bluuebunny/crossref_metadata_2025 huggingface dataset:
Chemical and Biological Components of Urban Aerosols in Africa: Current Status and Knowledge Gaps
Authors: Kalisa Egide , Archer Stephen , Nagato Edward , Bizuru Elias , Lee Kevin , Tang Ning , Pointing Stephen , Hayakawa Kazuichi , Lacap-Bugler Donnabella
Published: March 2019

Aerosolized particulate matter (PM) is a complex mixture that has been recognized as the greatest cause of premature human mortality in low- and middle-income countries. Its toxicity arises largely from its chemical and biological components. These include polycyclic aromatic hydrocarbons (PAHs) and their nitro-derivatives (NPAHs) as well as microorganisms. In Africa, fossil fuel combustion and biomass burning in urban settings are the major sources of human exposure to PM, yet data on the role of aerosols in disease association in Africa remains scarce. This review is the first to examine studies conducted in Africa on both PAHs/NPAHs and airborne microorganisms associated with PM. These studies demonstrate that PM exposure in Africa exceeds World Health Organization (WHO) safety limits and carcinogenic PAHs/NPAHs and pathogenic microorganisms are the major components of PM aerosols. The health impacts of PAHs/NPAHs and airborne microbial loadings in PM are reviewed. This will be important for future epidemiological evaluations and may contribute to the development of effective management strategies to improve ambient air quality in the African continent.
The Mediterranean Diet: From an Environment-Driven Food Culture to an Emerging Medical Prescription
Authors: Lăcătușu Cristina-Mihaela , Grigorescu Elena-Daniela , Floria Mariana , Onofriescu Alina , Mihai Bogdan-Mircea
Published: March 2019

The Mediterranean diet originates in the food cultures of ancient civilizations which developed around the Mediterranean Basin and is based on the regular consumption of olive oil (as the main source of added fat), plant foods (cereals, fruits, vegetables, legumes, tree nuts, and seeds), the moderate consumption of fish, seafood, and dairy, and low-to-moderate alcohol (mostly red wine) intake, balanced by a comparatively limited use of red meat and other meat products. A few decades ago, the Mediterranean diet drew the attention of medical professionals by proving extended health benefits. The first reports ascertained cardiovascular protection, as multiple large-scale clinical studies, starting with Ancel Keys’ Seven Countries Study, showed a marked reduction of atherosclerotic clinical events in populations with a Mediterranean dietary pattern. Ensuing trials confirmed favorable influences on the risk for metabolic syndrome, obesity, type 2 diabetes mellitus, cancer, and neurodegenerative diseases. While its health benefits are universally recognized today by medical professionals, the present state of the Mediterranean diet is challenged by major difficulties in implementing this protective dietary pattern in other geographical and cultural areas and keeping it alive in traditional Mediterranean territories, also tainted by the unhealthy eating habits brought by worldwide acculturation.
Analysis of the Influence Mechanism of CO2 Emissions and Verification of the Environmental Kuznets Curve in China
Authors: Fang Debin , Hao Peng , Wang Zhengxin , Hao Jian
Published: March 2019

Changes in economic development stage and growth type will lead to variations in the CO2 emissions. Traditional empirical analysis of the variations often only considers the impact of influencing factors on CO2 emissions from a single dimension. Under the background of China’s economy transferring from high-speed growth to high-quality development, this paper comprehensively considers the characteristics of the relevant influencing factors under different development stages and growth rates, and further calculates the panel gray incidence degree between CO2 emissions and these influencing factors in eastern, central, and western China. Based on the different development conditions, corresponding benchmarks of the indicators for the three regions (eastern, western, and central China) are accordingly set, highlighting the unity as well as the uniqueness between different regions. Furthermore, this paper verifies the environmental Kuznets curve (EKC) in the three regions. The result shows that all the factors of per capita Gross Domestic Product (GDP), Energy Intensity, Urbanization Level, and Trade Openness have a high correlation with CO2 emissions in the three regions, in which CO2 emissions are all between the two inflection points of the inverted N-shaped model.
Intimate Partner Violence among Women with Disabilities in Uganda
Authors: Valentine Anne , Akobirshoev Ilhom , Mitra Monika
Published: March 2019

Violence against women with disabilities is pervasive, yet a paucity of research examines intimate partner violence (IPV) experienced by women with disabilities in low- and middle-income countries. The purpose of this study is to document the prevalence and consequences of IPV exposure among Ugandan women with disabilities. Cross sectional data from the 2011 and 2016 Uganda Demographic and Health Surveys (UDHS) were used to study married and/or partnered women aged 15–49 who answered specific questions about lifetime intimate partner violence (N = 8592). Univariate and multivariate logistic regression models were used to investigate the relationship between disability, IPV, and indicators of maternal and child health. Compared to women without disabilities, women with disabilities were more likely to experience lifetime physical violence (odds ratio (OR) 1.4, p < 0.01), sexual violence (OR = 1.7, p < 0.01), and emotional abuse (1.4, p < 0.01) after controlling for sociodemographic and household characteristics. Study findings suggest that women with disabilities in Uganda may experience increased risk for IPV compared to women without disabilities, with concomitant risks to their health and the survival of their infants. Further research examining the prevalence and correlates of IPV in low- and middle-income countries is needed to address the needs and rights of women with disabilities.
Rates of Chronic Medical Conditions in 1991 Gulf War Veterans Compared to the General Population
Authors: Zundel Clara G. , Krengel Maxine H. , Heeren Timothy , Yee Megan K. , Grasso Claudia M. , Janulewicz Lloyd Patricia A. , Coughlin Steven S. , Sullivan Kimberly
Published: March 2019

Prevalence of nine chronic medical conditions in the population-based Ft. Devens Cohort (FDC) of GW veterans were compared with the population-based 2013–2014 National Health and Nutrition Examination Survey (NHANES) cohort. Excess prevalence was calculated as the difference in prevalence estimates from the Ft. Devens and NHANES cohorts; and confidence intervals and p-values are based on the standard errors for the two prevalence estimates. FDC males were at increased risk for reporting seven chronic medical conditions compared with NHANES males. FDC females were at decreased risk for high blood pressure and increased risk for diabetes when compared with NHANES females. FDC veterans reporting war-related chemical weapons exposure showed higher risk of high blood pressure; diabetes; arthritis and chronic bronchitis while those reporting taking anti-nerve gas pills had increased risk of heart attack and diabetes. GW veterans are at higher risk of chronic conditions than the general population and these risks are associated with self-reported toxicant exposures.
Validity of Maternal Recall to Assess Vaccination Coverage: Evidence from Six Districts in Zhejiang Province, China
Authors: Hu Yu , Chen Yaping , Wang Ying , Liang Hui
Published: March 2019

Background: Although recall-based data are collected by survey when the vaccination records are not available, the preferred estimates remain the record-based ones due to the limited validity of recall-based data. However, the evidence on validity of maternal recalls is limited and varied across vaccine types. To close the gaps, we validated the maternal recall on vaccination against record-based data in six districts in Zhejiang Province, China. Methods: We used a cross-sectional survey of about 648 households with mothers who delivered in the last 12 months prior to the survey in October 2017, from six districts in Zhejiang Province. Vaccination status on five vaccine types scheduled before 12 months of age were collected through maternal recall and vaccination records. The level of agreement and recall bias between the two resources, the sensitivity and specificity of maternal recall were evaluated. Risk factors for maternal recall bias were also identified through logistic regression model for each type of vaccine. Results: The level of agreement between recall and record was above 90% across vaccine types, with the recall bias ranged from 2.2% to 9.7%. Recall bias due to over-reporting was slightly higher than that due to under-reporting. Recall bias was positively associated with high parity, home delivery, younger mothers, mothers with low education, and migrant mothers. Conclusions: This study indicated most of the vaccination status across vaccine types was accurately identified through maternal recall and supported the use of maternal recall to estimate the vaccination coverage as an alternative in the absence of record-based data.
Taekwondo Enhances Cognitive Function as a Result of Increased Neurotrophic Growth Factors in Elderly Women
Authors: Cho Su-Youn , Roh Hee-Tae
Published: March 2019

The purpose of this study was to investigate the effects of regular taekwondo (TKD) training on physical fitness, neurotrophic growth factors, cerebral blood flow (CBF) velocity, and cognitive function in elderly women. Thirty-seven women aged 65 or older were randomly assigned to either TKD (n = 19) or control (n = 18) group. TKD training was performed at 50–80% maximum heart rate (HRmax) for 60 min, five times per week for 16 weeks. All participants underwent the following examinations before and after the intervention: Senior Fitness Test; serum levels of neurotrophic growth factors, including brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and insulin-like growth factor-1 (IGF-1); systolic, diastolic, and mean blood flow velocity and pulsatility index of the middle cerebral artery using Doppler ultrasonography; Mini-Mental State Examination for dementia screening (MMSE-DS); and Stroop Color and Word Test (word, color, and color-word). In the TKD group, lower body strength and flexibility, aerobic endurance levels, BDNF, VEGF, and IGF-1 serum levels as well as the color-word test scores were significantly increased after as compared to before the intervention (p < 0.05). No statistically significant differences were found in cerebral blood flow velocities and the MMSE-DS score (p > 0.05). These findings suggest that regular TKD training may be effective in improving not only fitness but also cognitive function in elderly women. The latter effect may be due to increased neurotrophic growth factor levels.
A Systematic Review of Data Collection Techniques Used to Measure Preschool Children’s Knowledge of and Preference for Physical Activity
Authors: Wiseman Nicola , Rossmann Christin , Harris Neil
Published: March 2019

Background: Early childhood has been identified as a crucial period in which children develop physical activity preferences and behaviors. Both the knowledge of and preferences for physical activity are key proximal indicators of activity choices in children. Thus, accurate data collection tools are required to measure these variables. This review evaluates the data collection techniques that have been utilised to assess preschool children’s knowledge of and preference for physical activity, and examines the validity and reliability of existing techniques. Methods: A systematic search for relevant studies published from 1980 through to December 2017 was conducted via ProQuest, CINAHL, Embase, Scopus, ERIC, PubMed, MEDLINE, and ScienceDirect. Results: Fourteen studies were eligible for inclusion in the review. The identified studies employed a limited but disparate range of techniques to assess children’s physical activity knowledge and preferences. Findings reveal that four techniques were consistently used across the reviewed studies, including: interviews, structured play-based activities, questionnaires, and observations. Only four out of 14 included studies reported the assessment of the validity of the data collection tool used, and six reported testing the measures for at least one type of reliability. Conclusion: There is a need for validated and reliable measures to assess children’s knowledge of and preference for physical activity. Greater consideration is required to align data collection techniques with the characteristics, needs and abilities of this study population.
Functional Fitness and Quality of Life among Women over 60 Years of Age Depending on Their Level of Objectively Measured Physical Activity
Authors: Nawrocka Agnieszka , Polechoński Jacek , Garbaciak Wiesław , Mynarski Władysław
Published: March 2019

The aim of this study was to identify the differences in functional fitness and quality of life among women over 60 years of age depending on their level of objectively measured physical activity (PA) according to Global Recommendations on Physical Activity for health. The study used a cross-sectional design with 213 female volunteers over 60 years of age. Physical activity was monitored for 7 days of the week using an Actigraph Gt3X monitor. The Senior Fitness Test battery and hand-grip strength tests were performed to assess functional fitness. Quality of life was self-reported using a short version of the World Health Organization Quality of Life questionnaire WHOQOL-bref. Women who met the PA recommendations achieved slightly better results in most functional tests and in all domains of quality of life. Significant differences were found in the upper body strength, dynamic balance, and social relationships domains of quality of life. Physical activity programs developed on the basis of World Health Organization (WHO) recommendations have the potential to improve functional fitness and quality of life. However, further experimental studies in this area are required.
Fractional Multi-Step Differential Transformed Method for Approximating a Fractional Stochastic SIS Epidemic Model with Imperfect Vaccination
Authors: Abuasad Salah , Yildirim Ahmet , Hashim Ishak , Abdul Karim Samsul Ariffin , Gómez-Aguilar J.F.
Published: March 2019

In this paper, we applied a fractional multi-step differential transformed method, which is a generalization of the multi-step differential transformed method, to find approximate solutions to one of the most important epidemiology and mathematical ecology, fractional stochastic SIS epidemic model with imperfect vaccination, subject to appropriate initial conditions. The fractional derivatives are described in the Caputo sense. Numerical results coupled with graphical representations indicate that the proposed method is robust and precise which can give new interpretations for various types of dynamical systems.
Smoking and Physical Activity Trajectories from Childhood to Midlife
Authors: Salin Kasper , Kankaanpää Anna , Hirvensalo Mirja , Lounassalo Irinja , Yang Xiaolin , Magnussen Costan , Hutri-Kähönen Nina , Rovio Suvi , Viikari Jorma , Raitakari Olli , Tammelin Tuija
Published: March 2019

Introduction: Despite substantial interest in the development of health behaviors, there is limited research that has examined the longitudinal relationship between physical activity (PA) and smoking trajectories from youth to adulthood in a Finnish population. This study aimed to identify trajectories of smoking and PA for males and females, and study the relationship between these trajectories from youth to adulthood. Methods: Latent profile analysis (LPA) was used to identify trajectories of smoking and PA separately for males and females among 3355 Finnish adults (52.1% females). Participants’ smoking and PA were assessed five to eight times over a 31-year period (3–18 years old at the baseline, 34–49 years at last follow-up). Multinomial logistic regression analysis was used to study the relationship between the trajectories of smoking and PA. Results: Five smoking trajectories and four to five PA trajectories were identified for males and females. Of the PA trajectory groups, the persistently active group were least likely to follow the trajectories of regular smoking and the inactive and low active groups were least likely to follow non-smoking trajectory group. Likewise, inactive (women only) and low active groups were less likely to belong to the non-smokers group. Conclusions: The study suggests that those who are persistently active or increasingly active have substantially reduced probabilities of being in the highest-risk smoking categories.
Knowledge, Attitude and Practice about Dengue Fever among Patients Experiencing the 2017 Outbreak in Vietnam
Authors: Nguyen Huong Van , Than Phung Quoc Tat , Nguyen Tu Huu , Vu Giang Thu , Hoang Chi Linh , Tran Tung Thanh , Truong Nu Thi , Nguyen Son Hoang , Do Huyen Phuc , Ha Giang Hai , Nguyen Huong Lan Thi , Dang Anh Kim , Do Cuong Duy , Tran Tung Hoang , Tran Bach Xuan , Latkin Carl A. , Ho Cyrus S. H. , Ho Roger C. M.
Published: March 2019

There is a gap in the literature on the understanding of the general Vietnamese population toward dengue fever (DF). This study aimed to explore knowledge, attitudes, practice (KAP) of dengue fever among Vietnamese participants and the potential associated factors. A cross-sectional study was conducted among 330 patients at the Bach Mai Hospital in Northern Vietnam. A Tobit regression model was utilized to investigate the associated factors. The average knowledge score was 4.6/19. Respondents perceived their risk of DF infection to be very low (39.5%) to low (20.7%) and had a neutral attitude about the necessity of hospitalization when being infected with DF (60.9%). A total of 17.6%, 9.8% and 6.6% of respondents reported frequently changing water, properly disposing of waste and covering water storage containers to eliminate larvae. Gender, education level, duration of illness and travel history were correlated with knowledge. Occupation, the presence of DF in the neighborhood, mosquito density at home and DF symptom severity were associated with attitudes. Occupation, mosquito density at home, type of patient, knowledge and attitudes were associated with practices. To enhance the KAP towards DF, further efforts should first be directed to improve knowledge through education, especially at the school level and people in less developed areas.
On the Use of Hair Analysis for Assessing Arsenic Intoxication
Authors: Katz Sidney A.
Published: March 2019

Correlations between the concentrations of arsenic in scalp hair and in drinking water as well as in blood and/or urine have been reported. These correlations clearly show exposure–absorption–excretion relationships. In addition, arsenic metabolites such as monomethylarsonic acid and dimethylarsinic acid have been identified and quantified in these tissues and fluids, leaving little doubt that elevated levels of arsenic in the hair can reflect systemic arsenic intoxication. Consequently, hair analysis has potential merit as a screening procedure for poisoning by arsenic. However, questions regarding the exogenous versus the endogenous deposition of arsenic in the hair, and uncertainties about the normal level of arsenic in the hair remain unresolved. Pending their resolution, the determination of arsenic in hair should remain a screening tool, and clinical signs and symptoms should be employed to complete the diagnosis of arsenic poisoning.
Identification of Candidate Ergosterol-Responsive Proteins Associated with the Plasma Membrane of Arabidopsis thaliana
Authors: Khoza Thembisile G. , Dubery Ian A. , Piater Lizelle A.
Published: March 2019

The impact of fungal diseases on crop production negatively reflects on sustainable food production and overall economic health. Ergosterol is the major sterol component in fungal membranes and regarded as a general elicitor or microbe-associated molecular pattern (MAMP) molecule. Although plant responses to ergosterol have been reported, the perception mechanism is still unknown. Here, Arabidopsis thaliana protein fractions were used to identify those differentially regulated following ergosterol treatment; additionally, they were subjected to affinity-based chromatography enrichment strategies to capture and categorize ergosterol-interacting candidate proteins using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Mature plants were treated with 250 nM ergosterol over a 24 h period, and plasma membrane-associated fractions were isolated. In addition, ergosterol was immobilized on two different affinity-based systems to capture interacting proteins/complexes. This resulted in the identification of defense-related proteins such as chitin elicitor receptor kinase (CERK), non-race specific disease resistance/harpin-induced (NDR1/HIN1)-like protein, Ras-related proteins, aquaporins, remorin protein, leucine-rich repeat (LRR)- receptor like kinases (RLKs), G-type lectin S-receptor-like serine/threonine-protein kinase (GsSRK), and glycosylphosphatidylinositol (GPI)-anchored protein. Furthermore, the results elucidated unknown signaling responses to this MAMP, including endocytosis, and other similarities to those previously reported for bacterial flagellin, lipopolysaccharides, and fungal chitin.
Toxins Utilize the Endoplasmic Reticulum-Associated Protein Degradation Pathway in Their Intoxication Process
Authors: Nowakowska-Gołacka Jowita , Sominka Hanna , Sowa-Rogozińska Natalia , Słomińska-Wojewódzka Monika
Published: March 2019

Several bacterial and plant AB-toxins are delivered by retrograde vesicular transport to the endoplasmic reticulum (ER), where the enzymatically active A subunit is disassembled from the holotoxin and transported to the cytosol. In this process, toxins subvert the ER-associated degradation (ERAD) pathway. ERAD is an important part of cellular regulatory mechanism that targets misfolded proteins to the ER channels, prior to their retrotranslocation to the cytosol, ubiquitination and subsequent degradation by a protein-degrading complex, the proteasome. In this article, we present an overview of current understanding of the ERAD-dependent transport of AB-toxins to the cytosol. We describe important components of ERAD and discuss their significance for toxin transport. Toxin recognition and disassembly in the ER, transport through ER translocons and finally cytosolic events that instead of overall proteasomal degradation provide proper folding and cytotoxic activity of AB-toxins are discussed as well. We also comment on recent reports presenting medical applications for toxin transport through the ER channels.
Abscisic Acid Regulates the 3-Hydroxy-3-methylglutaryl CoA Reductase Gene Promoter and Ginsenoside Production in Panax quinquefolium Hairy Root Cultures
Authors: Kochan Ewa , Balcerczak Ewa , Szymczyk Piotr , Sienkiewicz Monika , Zielińska-Bliźniewska Hanna , Szymańska Grażyna
Published: March 2019

Panax quinquefolium hairy root cultures synthesize triterpenoid saponins named ginsenosides, that have multidirectional pharmacological activity. The first rate-limiting enzyme in the process of their biosynthesis is 3-hydroxy-3-methylglutaryl CoA reductase (HMGR). In this study, a 741 bp fragment of the P. quinquefolium HMGR gene (PqHMGR), consisting of a proximal promoter, 5′UTR (5′ untranslated region) and 5′CDS (coding DNA sequence) was isolated. In silico analysis of an isolated fragment indicated a lack of tandem repeats, miRNA binding sites, and CpG/CpNpG elements. However, the proximal promoter contained potential cis-elements involved in the response to light, salicylic, and abscisic acid (ABA) that was represented by the motif ABRE (TACGTG). The functional significance of ABA on P. quinquefolium HMGR gene expression was evaluated, carrying out quantitative RT-PCR experiments at different ABA concentrations (0.1, 0.25, 0.5, and 1 mg·L−1). Additionally, the effect of abscisic acid and its time exposure on biomass and ginsenoside level in Panax quinquefolium hairy root was examined. The saponin content was determined using HPLC. The 28 day elicitation period with 1 mg·L−1 ABA was the most efficient for Rg2 and Re (17.38 and 1.83 times increase, respectively) accumulation; however, the protopanaxadiol derivative content decreased in these conditions.
Impact of Air Exposure Time on the Water Contact Angles of Daily Disposable Silicone Hydrogels
Authors: Eftimov Petar , Yokoi Norihiko , Peev Nikola , Georgiev Georgi As.
Published: March 2019

The wettability of silicone hydrogel (SiHy) contact lens (CLs) is crucial for the pre-lens tear film stability throughout the day. Therefore, sessile drop and captive bubble setups were used to study the advancing and receding water contact angles (CA) of four SiHy materials: narafilcon A (TE), senofilcon A (AOD), stenfilcon A (MD), and delefilcon A (DT). TE and AOD have 48% and 38% water content, respectively, and no surface coating. MD (54% water) implements “smart chemistry” with just 4.4% bulk silicone content, while DT has >80% water at its surface. These SiHy were subjected to continuous blink-like air exposure (10 s)/rehydration (1s) cycles for 0, 1, 2, 3, 4, 6, 8, 10, 12, 14, and 16 h. The advancing CA, which measures the rehydration propensity of the CL surface, proved to be the most sensitive parameter to discriminate between the samples. The order of performance for the entire time scale was DT > MD >> AOD ≥ TE. The extended desiccation/rehydration cycling increased the differences between the CA of DT and MD compared to AOD and TE. This suggests that the low Si surface content and the high surface hydration are major determinants of SiHy wettability.
Molecular Responses of Maize Shoot to a Plant Derived Smoke Solution
Authors: Aslam Muhammad Mudasar , Rehman Shafiq , Khatoon Amana , Jamil Muhammad , Yamaguchi Hisateru , Hitachi Keisuke , Tsuchida Kunihiro , Li Xinyue , Sunohara Yukari , Matsumoto Hiroshi , Komatsu Setsuko
Published: March 2019

Plant-derived smoke has effects on plant growth. To find the molecular mechanism of plant-derived smoke on maize, a gel-free/label-free proteomic technique was used. The length of root and shoot were increased in maize by plant-derived smoke. Proteomic analysis revealed that 2000 ppm plant-derived smoke changed the abundance of 69 proteins in 4-days old maize shoot. Proteins in cytoplasm, chloroplast, and cell membrane were altered by plant-derived smoke. Catalytic, signaling, and nucleotide binding proteins were changed. Proteins related to sucrose synthase, nucleotides, signaling, and glutathione were significantly increased; however, cell wall, lipids, photosynthetic, and amino acid degradations related proteins were decreased. Based on proteomic and immunoblot analyses, ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) was decreased; however, RuBisCO activase was not changed by plant-derived smoke in maize shoot. Ascorbate peroxidase was not affected; however, peroxiredoxin was decreased by plant-derived smoke. Furthermore, the results from enzyme-activity and mRNA-expression analyses confirmed regulation of ascorbate peroxidase and the peroxiredoxinin reactive oxygen scavenging system. These results suggest that increases in sucrose synthase, nucleotides, signaling, and glutathione related proteins combined with regulation of reactive oxygen species and their scavenging system in response to plant-derived smoke may improve maize growth.
Modulation of Disordered Proteins with a Focus on Neurodegenerative Diseases and Other Pathologies
Authors: Martinelli Anne H. S. , Lopes Fernanda C. , John Elisa B. O. , Carlini Célia R. , Ligabue-Braun Rodrigo
Published: March 2019

Intrinsically disordered proteins (IDPs) do not have rigid 3D structures, showing changes in their folding depending on the environment or ligands. Intrinsically disordered proteins are widely spread in eukaryotic genomes, and these proteins participate in many cell regulatory metabolism processes. Some IDPs, when aberrantly folded, can be the cause of some diseases such as Alzheimer′s, Parkinson′s, and prionic, among others. In these diseases, there are modifications in parts of the protein or in its entirety. A common conformational variation of these IDPs is misfolding and aggregation, forming, for instance, neurotoxic amyloid plaques. In this review, we discuss some IDPs that are involved in neurodegenerative diseases (such as beta amyloid, alpha synuclein, tau, and the “IDP-like” PrP), cancer (p53, c-Myc), and diabetes (amylin), focusing on the structural changes of these IDPs that are linked to such pathologies. We also present the IDP modulation mechanisms that can be explored in new strategies for drug design. Lastly, we show some candidate drugs that can be used in the future for the treatment of diseases caused by misfolded IDPs, considering that cancer therapy has more advanced research in comparison to other diseases, while also discussing recent and future developments in this area of research. Therefore, we aim to provide support to the study of IDPs and their modulation mechanisms as promising approaches to combat such severe diseases.
m6A Reader YTHDF2 Regulates LPS-Induced Inflammatory Response
Authors: Yu Ruiqing , Li Qimeng , Feng Zhihui , Cai Luhui , Xu Qiong
Published: March 2019

N6-methyladenosine (m6A) is an abundant mRNA modification that affects multiple biological processes, including those involved in the cell stress response and viral infection. YTH domain family 2 (YTHDF2) is an m6A-binding protein that affects the localization and stability of targeted mRNA. RNA-binding proteins (RBPs) can regulate the stability of inflammatory gene mRNA transcripts, thus participating in the regulation of inflammatory processes. As an RBP, the role of YTHDF2 in the LPS-induced inflammatory reaction has not been reported. To elucidate the function of YTHDF2 in the inflammatory response of macrophages, we first detected the expression level of YTHDF2 in RAW 264.7 cells, and found that it was upregulated after LPS stimulation. YTHDF2 knockdown significantly increased the LPS-induced IL-6, TNF-α, IL-1β, and IL-12 expression and the phosphorylation of p65, p38, and ERK1/2 in NF-κB and MAPK signaling. Moreover, the upregulated expression of TNF-α and IL-6 in cells with silenced YTHDF2 expression was downregulated by the NF-κB, p38, and ERK inhibitors. YTHDF2 depletion increased the expression and stability of MAP2K4 and MAP4K4 mRNAs. All of these results suggest that YTHDF2 knockdown increases mRNA expression levels of MAP2K4 and MAP4K4 via stabilizing the mRNA transcripts, which activate MAPK and NF-κB signaling pathways, which promote the expression of proinflammatory cytokines and aggravate the inflammatory response in LPS-stimulated RAW 264.7 cells.
QT Assessment in Early Drug Development: The Long and the Short of It
Authors: Lester Robert M. , Paglialunga Sabina , Johnson Ian A.
Published: March 2019

The QT interval occupies a pivotal role in drug development as a surface biomarker of ventricular repolarization. The electrophysiologic substrate for QT prolongation coupled with reports of non-cardiac drugs producing lethal arrhythmias captured worldwide attention from government regulators eventuating in a series of guidance documents that require virtually all new chemical compounds to undergo rigorous preclinical and clinical testing to profile their QT liability. While prolongation or shortening of the QT interval may herald the appearance of serious cardiac arrhythmias, the positive predictive value of an abnormal QT measurement for these arrhythmias is modest, especially in the absence of confounding clinical features or a congenital predisposition that increases the risk of syncope and sudden death. Consequently, there has been a paradigm shift to assess a compound’s cardiac risk of arrhythmias centered on a mechanistic approach to arrhythmogenesis rather than focusing solely on the QT interval. This entails both robust preclinical and clinical assays along with the emergence of concentration QT modeling as a primary analysis tool to determine whether delayed ventricular repolarization is present. The purpose of this review is to provide a comprehensive understanding of the QT interval and highlight its central role in early drug development.
Anti-Müllerian Hormone Expression in Endometrial Cancer Tissue
Authors: Gowkielewicz Marek , Lipka Aleksandra , Piotrowska Aleksandra , Szadurska-Noga Marta , Nowakowski Jacek J. , Dzięgiel Piotr , Majewski Mariusz Krzysztof , Jozwik Marcin , Majewska Marta
Published: March 2019

Anti-Müllerian hormone (AMH) is a commonly known factor secreted by Sertoli cells, responsible for regression of the Müllerian ducts in male fetuses. AMH has also other functions in humans. In vivo and in vitro studies have shown that AMH inhibits cell cycle and induces apoptosis in cancers with AMH receptors. The aim of the study was to assess whether the tissue of pre-cancerous states of endometrium (PCS) and various histopathologic types of endometrial cancer (EC) exhibit the presence of AMH. We aimed to investigate whether the potential presence of the protein concerns menopausal women or those regularly menstruating, and whether is related to cancers with a good or a bad prognosis, as well as what other factors may influence AMH expression. The undertaken analysis was carried out on tissues retrieved from 232 women who underwent surgical treatment for PCS and EC. Tissues were prepared for immunohistochemical assessment with the use of a tissue microarrays method. AMH expression was confirmed in 23 patients with well differentiated endometrioid adenocarcinoma (G1), moderately differentiated endometrioid adenocarcinoma (G2), clear cell carcinoma (CCA) and nonatypical hyperplasia. AMH was not found in EC tissues in regularly menstruating women. An appropriately long mean period of breastfeeding in line with a prolonged period of hormonal activity had a positive effect on AMH expression. Our results may suggest that AMH is a factor which protects the organism against cancer, and should be further investigated as a potential prognosis marker and a therapeutic agent.
Sulfonate-Functionalized Mesoporous Silica Nanoparticles as Carriers for Controlled Herbicide Diquat Dibromide Release through Electrostatic Interaction
Authors: Shan Yongpan , Cao Lidong , Xu Chunli , Zhao Pengyue , Cao Chong , Li Fengmin , Xu Bo , Huang Qiliang
Published: March 2019

Environmental stimuli-responsive pesticide release is desirable for enhanced efficiency and reduced side effects. In most cases, the loading and release of pesticides mainly depends on hydrophobic interactions and hydrogen bonding. Electrostatic interaction is less investigated as a weapon for achieving high loading content and controlled pesticide release. In this work, negative-charge decorated mesoporous silica nanoparticles (MSNs) were facilely fabricated by introducing sulfonate groups onto MSNs through a post-grafting method. Sulfonate-functionalized MSNs (MSN-SO3) were synthesized by conversion of epoxy group into sulfonate group using a bisulfite ion as a ring opening reagent. Diquat dibromide (DQ), one of the globally used quaternary ammonium herbicides, was efficiently loaded into these negatively charged MSN-SO3 nanoparticles. The loading content was increased to 12.73% compared to those using bare MSNs as carriers (5.31%). The release of DQ from DQ@MSN-SO3 nanoparticles was pH and ionic strength responsive, which was chiefly governed by the electrostatic interactions. Moreover, DQ@MSN-SO3 nanoparticles exhibited good herbicidal activity for the control of Datura stramonium L., and the bioactivity was affected by the ionic strength of the release medium. The strategy of cargo loading and release dependent on the electrostatic interactions could be generally used for charge-carrying pesticides using carriers possessing opposite charges to mitigate the potential negative impacts on the environment.
ROCK2 Regulates Monocyte Migration and Cell to Cell Adhesion in Vascular Endothelial Cells
Authors: Takeda Yusuke , Matoba Keiichiro , Kawanami Daiji , Nagai Yosuke , Akamine Tomoyo , Ishizawa Sho , Kanazawa Yasushi , Yokota Tamotsu , Utsunomiya Kazunori
Published: March 2019

The small GTPase Rho and its downstream effector, Rho-kinase (ROCK), regulate various cellular functions, including organization of the actin cytoskeleton, cell adhesion and migration. A pro-inflammatory lipid mediator, lysophosphatidic acid (LPA), is a potent activator of the Rho/ROCK signalling pathway and has been shown to induce the expression of chemokines and cell adhesion molecules (CAMs). In the present study, we aimed to elucidate the precise mechanism by which ROCK regulates LPA-induced expressions and functions of chemokines and CAMs. We observed that ROCK blockade reduced LPA-induced phosphorylation of IκBα and inhibited NF-κB RelA/p65 phosphorylation, leading to attenuation of RelA/p65 nuclear translocation. Furthermore, small interfering RNA-mediated ROCK isoform knockdown experiments revealed that LPA induces the expression of monocyte chemoattractant protein-1 (MCP-1) and E-selectin via ROCK2 in human aortic endothelial cells (HAECs). Importantly, we found that ROCK2 but not ROCK1 controls LPA-induced monocytic migration and monocyte adhesion toward endothelial cells. These findings demonstrate that ROCK2 is a key regulator of endothelial inflammation. We conclude that targeting endothelial ROCK2 is potentially effective in attenuation of atherosclerosis.
Telomeres and Telomerase in Cutaneous Squamous Cell Carcinoma
Authors: Ventura Alessandra , Pellegrini Cristina , Cardelli Ludovica , Rocco Tea , Ciciarelli Valeria , Peris Ketty , Fargnoli Maria Concetta
Published: March 2019

The role of telomere biology and telomerase activation in skin cancers has been investigated in melanoma and basal cell carcinoma but limited evidence is available for cutaneous squamous cell carcinoma (cSCC). We will review the current knowledge on the role of telomere and telomerase pathway in cSCC pathogenesis. At the somatic level, both long and short telomere lengths have been described in cSCC. This telomere dichotomy is probably related to two different mechanisms of tumour initiation which determines two tumour subtypes. Telomere shortening is observed during the invasive progression from in situ forms of cSCC, such as Bowen’s disease (BD) and actinic keratosis (AK), to invasive cSCC. At the germline level, controversial results have been reported on the association between constitutive telomere length and risk of cSCC. Approximately 75–85% of cSCC tumours are characterized by a high level of telomerase activity. Telomerase activation has been also reported in AKs and BD and in sun-damaged skin, thus supporting the hypothesis that UV modulates telomerase activity in the skin. Activating TERT promoter mutations have been identified in 32–70% of cSCCs, with the majority showing the UV-signature. No significant correlation was observed between TERT promoter mutations and cSCC clinico-pathological features. However, TERT promoter mutations have been recently suggested to be independent predictors of an adverse outcome. The attention on telomere biology and telomerase activity in cSCC is increasing for the potential implications in the development of effective tools for prognostic assessment and of therapeutic strategies in patients with cutaneous cSCC.
Distribution of Gadolinium in Rat Heart Studied by Fast Field Cycling Relaxometry and Imaging SIMS
Authors: Bonechi Claudia , Consumi Marco , Matteucci Marco , Tamasi Gabriella , Donati Alessandro , Leone Gemma , Menichetti Luca , Kusmic Claudia , Rossi Claudio , Magnani Agnese
Published: March 2019

Research on microcirculatory alterations in human heart disease is essential to understand the genesis of myocardial contractile dysfunction and its evolution towards heart failure. The use of contrast agents in magnetic resonance imaging is an important tool in medical diagnostics related to this dysfunction. Contrast agents significantly improve the imaging by enhancing the nuclear magnetic relaxation rates of water protons in the tissues where they are distributed. Gadolinium complexes are widely employed in clinical practice due to their high magnetic moment and relatively long electronic relaxation time. In this study, the behavior of gadolinium ion as a contrast agent was investigated by two complementary methods, relaxometry and secondary ion mass spectrometry. The study examined the distribution of blood flow within the microvascular network in ex vivo Langendorff isolated rat heart models, perfused with Omniscan® contrast agent. The combined use of secondary ion mass spectrometry and relaxometry allowed for both a qualitative mapping of agent distribution as well as the quantification of gadolinium ion concentration and persistence. This combination of a chemical mapping and temporal analysis of the molar concentration of gadolinium ion in heart tissue allows for new insights on the biomolecular mechanisms underlying the microcirculatory alterations in heart disease.
Hypoxia-Regulated miRNAs in Human Mesenchymal Stem Cells: Exploring the Regulatory Effects in Ischemic Disorders
Authors: Dell’Aversana Carmela , Cuomo Francesca , Botti Chiara , Maione Ciro , Carissimo Annamaria , Casamassimi Amelia , Altucci Lucia , Cobellis Gilda
Published: March 2019

Human mesenchymal/stromal stem cells (hMSC) are the most promising cell source for adult cell therapies in regenerative medicine. Many clinical trials have reported the use of autologous transplantation of hMSCs in several disorders, but with limited results. To exert their potential, hMSCs could exhibit efficient homing and migration toward lesion sites among other effects, but the underlying process is not clear enough. To further increase the knowledge, we studied the co-regulation between hypoxia-regulated genes and miRNAs. To this end, we investigated the miRNA expression profile of healthy hMSCs in low oxygen/nutrient conditions to mimic ischemia and compared with cells of patients suffering from critical limb ischemia (CLI). miRNAs are small, highly conserved, non-coding RNAs, skilled in the control of the target’s expression level in a fine-tuned way. After analyzing the miRNOme in CLI-derived hMSC cells and healthy controls, and intersecting the results with the mRNA expression dataset under hypoxic conditions, we identified two miRNAs potentially relevant to the disease: miR-29b as a pathological marker of the disease and miR-638 as a therapeutic target. This study yielded a deeper understanding of stem cell biology and ischemic disorders, opening new potential treatments in the future.
Hedgehog Signaling Regulates Taste Organs and Oral Sensation: Distinctive Roles in the Epithelium, Stroma, and Innervation
Authors: Mistretta Charlotte M. , Kumari Archana
Published: March 2019

The Hedgehog (Hh) pathway has regulatory roles in maintaining and restoring lingual taste organs, the papillae and taste buds, and taste sensation. Taste buds and taste nerve responses are eliminated if Hh signaling is genetically suppressed or pharmacologically inhibited, but regeneration can occur if signaling is reactivated within the lingual epithelium. Whereas Hh pathway disruption alters taste sensation, tactile and cold responses remain intact, indicating that Hh signaling is modality-specific in regulation of tongue sensation. However, although Hh regulation is essential in taste, the basic biology of pathway controls is not fully understood. With recent demonstrations that sonic hedgehog (Shh) is within both taste buds and the innervating ganglion neurons/nerve fibers, it is compelling to consider Hh signaling throughout the tongue and taste organ cell and tissue compartments. Distinctive signaling centers and niches are reviewed in taste papilla epithelium, taste buds, basal lamina, fibroblasts and lamellipodia, lingual nerves, and sensory ganglia. Several new roles for the innervation in lingual Hh signaling are proposed. Hh signaling within the lingual epithelium and an intact innervation each is necessary, but only together are sufficient to sustain and restore taste buds. Importantly, patients who use Hh pathway inhibiting drugs confront an altered chemosensory world with loss of taste buds and taste responses, intact lingual touch and cold sensation, and taste recovery after drug discontinuation.
DNA Methylation Patterns in the Early Human Embryo and the Epigenetic/Imprinting Problems: A Plea for a More Careful Approach to Human Assisted Reproductive Technology (ART)
Authors: Menezo Yves , Clément Patrice , Dale Brian
Published: March 2019

An increasing number of publications indicate that babies born after IVF (in vitro fertilization) procedures have higher rates of anomalies related to imprinting/epigenetic changes, which may be attributed to suboptimal culture conditions. Appropriate maintenance of DNA methylation during the first few days of an in vitro culture requires a supply of methyl donors, which are lacking in current in vitro culture systems. The absence of protection against oxidative stress in the culture increases the risks for errors in methylation. A decrease in the methylation processes is sometimes observed immediately post fertilization, due to delays that occur during the maternal–zygotic transition period. Care should be exercised in ART (assisted reproductive technology) procedures in order to avoid the risk of generating errors in methylation during the in vitro culture period immediately post fertilization, which has an impact on imprinting/epigenetics. Formulation of IVF culture media needs to be re-assessed in the perspective of current knowledge regarding embryo physiology.
Specificity of the Metallothionein-1 Response by Cadmium-Exposed Normal Human Urothelial Cells
Authors: McNeill Rhiannon V. , Mason Andrew S. , Hodson Mark E. , Catto James W.F. , Southgate Jennifer
Published: March 2019

Occupational and environmental exposure to cadmium is associated with the development of urothelial cancer. The metallothionein (MT) family of genes encodes proteins that sequester metal ions and modulate physiological processes, including zinc homeostasis. Little is known about the selectivity of expression of the different MT isoforms. Here, we examined the effect of cadmium exposure on MT gene and isoform expression by normal human urothelial (NHU) cell cultures. Baseline and cadmium-induced MT gene expression was characterized by next-generation sequencing and RT-PCR; protein expression was assessed by Western blotting using isoform-specific antibodies. Expression of the zinc transporter-1 (SLC30A1) gene was also assessed. NHU cells displayed transcription of MT-2A, but neither MT-3 nor MT-4 genes. Most striking was a highly inducer-specific expression of MT-1 genes, with cadmium inducing transcription of MT-1A, MT-1G, MT-1H, and MT-1M. Whereas MT-1G was also induced by zinc and nickel ions and MT-1H by iron, both MT-1A and MT-1M were highly cadmium-specific, which was confirmed for protein using isoform-specific antibodies. Protein but not transcript endured post-exposure, probably reflecting sequestration. SLC30A1 transcription was also affected by cadmium ion exposure, potentially reflecting perturbation of intracellular zinc homeostasis. We conclude that human urothelium displays a highly inductive profile of MT-1 gene expression, with two isoforms identified as highly specific to cadmium, providing candidate transcript and long-lived protein biomarkers of cadmium exposure.