bluuebunny/crossref_metadata_2025 huggingface dataset:
MICAL1 Monooxygenase in Autosomal Dominant Lateral Temporal Epilepsy: Role in Cytoskeletal Regulation and Relation to Cancer
Authors: Haikazian Sipan , Olson Michael F.
Published: April 2022

Autosomal dominant lateral temporal epilepsy (ADLTE) is a genetic focal epilepsy associated with mutations in the LGI1, RELN, and MICAL1 genes. A previous study linking ADLTE with two MICAL1 mutations that resulted in the substitution of a highly conserved glycine residue for serine (G150S) or a frameshift mutation that swapped the last three C-terminal amino acids for 59 extra residues (A1065fs) concluded that the mutations increased enzymatic activity and promoted cell contraction. The roles of the Molecule Interacting with CasL 1 (MICAL1) protein in tightly regulated semaphorin signaling pathways suggest that activating MICAL1 mutations could result in defects in axonal guidance during neuronal development. Further studies would help to illuminate the causal relationships of these point mutations with ADLTE. In this review, we discuss the proposed pathogenesis caused by mutations in these three genes, with a particular emphasis on the G150S point mutation discovered in MICAL1. We also consider whether these types of activating MICAL1 mutations could be linked to cancer.
Effects of Multi-Omics Characteristics on Identification of Driver Genes Using Machine Learning Algorithms
Authors: Li Feng , Chu Xin , Dai Lingyun , Wang Juan , Liu Jinxing , Shang Junliang
Published: April 2022

Cancer is a complex disease caused by genomic and epigenetic alterations; hence, identifying meaningful cancer drivers is an important and challenging task. Most studies have detected cancer drivers with mutated traits, while few studies consider multiple omics characteristics as important factors. In this study, we present a framework to analyze the effects of multi-omics characteristics on the identification of driver genes. We utilize four machine learning algorithms within this framework to detect cancer driver genes in pan-cancer data, including 75 characteristics among 19,636 genes. The 75 features are divided into four types and analyzed using Kullback–Leibler divergence based on CGC genes and non-CGC genes. We detect cancer driver genes in two different ways. One is to detect driver genes from a single feature type, while the other is from the top N features. The first analysis denotes that the mutational features are the best characteristics. The second analysis reveals that the top 45 features are the most effective feature combinations and superior to the mutational features. The top 45 features not only contain mutational features but also three other types of features. Therefore, our study extends the detection of cancer driver genes and provides a more comprehensive understanding of cancer mechanisms.
Graduating Nursing Students’ Empowerment and Related Factors: Comparative Study in Six European Countries
Authors: Visiers-Jiménez Laura , Kuokkanen Liisa , Leino-Kilpi Helena , Löyttyniemi Eliisa , Turjamaa Riitta , Brugnolli Anna , Gaspar Filomena , Nemcová Jana , Palese Alvisa , Rua Marília , Zelenikova Renata , Kajander-Unkuri Satu
Published: April 2022

New nurses are needed in healthcare. To meet the role expectations of a registered nurse, nursing students must feel empowered at graduation. However, there are only a few studies focusing on nursing students’ empowerment. This study aims to describe and analyze graduating nursing students’ level of empowerment in six European countries and potential related factors. A comparative and cross-sectional study was performed in the Czech Republic, Finland, Italy, Portugal, Slovakia, and Spain with graduating nursing students (n = 1746) using the Essential Elements of Nurse Empowerment scale. Potentially related factors included age, gender, a previous degree in health care, work experience in health care, graduation to first-choice profession, intention to leave the nursing profession, level of study achievements, satisfaction with the current nursing programme, clinical practicums, theoretical education, and generic competence measured with the Nurse Competence Scale. The data were analysed statistically. Graduating nursing students’ self-assessed level of empowerment was moderate, with statistical differences between countries. Those with high empowerment had no intention to leave the nursing profession, had a higher level of study achievements, and a higher self-assessed generic competence level. The results suggest that empowerment needs to be enhanced during nursing education. Further research is needed to understand the development of empowerment during the early years of a nursing career.
Post-Operative Endodontic Pain Management: An Overview of Systematic Reviews on Post-Operatively Administered Oral Medications and Integrated Evidence-Based Clinical Recommendations
Authors: Di Spirito Federica , Scelza Giuseppe , Fornara Roberto , Giordano Francesco , Rosa Donato , Amato Alessandra
Published: April 2022

Endodontic treatment comprises the overall management of pre-, intra- and post-operative symptoms, including post-operative endodontic pain, considered as a complication susceptible of chronicization. Post-operative pain is very common and highly unpreventable and has a multi-factorial etiology and a potential pathogenic link to the acute inflammation of the periapical area, secondary to localized chemical, mechanical, host and/or microbial damage occurring during endodontic treatment. Considering the multitude of heterogeneous technical and pharmacological approaches proposed to control post-operative endodontic pain, the present study primarily comprised an overview of systematic reviews of systematic reviews of randomized clinical trials, summarizing findings on post-operatively administered oral medications for post-operative endodontic pain control, in order to note the most effective type and dosage of such drugs. Secondarily, a narrative review of the current evidence on technical solutions to be observed during endodontic treatment procedures, to control post-operative pain, was conducted to provide integrated evidence-based clinical recommendations for optimal post-operative endodontic pain management.
Feasibility of Remediation of Heavy-Metal-Contaminated Marine Dredged Sediments by Active Capping with Enteromorpha Biochar
Authors: Wang Zhaowei , Song Shuang , Wang Huan , Yang Wenchao , Han Jianbo , Chen Hong
Published: April 2022

Enteromorpha biochar (BC) has been proposed as a potential absorbent in the marine environments. This study attempts to understand the process of active capping using Enteromorpha BC to prevent the release of heavy metals (Pb and Cd) from contaminated marine dredged sediments. The capping efficiency was assessed with a series of lab-scale column experiments. Results showed that the Enteromorpha BC exhibits rough pore structure and higher specific surface area, as well as more surface organic functional groups, which is favorable for its adsorption capacity and selectivity towards heavy metals. The capping thickness of 2 cm for Enteromorpha BC was sufficient to prevent the release of heavy metals from sediments, with the capping efficiency of 47% for Pb and 62% for Cd. Kinetic studies showed that heavy metals released into the overlying water can be described by a three-parameter sigmoidal kinetic model. Importantly, the fractions of heavy metals in the dredged sediments below the capping layer were analyzed to reveal the capping remediation mechanism. The outcomes of the present study indicate that capping with Enteromorpha BC is a promising method to regulate the water environment by preventing the release of heavy metals from the contaminated dredged sediments.
Challenges and Drawbacks of the EU Medical System Generated by the COVID-19 Pandemic in the Field of Health Systems’ Digitalization
Authors: Țăran Alexandra-Mădălina , Mustea Lavinia , Vătavu Sorana , Lobonț Oana-Ramona , Luca Magda-Mihaela
Published: April 2022

The COVID-19 pandemic and the digitalization of medical services present significant challenges for the medical sector of the European Union, with profound implications for health systems and the provision of high-performance public health services. The sustainability and resilience of health systems are based on the introduction of information and communication technology in health processes and services, eliminating the vulnerability that can have significant consequences for health, social cohesion, and economic progress. This research aims to assess the impact of digitalization on several dimensions of health, introducing specific implications of the COVID-19 pandemic. The research methodology consists of three procedures: cluster analysis performed through vector quantization, agglomerative clustering, and an analytical approach consisting of data mapping. The main results highlight the importance of effective national responses and provide recommendations, various priorities, and objectives to strengthen health systems at the European level. Finally, the results reveal the need to reduce the gaps between the EU member states and a new approach to policy, governance, investment, health spending, and the performing provision of digital services.
Influence of Matrix Type on Marginal Gap Formation of Deep Class II Bulk-Fill Composite Restorations
Authors: Hahn Britta , Haubitz Imme , Krug Ralf , Krastl Gabriel , Soliman Sebastian
Published: April 2022

Background: To test the hypothesis that transparent matrices result in more continuous margins of bulk-fill composite (BFC) restorations than metal matrices. Methods: Forty standardized MOD cavities in human molars with cervical margins in enamel and dentin were created and randomly assigned to four restorative treatment protocols: conventional nanohybrid composite (NANO) restoration (Tetric EvoCeram, Ivoclar Vivadent, Schaan, Liechtenstein) with a metal matrix (NANO-METAL) versus transparent matrix (NANO-TRANS), and bulk-fill composite restoration (Tetric EvoCeram Bulk Fill, Ivoclar Vivadent, Schaan, Liechtenstein) with a metal matrix (BFC-METAL) versus transparent matrix (BFC-TRANS). After artificial aging (2500 thermal cycles), marginal quality was evaluated by scanning electron microscopy using the replica technique. Statistical analyses were performed using the Mann–Whitney U-test and Wilcoxon test. The level of significance was p < 0.05. Results: Metal matrices yielded significantly (p = 0.0011) more continuous margins (46.211%) than transparent matrices (27.073%). Differences in continuous margins between NANO (34.482%) and BFC (38.802%) were not significant (p = 0.56). Matrix type did not influence marginal gap formation in BFC (p = 0.27) but did in NANO restorations (p = 0.001). Conclusion: Metal matrices positively influence the marginal quality of class II composite restorations, especially in deep cavity areas. The bulk-fill composite seems to be less sensitive to the influence of factors such as light polymerization and matrix type.
Associations of Dietary Intake with Urinary Melamine and Derivative Concentrations among Children in the GAPPS Cohort
Authors: Melough Melissa M. , Day Drew B. , Fretts Amanda M. , Wang Sarah , Flynn Joseph T. , de Boer Ian H. , Zhu Hongkai , Kannan Kurunthachalam , Sathyanarayana Sheela
Published: April 2022

Melamine is a nephrotoxic industrial chemical. Diet is one source of melamine exposure, yet little work has examined the main dietary contributors, particularly among children. We evaluated associations of diet with urinary melamine and derivative concentrations among 123 children aged 4–6 years in the Global Alliance to Prevent Prematurity and Stillbirth cohort. Children’s diets on the day preceding urine collection were assessed using 24-h dietary recalls. Associations of meat, fruit, and grain intakes with melamine exposure were examined using multiple linear regression. Remaining food groups were examined in secondary analyses. Mean (SD) melamine, ammelide, and cyanuric acid concentrations were 6.1 (12.4), 1.9 (2.1), and 60.6 (221.2) ng/mL, respectively. The second tertile of red meat consumers had 98% (95% CI: 15%, 241%) greater melamine exposure than non-consumers, yet the highest consumers did not have increased exposure. Greater consumption of certain fruits was associated with lower urinary ammelide. The top yogurt consumers had 112% (95% CI: 29%, 247%) greater melamine exposure than non-consumers. Consumption of starchy vegetables excluding potatoes was associated with 139% (95% CI: 6%, 437%) greater urinary ammelide. These observed associations should be confirmed in future studies using larger samples and increased monitoring of non-dietary routes of exposure.
A Method for the Analysis of Glyphosate, Aminomethylphosphonic Acid, and Glufosinate in Human Urine Using Liquid Chromatography-Tandem Mass Spectrometry
Authors: Li Zhong-Min , Kannan Kurunthachalam
Published: April 2022

The extensive use of herbicides, such as glyphosate and glufosinate, in crop production during recent decades has raised concerns about human exposure. Nevertheless, analysis of trace levels of these herbicides in human biospecimens has been challenging. Here, we describe a method for the determination of urinary glyphosate, its degradation product aminomethylphosphonic acid (AMPA), and glufosinate using liquid chromatography-tandem mass spectrometry (LC–MS/MS). The method was optimized using isotopically labelled internal standards (13C2, 15N-glyphosate, 13C, 15N, D2-AMPA, and D3-glufosinate) and solid-phase extraction (SPE) with cation-exchange and anion-exchange cartridges. The method provides excellent chromatographic retention, resolution and peak shape of target analytes without the need for strong acidic mobile phases and derivatization steps. The instrument linearity was in the range of 0.1–100 ng/mL, with R > 0.99 in the matrix for all analytes. The method detection limits (MDLs) and the method quantification limits (MQLs) were in the ranges of 0.12 (AMPA and glufosinate)–0.14 (glyphosate) ng/mL and 0.40 (AMPA)–0.48 (glyphosate) ng/mL, respectively. The recoveries of analytes spiked into urine matrix ranged from 79.1% to 119%, with coefficients of variation (CVs) of 4–10%. Repeated analysis of samples for over 2 weeks showed intra-day and inter-day analytical variations of 3.13–10.8% and 5.93–12.9%, respectively. The matrix effects for glyphosate, AMPA, and glufosinate spiked into urine matrix averaged −14.4%, 13.2%, and 22.2%, respectively. The method was further validated through the analysis of external quality assurance proficiency test (PT) urine samples. The method offers optimal sensitivity, accuracy, and precision for the urine-based assessment of human exposure to glyphosate, AMPA, and glufosinate.
Determination of Key Technical Parameters in the Study of New Pressure Sealing Technology for Coal Seam Gas Extraction
Authors: Sun Zhongguang , Li Xuelong , Wang Kequan , Wang Fakai , Chen Deyou , Li Zhen
Published: April 2022

Coal is affected by the concentrated stress disturbance of mining, the disturbance of drilling hole formation, and the concentrated stress of coal shrinkage and splitting of gas desorption from the hole wall; these result in a large number of secondary cracks that collect and leak gas. As a result, it is difficult for the coal seam sealing process to meet engineering quality sealing requirements, which results in problems such as low gas concentration during the extraction process. In this paper, based on the analysis of coal pore and fissure characteristics, and in view of the current situation of gas drainage and sealing in this coal seam, combined with the existing grouting and sealing technology, it is proposed to use pressure grouting and sealing to realize the sealing of deep coal bodies in the hole wall. According to the field conditions, the experimental pressure sealing parameter index is as follows: theoretical sealing length L1 = 9.69 m, the sealing length L2 = 13.98 m is verified, and the final sealing length is determined to be 15 m; the sealing radius is determined to be 0.6 m; the cement slurry was prepared on site with a water: cement ratio of 2:1; PG = 0.43 MPa was calculated; the range of the slurry diffusion radius R was 93.4–176.6 cm; the grouting pressure was determined to be 0.516 MPa. Field application practice has proved that: (1) Under the same drilling parameters and sealing parameters, the gas drainage effect of drilling with pressure sealing is 2.3 times higher than that without pressure sealing; (2) Using traditional sealing technology for drilling holes, the gas extraction concentration is far lower than the sealing operation effect of using the pressure sealing process; (3) Reasonably extending the length of the gas extraction drilling and sealing is a basic guarantee for realizing a substantial increase in the gas extraction concentration; (4) Sealing with pressure leads to a reliable and stable hole process.
Unethical Organization Behavior: Antecedents and Consequences in the Tourism Industry
Authors: Elshaer Ibrahim A. , Azazz Alaa M. S. , Saad Samar K.
Published: April 2022

The entire tourism and hospitality industry has witnessed a considerable increase in the number of ethical difficulties that occur in the workplace. It has been discovered that unethical organizational behavior (UOB) is the most significant category in tourists’ unpleasant experiences, driving them to switch and spread unfavorable word-of-mouth information. This study aims to explore the effects of three contextual factors on UOB (i.e., work intensification, job insecurity, and an unethical company-profit climate) and to investigate its possible employee-related consequences, including the feeling of guilt, emotional exhaustion, and customer-oriented citizenship behavior. A total of 970 employees working in hotels (5-star and 4-star) and travel agencies (Category A) participated, and the obtained data were analyzed by structural equation modeling. The results asserted that work intensification, job insecurity, and an unethical company-profit climate stimulate unethical organizational behavior, and unethical organizational behavior leads to feelings of guilt, emotional exhaustion, and customer-oriented citizenship behavior. Significant insights into theoretical and practical implications were further discussed.
Intimate Partner Violence in the COVID-19 Era: A Health, Psychological, Forensic and Legal Perspective
Authors: Barbara Giussy , Viero Alessia , Pellizzone Irene , Buggio Laura , Facchin Federica , Cattaneo Cristina , D’Amico Maria Elisa , Vercellini Paolo , Kustermann Alessandra
Published: April 2022

This commentary aims to provide a multidisciplinary framework on intimate partner violence (IPV) during the COVID-19 pandemic (with a specific focus on the most predominant form of gender-based violence, i.e., male violence towards women), commenting on the multiple negative consequences of the pandemic on gender violence and providing elements of effective practice. We searched literature for reports/studies on the issue of IPV during the COVID-19 pandemic, focusing on health, psychological, forensic, and legal aspects. The combined effects of lockdowns, isolation at home with abusive partners, quarantine, and economic worries/loss of a job could significantly facilitate violence against women and, at the same time, diminish women’s chances to seek for help, with a strong negative impact on their life. The continued offer of clinical, psychological, forensic, and legal services for survivors of violence, despite the modifications to the provision of these services due to the new needs related to the COVID-19 pandemic, appears of utmost importance. All actions to support survivors of IPV are expected to be multidisciplinary, including the involvement of social and/or legal services and health systems, and woman-centred. Implementing these measures in the COVID-19 era appears challenging but is of primary importance.
Cholera in the Time of MINUSTAH: Experiences of Community Members Affected by Cholera in Haiti
Authors: Bartels Susan A. , Fraulin Georgia , Etienne Stéphanie , Wisner Sandra C. , Lee Sabine
Published: April 2022

In 2010, Haiti experienced one of the deadliest cholera outbreaks of the 21st century. United Nations (UN) peacekeepers are widely believed to have introduced cholera, and the UN has formally apologized to Haitians and accepted responsibility. The current analysis examines how Haitian community members experienced the epidemic and documents their attitudes around accountability. Using SenseMaker, Haitian research assistants collected micronarratives surrounding 10 UN bases in Haiti. Seventy-seven cholera-focused micronarratives were selected for a qualitative thematic analysis. The five following major themes were identified: (1) Cholera cases and deaths; (2) Accessing care and services; (3) Protests and riots against the UN; (4) Compensation; and (5) Anti-colonialism. Findings highlight fear, frustration, anger, and the devastating impact that cholera had on families and communities, which was sometimes compounded by an inability to access life-saving medical care. Most participants believed that the UN should compensate cholera victims through direct financial assistance but there was significant misinformation about the UN’s response. In conclusion, Haiti’s cholera victims and their families deserve transparent communication and appropriate remedies from the UN. To rebuild trust in the UN and foreign aid, adequate remedies must be provided in consultation with victims.
Analysis on Recycling Channel Selection of Construction and Demolition Waste in China from the Perspective of Supply Chain
Authors: Tan Ruwen , Qing Xiang , Yang Jingsong , Zhang Jing , Li Deng
Published: April 2022

Although construction and demolition waste (C&D waste) recycling has been widely regarded as an effective way to save resources, its selection of recycling channels has received little attention. In order to improve the recycling efficiency of C&D waste and promote the process of C&D waste management, we innovatively propose a dual-channel recycling problem of C&D waste from the perspective of supply-chain operation, aiming to study the impact of the selection of recycling channels and the government’s economic intervention on pricing decisions. Specifically, we build in this paper a three-echelon construction material supply chain including a construction contractor, a professional recycling agency, and a building materials manufacturer, considering two modes: the construction contractor does the recycling job alone (as the direct channel) and the construction contractor entrusts the recycling job to the professional recycling agency (as the indirect channel). We use game theory to analyze the optimal decision strategies of the members with or without governmental intervention and the equilibrium strategies are obtained. At the same time, taking Chongqing city as an example, we apply the model to carry out numerical simulation, and the results reveal that greater recycling costs of C&D waste leads to lower profits for the members. When the market capacity of first-class renewable building materials increases, the recycler’s recycling cost of C&D waste decreases, and the remanufacturing cost of recycled materials processed into first-class renewable building materials decreases, the supply-chain members will choose the indirect channel to perform the recycling job. In the case when government intervention exists, the recycling quantity of C&D waste increases, the price of the final products decreases, and both the total profit of the system and the profit of the supply-chain members increase; there is a positive correlation with the government subsidies. The study provides some insights on managerial significance to C&D waste recycling management.
Understanding SNAP Recipient Characteristics to Guide Equitable Expansion of Nutrition Incentive Programs in Diverse Food Retail Settings
Authors: Vargo Lauren , Ciesielski Timothy H. , Embaye Milen , Bird Ana , Freedman Darcy A.
Published: April 2022

Structural barriers, such as food costs, reduce access to healthy foods for populations with limited income, including those benefitting from the Supplemental Nutrition Assistance Program (SNAP). Nutrition incentive programs seek to address this barrier. Evaluations of SNAP-based incentive programming often focus on one setting (i.e., either farmers’ markets or grocery stores). We examined use patterns, characteristics, and preferences among 253 SNAP consumers with access to incentive programming at both a farmers’ market and a grocery store located within five miles of their home. Cross-sectional survey data were collected in 2019 in two Ohio cities. Despite geographic access, 45% of those surveyed were not using the incentive program; most non-users (80.5%) were unaware of the program. Program users compared to non-users had higher household incomes (p < 0.001) and knew more people using the program (p < 0.001). Grocery stores were the most common setting of use (59%); 29% used at farmers’ markets; 11% used in both settings. User characteristics varied by store setting based on demographics, program experience, fruit and vegetable purchasing and consumption patterns, and social dynamics related to use. Our findings support comprehensive awareness-raising efforts and tailored implementation of incentive programming that attends to diverse segments of SNAP consumers to promote equity in program reach.
The Transcriptome and Metabolome Reveal the Potential Mechanism of Lodging Resistance in Intergeneric Hybrids between Brassica napus and Capsella bursa-pastoris
Authors: Zhang Libin , Miao Liyun , He Jianjie , Li Huaixin , Li Maoteng
Published: April 2022

Lodging is one of the main reasons for the reduction in seed yield and is the limitation of mechanized harvesting in B. napus. The dissection of the regulatory mechanism of lodging resistance is an important goal in B. napus. In this study, the lodging resistant B. napus line, YG689, derived from the hybridization between B. napus cv. Zhongyou 821 (ZY821) and Capsella bursa-pastoris, was used to dissect the regulation mechanism of hard stem formation by integrating anatomical structure, transcriptome and metabolome analyses. It was shown that the lignocellulose content of YG689 is higher than that of ZY821, and some differentially expressed genes (DEGs) involved in the lignocellulose synthesis pathway were revealed by transcriptome analyses. Meanwhile, GC–TOF–MS and UPLC–QTOF–MS identified 40, 54, and 31 differential metabolites in the bolting stage, first flower stage, and the final flower stage. The differential accumulation of these metabolites might be associated with the lignocellulose biosynthesis in B. napus. Finally, some important genes that regulate the metabolic pathway of lignocellulose biosynthesis, such as BnaA02g18920D, BnaA10g15590D, BnaC05g48040D, and NewGene_216 were identified in B. napus through the combination of transcriptomics and metabolomics data. The present results explored the potential regulatory mechanism of lignocellulose biosynthesis, which provided a new clue for the breeding of B. napus with lodging resistance in the future.
Free Fatty Acid Receptor 4 (FFA4) Activation Ameliorates Imiquimod-Induced Psoriasis in Mice
Authors: Son So-Eun , Koh Jung-Min , Im Dong-Soon
Published: April 2022

Dietary supplementation with n-3 polyunsaturated fatty acids (n-3 PUFA) has been used as an adjunct therapy for psoriasis due to its anti-inflammatory properties. Free fatty acid receptor 4 (FFA4 or GPR120) is a receptor-sensing n-3 PUFA. In the present study, we examined whether FFA4 acted as a therapeutic target for n-3 PUFA in psoriasis therapy. Experimentally, psoriasis-like skin lesions were induced by treatment with imiquimod for 6 consecutive days. A selective FFA4 agonist, Compound A (30 mg/kg), was used in FFA4 WT and FFA4 KO mice. Imiquimod-induced psoriasis-like skin lesions, which present as erythematous papules and plaques with silver scaling, as well as markedly elevated IL-17/IL-23 cytokine levels in skin tissues, were significantly suppressed by Compound A in FFA4 WT mice, but not in FFA4 KO mice. Enlarged lymph nodes and spleens, as well as imiquimod-induced, elevated IL-17/IL-23 cytokine levels, were also strongly suppressed by Compound A in FFA4 WT mice, but not in FFA4 KO mice. Imiquimod-induced increases in the CD4+IL-17A+ T cell population in lymph nodes and spleens were suppressed by Compound A treatment in FFA4 WT mice; however, this was not seen in FFA4 KO mice. Furthermore, compound A suppressed the differentiation of CD4+ naïve T cells from splenocytes into TH17 cells in an FFA4-dependent manner. In conclusion, we demonstrated that the activation of FFA4 ameliorates imiquimod-induced psoriasis, and the suppression of the differentiation of TH17 cells may partly contribute to its efficacy. Therefore, we suggest that FFA4 could be a therapeutic target for psoriasis therapy.
Therapeutic Potential of Exosomes Derived from Adipose Tissue-Sourced Mesenchymal Stem Cells in the Treatment of Neural and Retinal Diseases
Authors: Harrell Carl Randall , Volarevic Vladislav , Djonov Valentin , Volarevic Ana
Published: April 2022

Therapeutic agents that are able to prevent or attenuate inflammation and ischemia-induced injury of neural and retinal cells could be used for the treatment of neural and retinal diseases. Exosomes derived from adipose tissue-sourced mesenchymal stem cells (AT-MSC-Exos) are extracellular vesicles that contain neurotrophins, immunoregulatory and angio-modulatory factors secreted by their parental cells. AT-MSC-Exos are enriched with bioactive molecules (microRNAs (miRNAs), enzymes, cytokines, chemokines, immunoregulatory, trophic, and growth factors), that alleviate inflammation and promote the survival of injured cells in neural and retinal tissues. Due to the nano-sized dimension and bilayer lipid envelope, AT-MSC-Exos easily bypass blood–brain and blood–retinal barriers and deliver their cargo directly into the target cells. Accordingly, a large number of experimental studies demonstrated the beneficial effects of AT-MSC-Exos in the treatment of neural and retinal diseases. By delivering neurotrophins, AT-MSC-Exos prevent apoptosis of injured neurons and retinal cells and promote neuritogenesis. AT-MSC-Exos alleviate inflammation in the injured brain, spinal cord, and retinas by delivering immunoregulatory factors in immune cells, suppressing their inflammatory properties. AT-MSC-Exos may act as biological mediators that deliver pro-angiogenic miRNAs in endothelial cells, enabling re-vascularization of ischemic neural and retinal tissues. Herewith, we summarized current knowledge about molecular mechanisms which were responsible for the beneficial effects of AT-MSC-Exos in the treatment of neural and retinal diseases, emphasizing their therapeutic potential in neurology and ophthalmology.
Structure Elucidation of Fucan Sulfate from Sea Cucumber Holothuria fuscopunctata through a Bottom-Up Strategy and the Antioxidant Activity Analysis
Authors: Gao Li , Xu Chen , Tao Xuelin , Zuo Zhichuang , Ning Zimo , Wang Linghui , Gao Na , Zhao Jinhua
Published: April 2022

Fucan sulfate I (FSI) from the sea cucumber Holothuria fuscopunctata was purified and its structure was clarified based on a bottom-up strategy. The unambiguous structures of a series of oligosaccharides including disaccharides, trisaccharides, and tetrasaccharides, which were released from mild acid hydrolysis of FSI, were identified by one-dimensional (1D)/two-dimensional (2D) nuclear magnetic resonance (NMR) and mass spectrometry (MS) analysis. All the glycosidic bonds in these oligosaccharides were presented as α1,3 linkages confirmed by correlated signals from their 1H-1H ROESY and 1H-13C HMBC spectra. The structural sequence of these oligosaccharides formed by Fuc2S4S, Fuc2S, and non-sulfated ones (Fuc0S), along with the general structural information of FSI, indicated that the structure of FSI could be elucidated as: [-L-Fuc2S4S-α1,3-L-Fuc(2S)-α1,3-L-Fuc2S-α1,3-L-Fuc0S-α1,3-1-]n. Moreover, the L-Fuc0S-α1,3-L-Fuc2S4S linkage in FSI was susceptible to be cleaved by mild acid hydrolysis. The antioxidant activity assays in vitro showed that FSI and the depolymerized product (dFSI′) had potent activities for superoxide radical scavenging activity with IC50 of 65.71 and 83.72 μg/mL, respectively, while there was no scavenging effect on DPPH, hydroxyl and ABTS radicals.
Overexpression of Neuregulin-1 Type III Has Impact on Visual Function in Mice
Authors: Su Nan , Zhang Weiqi , Eter Nicole , Heiduschka Peter , Zhang Mingyue
Published: April 2022

Schizophrenia is associated with several brain deficits, including abnormalities in visual processes. Neuregulin-1 (Nrg1) is a family of trophic factors containing an epidermal growth factor (EGF)-like domain. It is thought to play a role in neural development and has been linked to neuropsychiatric disorders. Abnormal Nrg1 expression has been observed in schizophrenia in clinical studies. Moreover, in schizophrenia, there is more and more evidence found about pathological changes of the retina regarding structural, neurochemical and physiological parameters. However, mechanisms of these changes are not well known. To investigate this, we analysed the function of the visual system using electroretinography (ERG) and the measurement of visual evoked potentials (VEP) in transgenic mice overexpressing Nrg1 type III of three different ages (12 weeks, 24 weeks and 55 weeks). ERG amplitudes tended to be higher in transgenic mice than in control mice in 12-week old mice, whereas the amplitudes were almost similar in older mice. VEP amplitudes were larger in transgenic mice at all ages, with significant differences at 12 and 55 weeks (p values between 0.003 and 0.036). Latencies in ERG and VEP measurements did not differ considerably between control mice and transgenic mice at any age. Our data show for the first time that overexpression of Nrg1 type III changed visual function in transgenic mice. Overall, this investigation of visual function in transgenic mice may be helpful to understand corresponding changes that occur in schizophrenia, as they may find use as biomarkers for psychiatric disorders as well as a potential tool for diagnosis in psychiatry.
Epigenetic Deregulation of Protein Tyrosine Kinase 6 Promotes Carcinogenesis of Oral Squamous Cell Carcinoma
Authors: Hsieh Yi-Ping , Chen Ken-Chung , Chen Meng-Yen , Huang Ling-Yu , Su An-Yu , Chiang Wei-Fan , Huang Wen-Tsung , Huang Tze-Ta
Published: April 2022

Oral squamous cell carcinoma (OSCC) accounts for over 90% of oral cancers and causes considerable morbidity and mortality. Epigenetic deregulation is a common mechanism underlying carcinogenesis. DNA methylation deregulation is the epigenetic change observed during the transformation of normal cells to precancerous and eventually cancer cells. This study investigated the DNA methylation patterns of PTK6 during the development of OSCC. Bisulfite genomic DNA sequencing was performed to determine the PTK6 methylation level. OSCC animal models were established to examine changes in PTK6 expression in the different stages of OSCC development. The DNA methylation of PTK6 was decreased during the development of OSCC. The mRNA and protein expression of PTK6 was increased in OSCC cell lines compared with human normal oral keratinocytes. In mice, the methylation level of PTK6 decreased after treatment with 4-nitroquinoline 1-oxide and arecoline, and the mRNA and protein expression of PTK6 was increased. PTK6 hypomethylation can be a diagnostic marker of OSCC. Upregulation of PTK6 promoted the proliferation, migration, and invasion of OSCC cells. PTK6 promoted carcinogenesis and metastasis by increasing STAT3 phosphorylation and ZEB1 expression. The epigenetic deregulation of PTK6 can serve as a biomarker for the early detection of OSCC and as a treatment target.
Pathophysiological Features of Nigral Dopaminergic Neurons in Animal Models of Parkinson’s Disease
Authors: Guatteo Ezia , Berretta Nicola , Monda Vincenzo , Ledonne Ada , Mercuri Nicola Biagio
Published: April 2022

The degeneration of nigral dopaminergic neurons is considered the hallmark of Parkinson’s disease (PD), and it is triggered by different factors, including mitochondrial dysfunction, Lewy body accumulation, neuroinflammation, excitotoxicity and metal accumulation. Despite the extensive literature devoted to unravelling the signalling pathways involved in neuronal degeneration, little is known about the functional impairments occurring in these cells during illness progression. Of course, it is not possible to obtain direct information on the properties of the dopaminergic cells in patients. However, several data are available in the literature reporting changes in the function of these cells in PD animal models. In the present manuscript, we focus on dopaminergic neuron functional properties and summarize shared or peculiar features of neuronal dysfunction in different PD animal models at different stages of the disease in an attempt to design a picture of the functional modifications occurring in nigral dopaminergic neurons during disease progression preceding their eventual death.
High SOX9 Maintains Glioma Stem Cell Activity through a Regulatory Loop Involving STAT3 and PML
Authors: Aldaz Paula , Martín-Martín Natalia , Saenz-Antoñanzas Ander , Carrasco-Garcia Estefania , Álvarez-Satta María , Elúa-Pinin Alejandro , Pollard Steven M. , Lawrie Charles H. , Moreno-Valladares Manuel , Samprón Nicolás , Hench Jürgen , Lovell-Badge Robin , Carracedo Arkaitz , Matheu Ander
Published: April 2022

Glioma stem cells (GSCs) are critical targets for glioma therapy. SOX9 is a transcription factor with critical roles during neurodevelopment, particularly within neural stem cells. Previous studies showed that high levels of SOX9 are associated with poor glioma patient survival. SOX9 knockdown impairs GSCs proliferation, confirming its potential as a target for glioma therapy. In this study, we characterized the function of SOX9 directly in patient-derived glioma stem cells. Notably, transcriptome analysis of GSCs with SOX9 knockdown revealed STAT3 and PML as downstream targets. Functional studies demonstrated that SOX9, STAT3, and PML form a regulatory loop that is key for GSC activity and self-renewal. Analysis of glioma clinical biopsies confirmed a positive correlation between SOX9/STAT3/PML and poor patient survival among the cases with the highest SOX9 expression levels. Importantly, direct STAT3 or PML inhibitors reduced the expression of SOX9, STAT3, and PML proteins, which significantly reduced GSCs tumorigenicity. In summary, our study reveals a novel role for SOX9 upstream of STAT3, as a GSC pathway regulator, and presents pharmacological inhibitors of the signaling cascade.
Comparative Genomic Analysis of Vibrio cincinnatiensis Provides Insights into Genetic Diversity, Evolutionary Dynamics, and Pathogenic Traits of the Species
Authors: Du Yuhui , Jin Yuan , Li Beiping , Yue Junjie , Yin Zhiqiu
Published: April 2022

Vibrio cincinnatiensis is a poorly understood pathogenic Vibrio species, and the underlying mechanisms of its genetic diversity, genomic plasticity, evolutionary dynamics, and pathogenicity have not yet been comprehensively investigated. Here, a comparative genomic analysis of V. cincinnatiensis was constructed. The open pan-genome with a flexible gene repertoire exhibited genetic diversity. The genomic plasticity and stability were characterized by the determinations of diverse mobile genetic elements (MGEs) and barriers to horizontal gene transfer (HGT), respectively. Evolutionary divergences were exhibited by the difference in functional enrichment and selective pressure between the different components of the pan-genome. The evolution on the Chr I and Chr II core genomes was mainly driven by purifying selection. Predicted essential genes in V. cincinnatiensis were mainly found in the core gene families on Chr I and were subject to stronger evolutionary constraints. We identified diverse virulence-related elements, including the gene clusters involved in encoding flagella, secretion systems, several pili, and scattered virulence genes. Our results indicated the pathogenic potential of V. cincinnatiensis and highlighted that HGT events from other Vibrio species promoted pathogenicity. This pan-genome study provides comprehensive insights into this poorly understood species from the genomic perspective.
Organophosphorus Pesticides as Modulating Substances of Inflammation through the Cholinergic Pathway
Authors: Camacho-Pérez Milton Rafael , Covantes-Rosales Carlos Eduardo , Toledo-Ibarra Gladys Alejandra , Mercado-Salgado Ulises , Ponce-Regalado María Dolores , Díaz-Resendiz Karina Janice Guadalupe , Girón-Pérez Manuel Iván
Published: April 2022

Organophosphorus pesticides (OPs) are widespread insecticides used for pest control in agricultural activities and the control of the vectors of human and animal diseases. However, OPs’ neurotoxic mechanism involves cholinergic components, which, beyond being involved in the transmission of neuronal signals, also influence the activity of cytokines and other pro-inflammatory molecules; thus, acute and chronic exposure to OPs may be related to the development of chronic degenerative pathologies and other inflammatory diseases. The present article reviews and discusses the experimental evidence linking inflammatory process with OP-induced cholinergic dysregulation, emphasizing the molecular mechanisms related to the role of cytokines and cellular alterations in humans and other animal models, and possible therapeutic targets to inhibit inflammation.
Pravastatin Administration Alleviates Kanamycin-Induced Cochlear Injury and Hearing Loss
Authors: Lee Chang Ho , Jeon Jiwon , Lee So Min , Kim So Young
Published: April 2022

The effect of statins on aminoglycoside-induced ototoxicity is controversial. This study aimed to explore the role of pravastatin (PV) in kanamycin-induced hearing loss in rats. Adult rats were intraperitoneally treated with 20 mg/kg/day of kanamycin (KM) for 10 days. In the PV- and PV + KM-treated rats, 25 mg/kg/day of PV was intraperitoneally administered for 5 days. The auditory brainstem response (ABR) thresholds were measured before and after drug treatment using a smartEP system at 4, 8, 16, and 32 kHz. Cochlear changes in poly ADP-ribose (PAR) polymerase (PARP), PAR, and caspase 3 were estimated using Western blotting. PV administration did not increase the ABR thresholds. The KM-treated rats showed elevated ABR thresholds at 4, 8, 16, and 32 kHz. The PV + KM-treated rats demonstrated lower ABR thresholds than the KM-treated rats at 4, 8, and 16 kHz. The cochlear outer hair cells and spiral ganglion cells were relatively preserved in the PV + KM-treated rats when compared with that in the KM-treated rats. The cochlear expression levels of PARP, PAR, and caspase 3 were higher in the KM-treated rats. The PV + KM-treated rats showed lower levels of PARP, PAR, and caspase 3 than the KM-treated rats. PV protected cochleae from KM-induced hearing loss in rats. The regulation of autophagy and apoptosis mediated the otoprotective effects of PV.
RNA Microarray-Based Comparison of Innate Immune Phenotypes between Human THP-1 Macrophages Stimulated with Two BCG Strains
Authors: Molina-Olvera Gabriela , Rivas-Ortiz Claudia I. , Schcolnik-Cabrera Alejandro , Castillo-Rodal Antonia I. , López-Vidal Yolanda
Published: April 2022

Currently, the only available vaccine against tuberculosis is Mycobacterium bovis Bacille Calmette-Guérin (BCG). Pulmonary tuberculosis protection provided by the vaccine varies depending on the strain, the patient’s age and the evaluated population. Although the adaptive immune responses induced by different BCG strains have been widely studied, little conclusive data is available regarding innate immune responses, especially in macrophages. Here, we aimed to characterize the innate immune responses of human THP-1-derived macrophages at the transcriptional level following a challenge with either the BCG Mexico (M.BCG) or Phipps (P.BCG) strains. After a brief in vitro characterization of the bacterial strains and the innate immune responses, including nitric oxide production and cytokine profiles, we analyzed the mRNA expression patterns and performed pathway enrichment analysis using RNA microarrays. Our results showed that multiple biological processes were enriched, especially those associated with innate inflammatory and antimicrobial responses, including tumor necrosis factor (TNF)-α, type I interferon (IFN-I) and IFN-γ. However, four DEGs were identified in macrophages infected with M.BCG compared to P. BCG. These findings indicated the proinflammatory stimulation of macrophages induced by both BCG strains, at the cytokine level and in terms of gene expression, suggesting a differential expression pattern of innate immune transcripts depending on the mycobacterial strain.
Efficient and Easy Conversion of Human iPSCs into Functional Induced Microglia-like Cells
Authors: Lanfer Jonas , Kaindl Johanna , Krumm Laura , Gonzalez Acera Miguel , Neurath Markus , Regensburger Martin , Krach Florian , Winner Beate
Published: April 2022

Current protocols converting human induced pluripotent stem cells (iPSCs) into induced microglia-like cells (iMGL) are either dependent on overexpression of transcription factors or require substantial experience in stem-cell technologies. Here, we developed an easy-to-use two-step protocol to convert iPSCs into functional iMGL via: (1) highly efficient differentiation of hematopoietic progenitor cells (HPCs) from iPSCs, and (2) optimized maturation of HPCs to iMGL. A sequential harvesting approach led to an increased HPC yield. The protocol implemented a freezing step, thus allowing HPC biobanking and flexible timing of differentiation into iMGL. Our iMGL responded adequately to the inflammatory stimuli LPS, and iMGL RNAseq analysis matched those of other frequently used protocols. Comparing three different coating modalities, we increased the iMGL yield by culturing on uncoated glass surfaces, thereby retaining differentiation efficiency and functional hallmarks of iMGL. In summary, we provide a high-quality, easy-to-use protocol, rendering generation and functional studies on iMGL an accessible lab resource.
Effect of Quartz Nano-Particles on the Performance Characteristics of Asphalt Mixture
Authors: Haroon Waqas , Ahmad Naveed , Mashaan Nuha
Published: April 2022

Nano-technology has played a vital role in upgrading the durability and sustainability of asphalt pavements during the last decade. Conventional bitumen does not provide adequate performance against permanent deformation in severe weather conditions. Quartz nano-size particles (QNPs) (1, 3, and 5% by weight of the bitumen) were employed in this research to modify the conventional base bitumen PG 58–16. Conventional physical (penetration, softening, ductility, and flash and fire point), rheological, frequency sweep, high-performance grading, and moisture susceptibility tests were performed to investigate the enhancement of the base bitumen performance. Marshall mix design was conducted on each asphalt mixture to determine the optimum bitumen content (OBC) percentage for the preparation of wheel tracker samples to evaluate the effect of QNPs on asphalt mixtures. Laboratory test findings showed that the optimum concentration of QNPs is 5% by weight of base bitumen. The homogeneity and proper stable dispersion of QNPs in the bitumen were validated via scanning electron microscope (SEM), Fourier transform infrared spectroscopy (FTIR), and storage stability tests. At higher temperatures, the QNP-modified asphalt mixtures exhibited higher stiffness, stripping resistance, and rutting potential. It was concluded that QNPs effectively upgrade durability and permanent deformation resistance at high temperatures and, therefore, the sustainability of asphalt roads.