remains incompletely understood. To help understand the mechanisms involved, we used human GD-induced pluripotent stem cell (iPSC)-derived macrophages. We found that GD macrophages exhibit exacerbated production of inflammatory cytokines via an innate immune response mediated by receptor 1 for complement component C5a (C5aR1). Quantitative RT-PCR and ELISA assays showed that in the presence of recombinant C5a (rC5a), GD macrophages secreted 8–10-fold higher levels of TNF-α compared to rC5a-stimulated control macrophages. PMX53, a C5aR1 blocker, reversed the enhanced GD macrophage TNF-α production, indicating that the observed effect was predominantly C5aR1-mediated. To further analyze the extent of changes induced by rC5a stimulation, we performed gene array analysis of the rC5a-treated macrophage transcriptomes. We found that rC5a-stimulated GD macrophages exhibit increased expression of genes involved in TNF-α inflammatory responses compared to rC5a-stimulated controls. Our results suggest that rC5a-induced inflammation in GD macrophages activates a unique immune response, supporting the potential use of inhibitors of the C5a-C5aR1 receptor axis to mitigate the chronic inflammatory abnormalities associated with GD.
The Short-Chain Fatty Acid Butyrate Attenuates Pulmonary Vascular Remodeling and Inflammation in Hypoxia-Induced Pulmonary Hypertension
Authors: Karoor Vijaya , Strassheim Derek , Sullivan Timothy , Verin Alexander , Umapathy Nagavedi S. , Dempsey Edward C. , Frank Daniel N. , Stenmark Kurt R. , Gerasimovskaya Evgenia
Published: September 2021

Pulmonary hypertension (PH) is a progressive cardiovascular disorder in which local vascular inflammation leads to increased pulmonary vascular remodeling and ultimately to right heart failure. The HDAC inhibitor butyrate, a product of microbial fermentation, is protective in inflammatory intestinal diseases, but little is known regarding its effect on extraintestinal diseases, such as PH. In this study, we tested the hypothesis that butyrate is protective in a Sprague–Dawley (SD) rat model of hypoxic PH. Treatment with butyrate (220 mg/kg intake) prevented hypoxia-induced right ventricular hypertrophy (RVH), hypoxia-induced increases in right ventricular systolic pressure (RVSP), pulmonary vascular remodeling, and permeability. A reversal effect of butyrate (2200 mg/kg intake) was observed on elevated RVH. Butyrate treatment also increased the acetylation of histone H3, 25–34 kDa, and 34–50 kDa proteins in the total lung lysates of butyrate-treated animals. In addition, butyrate decreased hypoxia-induced accumulation of alveolar (mostly CD68+) and interstitial (CD68+ and CD163+) lung macrophages. Analysis of cytokine profiles in lung tissue lysates showed a hypoxia-induced upregulation of TIMP-1, CINC-1, and Fractalkine and downregulation of soluble ICAM (sICAM). The expression of Fractalkine and VEGFα, but not CINC-1, TIMP-1, and sICAM was downregulated by butyrate. In rat microvascular endothelial cells (RMVEC), butyrate (1 mM, 2 and 24 h) exhibited a protective effect against TNFα- and LPS-induced barrier disruption. Butyrate (1 mM, 24 h) also upregulated tight junctional proteins (occludin, cingulin, claudin-1) and increased the acetylation of histone H3 but not α-tubulin. These findings provide evidence of the protective effect of butyrate on hypoxic PH and suggest its potential use as a complementary treatment for PH and other cardiovascular diseases.
Nitrogen-Doped Carbon Aerogels Derived from Starch Biomass with Improved Electrochemical Properties for Li-Ion Batteries
Authors: Kubicka Marcelina , Bakierska Monika , Chudzik Krystian , Świętosławski Michał , Molenda Marcin
Published: September 2021

Among all advanced anode materials, graphite is regarded as leading and still-unrivaled. However, in the modern world, graphite-based anodes cannot fully satisfy the customers because of its insufficient value of specific capacity. Other limitations are being nonrenewable, restricted natural graphite resources, or harsh conditions required for artificial graphite production. All things considered, many efforts have been made in the investigation of novel carbonaceous materials with desired properties produced from natural, renewable resources via facile, low-cost, and environmentally friendly methods. In this work, we obtained N-doped, starch-based carbon aerogels using melamine and N2 pyrolysis as the source of nitrogen. The materials were characterized by X-ray powder diffraction, elemental analysis, X-ray photoelectron spectroscopy, galvanostatic charge–discharge tests, cyclic voltammetry, and electrochemical impedance spectroscopy. Depending on the doping method and the nitrogen amount, synthesized samples achieved different electrochemical behavior. N-doped, bioderived carbons exhibit far better electrochemical properties in comparison with pristine ones. Materials with the optimal amount of nitrogen (such as MCAGPS-N8.0%—carbon aerogel made from potato starch modified with melamine and CAGPS-N1.2%—carbon aerogel made from potato starch modified by N2 pyrolysis) are also competitive to graphite, especially for high-performance battery applications. N-doping can enhance the efficiency of Li-ion cells mostly by inducing more defects in the carbon matrix, improving the binding ability of Li+ and charge-transfer process.
Fenton-Chemistry-Based Oxidative Modification of Proteins Reflects Their Conformation
Authors: Nehls Thomas , Heymann Tim , Meyners Christian , Hausch Felix , Lermyte Frederik
Published: September 2021

In order to understand protein structure to a sufficient extent for, e.g., drug discovery, no single technique can provide satisfactory information on both the lowest-energy conformation and on dynamic changes over time (the ‘four-dimensional’ protein structure). Instead, a combination of complementary techniques is required. Mass spectrometry methods have shown promise in addressing protein dynamics, but often rely on the use of high-end commercial or custom instruments. Here, we apply well-established chemistry to conformation-sensitive oxidative protein labelling on a timescale of a few seconds, followed by analysis through a routine protein analysis workflow. For a set of model proteins, we show that site selectivity of labelling can indeed be rationalised in terms of known structural information, and that conformational changes induced by ligand binding are reflected in the modification pattern. In addition to conventional bottom-up analysis, further insights are obtained from intact mass measurement and native mass spectrometry. We believe that this method will provide a valuable and robust addition to the ‘toolbox’ of mass spectrometry researchers studying higher-order protein structure.
A Novel Carbon Dots/Thermo-Sensitive In Situ Gel for a Composite Ocular Drug Delivery System: Characterization, Ex-Vivo Imaging, and In Vivo Evaluation
Authors: Wang Lijie , Pan Hao , Gu Donghao , Sun Haowei , Chen Kai , Tan Guoxin , Pan Weisan
Published: September 2021

We developed a potential composite ocular drug delivery system for the topical administration of diclofenac sodium (DS). The novel carbon dot CDC-HP was synthesized by the pyrolysis of hyaluronic acid and carboxymethyl chitosan through a one-step hydrothermal method and then embedded in a thermosensitive in situ gel of poloxamer 407 and poloxamer 188 through swelling loading. The physicochemical characteristics of these carbon dots were investigated. The results of the in vitro release test showed that this composite ocular drug delivery system (DS-CDC-HP-Gel) exhibited sustained release for 12 h. The study of the ex vivo fluorescence distribution in ocular tissues showed that it could be used for bioimaging and tracing in ocular tissues and prolong precorneal retention. Elimination profiles in tears corresponded to the study of ex vivo fluorescence imaging. The area under the curve of DS in the aqueous humor in the DS-CDC-HP-Gel group was 3.45-fold that in the DS eye drops group, indicating a longer precorneal retention time. DS-CDC-HP with a positive charge and combined with a thermosensitive in situ gel might strengthen adherence to the corneal surface and prolong the ocular surface retention time to improve the bioavailability. This composite ocular delivery system possesses potential applications in ocular imaging and drug delivery.
Comparative Analysis of Chromatin-Delivered Biomarkers in the Monitoring of Sepsis and Septic Shock: A Pilot Study
Authors: Beltrán-García Jesús , Manclús Juan J. , García-López Eva M. , Carbonell Nieves , Ferreres José , Rodríguez-Gimillo María , Garcés Concepción , Pallardó Federico V. , García-Giménez José L. , Montoya Ángel , Romá-Mateo Carlos
Published: September 2021

Sepsis management remains one of the most important challenges in modern clinical practice. Rapid progression from sepsis to septic shock is practically unpredictable, hence the critical need for sepsis biomarkers that can help clinicians in the management of patients to reduce the probability of a fatal outcome. Circulating nucleoproteins released during the inflammatory response to infection, including neutrophil extracellular traps, nucleosomes, and histones, and nuclear proteins like HMGB1, have been proposed as markers of disease progression since they are related to inflammation, oxidative stress, endothelial damage, and impairment of the coagulation response, among other pathological features. The aim of this work was to evaluate the actual potential for decision making/outcome prediction of the most commonly proposed chromatin-related biomarkers (i.e., nucleosomes, citrullinated H3, and HMGB1). To do this, we compared different ELISA measuring methods for quantifying plasma nucleoproteins in a cohort of critically ill patients diagnosed with sepsis or septic shock compared to nonseptic patients admitted to the intensive care unit (ICU), as well as to healthy subjects. Our results show that all studied biomarkers can be used to monitor sepsis progression, although they vary in their effectiveness to separate sepsis and septic shock patients. Our data suggest that HMGB1/citrullinated H3 determination in plasma is potentially the most promising clinical tool for the monitoring and stratification of septic patients.
Design of Alginate-Based Bionanocomposites with Electrical Conductivity for Active Food Packaging
Authors: Alves Zélia , Ferreira Nuno M. , Mendo Sónia , Ferreira Paula , Nunes Cláudia
Published: September 2021

Bionanocomposite materials have been designed as a promising route to enhance biopolymer properties, especially for food packaging application. The present study reports the preparation of bionanocomposite films of alginate with different loadings of pure reduced graphene oxide (rGO) or of mixed zinc oxide-rGO (ZnO-rGO) fillers by solvent casting. Sepiolite is used to make compatible rGO with the hydrophilic matrix. The addition of fillers to alginate matrix maintains the low water solubility promoted by the calcium chloride treatment, and, additionally, they demonstrate a weaker mechanical properties, and a slight increase in water vapor permeability and wettability. Due to the properties of ZnO-rGO, the alginate bionanocomposites show an increase of electrical conductivity with the increase of filler content. While the highest electrical conductivity (0.1 S/m) is achieved by the in-plane measurement, it is in the through-plane measurement the remarkable enhancement of almost 30 times greater than the alginate film. With 50% of ZnO-rGO filler, the bionanocomposites present the highest antioxidant and antibacterial activities. The combination of electrical conductivity with bioactive properties makes these films promising not only to extend food shelf-life but also to allow packaged food sterilization at low temperature.
P300/CBP-Associated Factor Activates Cardiac Fibroblasts by SMAD2 Acetylation
Authors: Lim Yongwoon , Jeong Anna , Kwon Duk-Hwa , Lee Yeong-Un , Kim Young-Kook , Ahn Youngkeun , Kook Taewon , Park Woo-Jin , Kook Hyun
Published: September 2021

Various heart diseases cause cardiac remodeling, which in turn leads to ineffective contraction. Although it is an adaptive response to injury, cardiac fibrosis contributes to this remodeling, for which the reactivation of quiescent myofibroblasts is a key feature. In the present study, we investigated the role of the p300/CBP-associated factor (PCAF), a histone acetyltransferase, in the activation of cardiac fibroblasts. An intraperitoneal (i.p.) injection of a high dose (160 mg/kg) of isoproterenol (ISP) induced cardiac fibrosis and reduced the amount of the PCAF in cardiac fibroblasts in the mouse heart. However, the PCAF activity was significantly increased in cardiac fibroblasts, but not in cardiomyocytes, obtained from ISP-administered mice. An in vitro study using human cardiac fibroblast cells recapitulated the in vivo results; an treatment with transforming growth factor-β1 (TGF-β1) reduced the PCAF, whereas it activated the PCAF in the fibroblasts. PCAF siRNA attenuated the TGF-β1-induced increase in and translocation of fibrosis marker proteins. PCAF siRNA blocked TGF-β1-mediated gel contraction and cell migration. The PCAF directly interacted with and acetylated mothers against decapentaplegic homolog 2 (SMAD2). PCAF siRNA prevented TGF-β1-induced phosphorylation and the nuclear localization of SMAD2. These results suggest that the increase in PCAF activity during cardiac fibrosis may participate in SMAD2 acetylation and thereby in its activation.
How Are Epigenetic Modifications Related to Cardiovascular Disease in Older Adults?
Authors: Gharipour Mojgan , Mani Arya , Amini Baghbahadorani Mona , de Souza Cardoso Camila Kellen , Jahanfar Shayesteh , Sarrafzadegan Nizal , de Oliveira Cesar , Silveira Erika Aparecida
Published: September 2021

The rate of aging has increased globally during recent decades and has led to a rising burden of age-related diseases such as cardiovascular disease (CVD). At the molecular level, epigenetic modifications have been shown recently to alter gene expression during the life course and impair cellular function. In this regard, several CVD risk factors, such as lifestyle and environmental factors, have emerged as key factors in epigenetic modifications within the cardiovascular system. In this study, we attempted to summarized recent evidence related to epigenetic modification, inflammation response, and CVD in older adults as well as the effect of lifestyle modification as a preventive strategy in this age group. Recent evidence showed that lifestyle and environmental factors may affect epigenetic mechanisms, such as DNA methylation, histone acetylation, and miRNA expression. Several substances or nutrients such as selenium, magnesium, curcumin, and caffeine (present in coffee and some teas) could regulate epigenetics. Similarly, physical inactivity, alcohol consumption, air pollutants, psychological stress, and shift working are well-known modifiers of epigenetic patterns. Understanding the exact ways that lifestyle and environmental factors could affect the expression of genes could help to influence the time of incidence and severity of aging-associated diseases. This review highlighted that a healthy lifestyle throughout the life course, such as a healthy diet rich in fibers, vitamins, and essential elements, and specific fatty acids, adequate physical activity and sleep, smoking cessation, and stress control, could be useful tools in preventing epigenetic changes that lead to impaired cardiovascular function.
Acute Glucose Shift Induces the Activation of the NLRP3 Inflammasome in THP-1 Cells
Authors: Lee Ji Yeon , Kang Yup , Kim Hae Jin , Kim Dae Jung , Lee Kwan Woo , Han Seung Jin
Published: September 2021

We aimed to investigate the effect of acute glucose shift on the activation of the NLRP3 inflammasome, IL-1β secretion, and underlying signaling pathways in THP-1 cells. THP-1 cells were divided into four groups and exposed to the following glucose concentrations for 24 h: constant normal glucose (NG, 5.5 mM), constant high glucose (HG, 25 mM), normal to high glucose shift (NG-to-HG, 5.5 to 25 mM), and high to normal glucose shift (HG-to-NG, 25 to 5.5 mM). Cell viability, oxidative stress, and the levels of NLRP3 inflammasome components were assessed. Both directions of the acute glucose shift increased the activation of the NLRP3 inflammasome, generation of reactive oxygen species (ROS), and expression of phosphorylated p38 MAPK, JNK, and NF-κB compared with either constant NG or HG. Treatment with N-acetylcysteine, a pharmacological antioxidant, inhibited the acute glucose shift-induced generation of ROS, activation of NLRP3 inflammasome, and upregulation of MAPK-NF-κB. Further analysis using inhibitors of p38 MAPK, JNK, and NF-κB indicated that acute glucose shifts promoted IL-1β secretion by activating the signaling pathway in a ROS-MAPK-NF-κB-NLRP3 inflammasome in THP-1 cells. These findings suggested that acute changes in glucose concentration might cause monocyte inflammation, which is associated with diabetic complications.
WGCNA Identifies Translational and Proteasome-Ubiquitin Dysfunction in Rett Syndrome
Authors: Haase Florencia , Gloss Brian S. , Tam Patrick P. L. , Gold Wendy A.
Published: September 2021

Rett Syndrome (RTT) is an X linked neurodevelopmental disorder caused by mutations in the methyl-CpG-binding protein 2 (MECP2) gene, resulting in severe cognitive and physical disabilities. Despite an apparent normal prenatal and postnatal development period, symptoms usually present around 6 to 18 months of age. Little is known about the consequences of MeCP2 deficiency at a molecular and cellular level before the onset of symptoms in neural cells, and subtle changes at this highly sensitive developmental stage may begin earlier than symptomatic manifestation. Recent transcriptomic studies of patient induced pluripotent stem cells (iPSC)-differentiated neurons and brain organoids harbouring pathogenic mutations in MECP2, have unravelled new insights into the cellular and molecular changes caused by these mutations. Here we interrogated transcriptomic modifications in RTT patients using publicly available RNA-sequencing datasets of patient iPSCs harbouring pathogenic mutations and healthy control iPSCs by Weighted Gene Correlation Network Analysis (WGCNA). Preservation analysis identified core gene pathways involved in translation, ribosomal function, and ubiquitination perturbed in some MECP2 mutant iPSC lines. Furthermore, differential gene expression of the parental fibroblasts and iPSC-derived neurons revealed alterations in genes in the ubiquitination pathway and neurotransmission in fibroblasts and differentiated neurons respectively. These findings might suggest that global translational dysregulation and proteasome ubiquitin function in Rett syndrome begins in progenitor cells prior to lineage commitment and differentiation into neural cells.
The Effect of High Selenite and Selenate Concentrations on Ferric Oxyhydroxides Transformation under Alkaline Conditions
Authors: Matulová Michaela , Bujdoš Marek , Miglierini Marcel B. , Cesnek Martin , Duborská Eva , Mosnáčková Katarína , Vojtková Hana , Kmječ Tomáš , Dekan Július , Matúš Peter , Urík Martin
Published: September 2021

Iron-based nanomaterials have high technological impacts on various pro-environmental applications, including wastewater treatment using the co-precipitation method. The purpose of this research was to identify the changes of iron nanomaterial’s structure caused by the presence of selenium, a typical water contaminant, which might affect the removal when the iron co-precipitation method is used. Therefore, we have investigated the maturation of co-precipitated nanosized ferric oxyhydroxides under alkaline conditions and their thermal transformation into hematite in the presence of selenite and selenate with high concentrations. Since the association of selenium with precipitates surfaces has been proven to be weak, the mineralogy of the system was affected insignificantly, and the goethite was identified as an only ferric phase in all treatments. However, the morphology and the crystallinity of ferric oxyhydroxides was slightly altered. Selenium affected the structural order of precipitates, especially at the initial phase of co-precipitation. Still, the crystal integrity and homogeneity increased with time almost constantly, regardless of the treatment. The thermal transformation into well crystalized hematite was more pronounced in the presence of selenite, while selenate-treated and selenium-free samples indicated the presence of highly disordered fraction. This highlights that the aftermath of selenium release does not result in destabilization of ferric phases; however, since weak interactions of selenium are dominant at alkaline conditions with goethite’s surfaces, it still poses a high risk for the environment. The findings of this study should be applicable in waters affected by mining and metallurgical operations.
Genome-Wide Identification and Analyses of Drought/Salt-Responsive Cytochrome P450 Genes in Medicago truncatula
Authors: Xia Yaying , Yang Junfeng , Ma Lin , Yan Su , Pang Yongzhen
Published: September 2021

Cytochrome P450 monooxygenases (P450s) catalyze a great number of biochemical reactions and play vital roles in plant growth, development and secondary metabolism. As yet, the genome-scale investigation on P450s is still lacking in the model legume Medicago truncatula. In particular, whether and how many MtP450s are involved in drought and salt stresses for Medicago growth, development and yield remain unclear. In this study, a total of 346 MtP450 genes were identified and classified into 10 clans containing 48 families. Among them, sixty-one MtP450 genes pairs are tandem duplication events and 10 MtP450 genes are segmental duplication events. MtP450 genes within one family exhibit high conservation and specificity in intron–exon structure. Meanwhile, many Mt450 genes displayed tissue-specific expression pattern in various tissues. Specifically, the expression pattern of 204 Mt450 genes under drought/NaCl treatments were analyzed by using the weighted correlation network analysis (WGCNA). Among them, eight genes (CYP72A59v1, CYP74B4, CYP71AU56, CYP81E9, CYP71A31, CYP704G6, CYP76Y14, and CYP78A126), and six genes (CYP83D3, CYP76F70, CYP72A66, CYP76E1, CYP74C12, and CYP94A52) were found to be hub genes under drought/NaCl treatments, respectively. The expression levels of these selected hub genes could be induced, respectively, by drought/NaCl treatments, as validated by qPCR analyses, and most of these genes are involved in the secondary metabolism and fatty acid pathways. The genome-wide identification and co-expression analyses of M. truncatulaP450 superfamily genes established a gene atlas for a deep and systematic investigation of P450 genes in M. truncatula, and the selected drought-/salt-responsive genes could be utilized for further functional characterization and molecular breeding for resistance in legume crops.
A Shotgun Proteomic Platform for a Global Mapping of Lymphoblastoid Cells to Gain Insight into Nasu-Hakola Disease
Authors: De Palma Antonella , Agresta Anna Maria , Viglio Simona , Rossi Rossana , D’Amato Maura , Di Silvestre Dario , Mauri Pierluigi , Iadarola Paolo
Published: September 2021

Nasu-Hakola Disease (NHD) is a recessively inherited systemic leukodystrophy disorder characterized by a combination of frontotemporal presenile dementia and lytic bone lesions. NHD is known to be genetically related to a structural defect of TREM2 and DAP12, two genes that encode for different subunits of the membrane receptor signaling complex expressed by microglia and osteoclast cells. Because of its rarity, molecular or proteomic studies on this disorder are absent or scarce, only case reports based on neuropsychological and genetic tests being reported. In light of this, the aim of this paper is to provide evidence on the potential of a label-free proteomic platform based on the Multidimensional Protein Identification Technology (MudPIT), combined with in-house software and on-line bioinformatics tools, to characterize the protein expression trends and the most involved pathways in NHD. The application of this approach on the Lymphoblastoid cells from a family composed of individuals affected by NHD, healthy carriers and control subjects allowed for the identification of about 3000 distinct proteins within the three analyzed groups, among which proteins anomalous to each category were identified. Of note, several differentially expressed proteins were associated with neurodegenerative processes. Moreover, the protein networks highlighted some molecular pathways that may be involved in the onset or progression of this rare frontotemporal disorder. Therefore, this fully automated MudPIT platform which allowed, for the first time, the generation of the whole protein profile of Lymphoblastoid cells from Nasu-Hakola subjects, could be a valid approach for the investigation of similar neurodegenerative diseases.
Medical Genetics, Genomics and Bioinformatics Aid in Understanding Molecular Mechanisms of Human Diseases
Authors: Orlov Yuriy L. , Anashkina Anastasia A. , Klimontov Vadim V. , Baranova Ancha V.
Published: September 2021

Molecular mechanisms of human disease progression often have complex genetic underpinnings, and sophisticated sequencing approaches coupled with advanced analytics [...]
Fractionated Irradiation of Right Thorax Induces Abscopal Damage on Bone Marrow Cells via TNF-α and SAA
Authors: Song Yimeng , Hu Songling , Zhang Junling , Zhu Lin , Zhao Xinrui , Chen Qianping , Zhang Jianghong , Bai Yang , Pan Yan , Shao Chunlin
Published: September 2021

Radiation-induced abscopal effect (RIAE) outside of radiation field is becoming more attractive. However, the underlying mechanisms are still obscure. This work investigated the deleterious effect of thoracic irradiation (Th-IR) on distant bone marrow and associated signaling factors by irradiating the right thorax of mice with fractionated doses (8 Gy × 3). It was found that this localized Th-IR increased apoptosis of bone marrow cells and micronucleus formation of bone marrow polychromatic erythrocytes after irradiation. Tandem mass tagging (TMT) analysis and ELISA assay showed that the concentrations of TNF-α and serum amyloid A (SAA) in the mice were significantly increased after Th-IR. An immunohistochemistry assay revealed a robust increase in SAA expression in the liver rather than in the lungs after Th-IR. In vitro experiments demonstrated that TNF-α induced SAA expression in mouse hepatoma Hepa1–6 cells, and these two signaling factors induced DNA damage in bone marrow mesenchymal stem cells (BMSCs) by increasing reactive oxygen species (ROS). On the other hand, injection with TNF-α inhibitor before Th-IR reduced the secretion of SAA and attenuated the abscopal damage in bone marrow. ROS scavenger NAC could also mitigated Th-IR/SAA-induced bone marrow damage in mice. Our findings indicated that Th-IR triggered TNF-α release from lung, which further promoted SAA secretion from liver in a manner of cascade reaction. Consequently, these signaling factors resulted in induction of abscopal damage on bone marrow of mice.
Sex Dimorphism of Nonalcoholic Fatty Liver Disease (NAFLD) in Pparg-Null Mice
Authors: Schiffrin Mariano , Winkler Carine , Quignodon Laure , Naldi Aurélien , Trötzmüller Martin , Köfeler Harald , Henry Hugues , Parini Paolo , Desvergne Béatrice , Gilardi Federica
Published: September 2021

Men with nonalcoholic fatty liver disease (NAFLD) are more exposed to nonalcoholic steatohepatitis (NASH) and liver fibrosis than women. However, the underlying molecular mechanisms of NALFD sex dimorphism are unclear. We combined gene expression, histological and lipidomic analyses to systematically compare male and female liver steatosis. We characterized hepatosteatosis in three independent mouse models of NAFLD, ob/ob and lipodystrophic fat-specific (PpargFΔ/Δ) and whole-body PPARγ-null (PpargΔ/Δ) mice. We identified a clear sex dimorphism occurring only in PpargΔ/Δ mice, with females showing macro- and microvesicular hepatosteatosis throughout their entire life, while males had fewer lipid droplets starting from 20 weeks. This sex dimorphism in hepatosteatosis was lost in gonadectomized PpargΔ/Δ mice. Lipidomics revealed hepatic accumulation of short and highly saturated TGs in females, while TGs were enriched in long and unsaturated hydrocarbon chains in males. Strikingly, sex-biased genes were particularly perturbed in both sexes, affecting lipid metabolism, drug metabolism, inflammatory and cellular stress response pathways. Most importantly, we found that the expression of key sex-biased genes was severely affected in all the NAFLD models we tested. Thus, hepatosteatosis strongly affects hepatic sex-biased gene expression. With NAFLD increasing in prevalence, this emphasizes the urgent need to specifically address the consequences of this deregulation in humans.
Personalised Medicine for Colorectal Cancer Using Mechanism-Based Machine Learning Models
Authors: Nwaokorie Annabelle , Fey Dirk
Published: September 2021

Gaining insight into the mechanisms of signal transduction networks (STNs) by using critical features from patient-specific mathematical models can improve patient stratification and help to identify potential drug targets. To achieve this, these models should focus on the critical STNs for each cancer, include prognostic genes and proteins, and correctly predict patient-specific differences in STN activity. Focussing on colorectal cancer and the WNT STN, we used mechanism-based machine learning models to identify genes and proteins with significant associations to event-free patient survival and predictive power for explaining patient-specific differences of STN activity. First, we identified the WNT pathway as the most significant pathway associated with event-free survival. Second, we built linear-regression models that incorporated both genes and proteins from established mechanistic models in the literature and novel genes with significant associations to event-free patient survival. Data from The Cancer Genome Atlas and Clinical Proteomic Tumour Analysis Consortium were used, and patient-specific STN activity scores were computed using PROGENy. Three linear regression models were built, based on; (1) the gene-set of a state-of-the-art mechanistic model in the literature, (2) novel genes identified, and (3) novel proteins identified. The novel genes and proteins were genes and proteins of the extant WNT pathway whose expression was significantly associated with event-free survival. The results show that the predictive power of a model that incorporated novel event-free associated genes is better compared to a model focussing on the genes of a current state-of-the-art mechanistic model. Several significant genes that should be integrated into future mechanistic models of the WNT pathway are DVL3, FZD5, RAC1, ROCK2, GSK3B, CTB2, CBT1, and PRKCA. Thus, the study demonstrates that using mechanistic information in combination with machine learning can identify novel features (genes and proteins) that are important for explaining the STN heterogeneity between patients and their association to clinical outcomes.
Prostate Cancer Radiogenomics—From Imaging to Molecular Characterization
Authors: Ferro Matteo , de Cobelli Ottavio , Vartolomei Mihai Dorin , Lucarelli Giuseppe , Crocetto Felice , Barone Biagio , Sciarra Alessandro , Del Giudice Francesco , Muto Matteo , Maggi Martina , Carrieri Giuseppe , Busetto Gian Maria , Falagario Ugo , Terracciano Daniela , Cormio Luigi , Musi Gennaro , Tataru Octavian Sabin
Published: September 2021

Radiomics and genomics represent two of the most promising fields of cancer research, designed to improve the risk stratification and disease management of patients with prostate cancer (PCa). Radiomics involves a conversion of imaging derivate quantitative features using manual or automated algorithms, enhancing existing data through mathematical analysis. This could increase the clinical value in PCa management. To extract features from imaging methods such as magnetic resonance imaging (MRI), the empiric nature of the analysis using machine learning and artificial intelligence could help make the best clinical decisions. Genomics information can be explained or decoded by radiomics. The development of methodologies can create more-efficient predictive models and can better characterize the molecular features of PCa. Additionally, the identification of new imaging biomarkers can overcome the known heterogeneity of PCa, by non-invasive radiological assessment of the whole specific organ. In the future, the validation of recent findings, in large, randomized cohorts of PCa patients, can establish the role of radiogenomics. Briefly, we aimed to review the current literature of highly quantitative and qualitative results from well-designed studies for the diagnoses, treatment, and follow-up of prostate cancer, based on radiomics, genomics and radiogenomics research.
A Comparative Study of Interaction Time and Usability of Using Controllers and Hand Tracking in Virtual Reality Training
Authors: Khundam Chaowanan , Vorachart Varunyu , Preeyawongsakul Patibut , Hosap Witthaya , Noël Frédéric
Published: September 2021

Virtual Reality (VR) technology is frequently applied in simulation, particularly in medical training. VR medical training often requires user input either from controllers or free-hand gestures. Nowadays, hand gestures are commonly tracked via built-in cameras from a VR headset. Like controllers, hand tracking can be used in VR applications to control virtual objects. This research developed VR intubation training as a case study and applied controllers and hand tracking for four interactions—namely collision, grabbing, pressing, and release. The quasi-experimental design assigned 30 medical students in clinical training to investigate the differences between using VR controller and hand tracking in medical interactions. The subjects were divided into two groups, one with VR controllers and the other with VR hand tracking, to study the interaction time and user satisfaction in seven procedures. System Usability Scale (SUS) and User Satisfaction Evaluation Questionnaire (USEQ) were used to measure user usability and satisfaction, respectively. The results showed that the interaction time of each procedure was not different. Similarly, according to SUS and USEQ scores, satisfaction and usability were also not different. Therefore, in VR intubation training, using hand tracking has no difference in results to using controllers. As medical training with free-hand gestures is more natural for real-world situations, hand tracking will play an important role as user input for VR medical training. This allows trainees to recognize and correct their postures intuitively, which is more beneficial for self-learning and practicing.