bluuebunny/crossref_metadata_2025 huggingface dataset:
A Meta-Synthesis of Policy Recommendations Regarding Human Mobility in the Context of Climate Change
Authors: Nayna Schwerdtle Patricia , Stockemer Julia , Bowen Kathryn J. , Sauerborn Rainer , McMichael Celia , Danquah Ina
Published: December 2020

Changing mobility patterns combined with changes in the climate present challenges and opportunities for global health, requiring effective, relevant, and humane policy responses. This study used data from a systematic literature review that examined the intersection between climate change, migration, and health. The study aimed to synthesize policy recommendations in the peer-reviewed literature, regarding this type of environmental migration with respect to health, to strengthen the evidence-base. Systematic searches were conducted in four academic databases (PubMed, Ovid Medline, Global Health and Scopus) and Google Scholar for empirical studies published between 1990–2020 that used any study design to investigate migration and health in the context of climate change. Studies underwent a two-stage protocol-based screening process and eligible studies were appraised for quality using a standardized mixed-methods tool. From the initial 2425 hits, 68 articles were appraised for quality and included in the synthesis. Among the policy recommendations, six themes were discernible: (1) avoid the universal promotion of migration as an adaptive response to climate risk; (2) preserve cultural and social ties of mobile populations; (3) enable the participation of migrants in decision-making in sites of relocation and resettlement; (4) strengthen health systems and reduce barriers for migrant access to health care; (5) support and promote optimization of social determinants of migrant health; (6) integrate health into loss and damage assessments related to climate change, and consider immobile and trapped populations. The results call for transformative policies that support the health and wellbeing of people engaging in or affected by mobility responses, including those whose migration decisions and experiences are influenced by climate change, and to establish and develop inclusive migrant healthcare.
A Randomised Controlled Trial of a Caregiver-Facilitated Problem-Solving Based Self-Learning Program for Family Carers of People with Early Psychosis
Authors: Chien Wai Tong , Bressington Daniel , Lubman Dan I. , Karatzias Thanos
Published: December 2020

Facilitated self-help and problem-solving strategies can empower and support family carers to cope with caregiving for people with severe mental illnesses. This single-blind multi-site randomised controlled trial examined the effects of a five-month family-facilitated problem-solving based self-learning program (PBSP in addition to usual care), versus a family psychoeducation group program and usual psychiatric care only in recent-onset psychosis, with a six-month follow-up. In each of three study sites (integrated community centres for mental wellness), 114 people with early psychosis (≤5 years illness onset) and their family carers were randomly selected and allocated to one of three study groups (n = 38). Caregiving burden (primary outcome) and patients’ and carers’ health conditions were assessed at recruitment, and one-month and six-months post-intervention. Overall, 106 (94.7%) participants completed the assigned intervention and ≥1 post-test. Generalised estimating equations and subsequent contrast tests indicated that the PBSP participants showed significantly greater improvements in carers’ burden, caregiving experiences and problem-solving ability, and patients’ psychotic symptoms, recovery, and duration of re-hospitalisations over the six-month follow-up, compared with the other two groups (moderate to large effect size, η2 = 0.12–0.24). Family-assisted problem-solving based self-learning programs were found to be effective to improve both psychotic patients’ and their carers’ psychosocial health over a medium term, thus reducing patients’ risk of relapse.
The Influence of South East Asia Forest Fires on Ambient Particulate Matter Concentrations in Singapore: An Ecological Study Using Random Forest and Vector Autoregressive Models
Authors: Rajarethinam Jayanthi , Aik Joel , Tian Jing
Published: December 2020

Haze, due to biomass burning, is a recurring problem in Southeast Asia (SEA). Exposure to atmospheric particulate matter (PM) remains an important public health concern. In this paper, we examined the long-term seasonality of PM2.5 and PM10 in Singapore. To study the association between forest fires in SEA and air quality in Singapore, we built two machine learning models, including the random forest (RF) model and the vector autoregressive (VAR) model, using a benchmark air quality dataset containing daily PM2.5 and PM10 from 2009 to 2018. Furthermore, we incorporated weather parameters as independent variables. We observed two annual peaks, one in the middle of the year and one at the end of the year for both PM2.5 and PM10. Singapore was more affected by fires from Kalimantan compared to fires from other SEA countries. VAR models performed better than RF with Mean Absolute Percentage Error (MAPE) values being 0.8% and 6.1% lower for PM2.5 and PM10, respectively. The situation in Singapore can be reasonably anticipated with predictive models that incorporate information on forest fires and weather variations. Public communication of anticipated air quality at the national level benefits those at higher risk of experiencing poorer health due to poorer air quality.
Cyberattacks Detection in IoT-Based Smart City Applications Using Machine Learning Techniques
Authors: Rashid Md Mamunur , Kamruzzaman Joarder , Hassan Mohammad Mehedi , Imam Tasadduq , Gordon Steven
Published: December 2020

In recent years, the widespread deployment of the Internet of Things (IoT) applications has contributed to the development of smart cities. A smart city utilizes IoT-enabled technologies, communications and applications to maximize operational efficiency and enhance both the service providers’ quality of services and people’s wellbeing and quality of life. With the growth of smart city networks, however, comes the increased risk of cybersecurity threats and attacks. IoT devices within a smart city network are connected to sensors linked to large cloud servers and are exposed to malicious attacks and threats. Thus, it is important to devise approaches to prevent such attacks and protect IoT devices from failure. In this paper, we explore an attack and anomaly detection technique based on machine learning algorithms (LR, SVM, DT, RF, ANN and KNN) to defend against and mitigate IoT cybersecurity threats in a smart city. Contrary to existing works that have focused on single classifiers, we also explore ensemble methods such as bagging, boosting and stacking to enhance the performance of the detection system. Additionally, we consider an integration of feature selection, cross-validation and multi-class classification for the discussed domain, which has not been well considered in the existing literature. Experimental results with the recent attack dataset demonstrate that the proposed technique can effectively identify cyberattacks and the stacking ensemble model outperforms comparable models in terms of accuracy, precision, recall and F1-Score, implying the promise of stacking in this domain.
Erratum: Lasheras, I.; et al. Prevalence of Anxiety in Medical Students during the COVID-19 Pandemic: A Rapid Systematic Review with Meta-Analysis. Int. J. Environ. Res. Public Health 2020, 17, 6603
Authors: Lasheras Isabel , Gracia-García Patricia , Lipnicki Darren , Bueno-Notivol Juan , López-Antón Raúl , de la Cámara Concepción , Lobo Antonio , Santabárbara Javier
Published: December 2020

The source of funding was not included in our original article [...]
A Systematic Review and Meta-Analysis of Depression among Farming Populations Worldwide
Authors: Hagen Briana N. M. , Winder Charlotte B. , Wootten Jared , McMullen Carrie K. , Jones-Bitton Andria
Published: December 2020

A systematic review and meta-analysis were conducted to determine the overall prevalence of depression among farming populations globally, and explore any heterogeneity present. Eligible studies were primary research articles published in English, which involved the collection of data for the purpose of determining the prevalence of depression among a farming population. Four relevant databases were searched in January 2019. Potential for bias was assessed using a modified Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool. From 7662 records, 72 articles were deemed relevant and had data extracted. Of these, 45 utilized the Center for Epidemiologic Studies—Depression Revised scale (CES-D/DR) to quantify depression, 42 of which were conducted in the United States (U.S.). As a result, meta-analyses were restricted to this geographic location. Substantial heterogeneity was seen in the initial whole-group analysis (I2 = 97%), and while sub-group exploration suggested a significantly higher prevalence of depression among migrant farm workers (26%, 95% CI = 21–31%) than in studies examining a non-migrant farming population (12%, 95% CI = 8–17%), substantial heterogeneity remained (I2 = 96%), indicating that the majority of between study variation was due to factors other than sampling error. Additionally, the majority of studies (81%) in migrant farm worker populations were published since 2010, while only 21% of studies in non-migrant farming populations were published in this timeframe. It is possible with recent efforts to de-stigmatize mental illness, participants in more recent studies may be more likely to self-report depressive symptoms. Hence, while it appears that migrant farmworker populations may have an elevated prevalence of depression, it is also apparent that little research in the U.S. has been done to evaluate depression among non-migrant farming populations in recent years. Perhaps a reporting bias may account for some of the difference between the two populations. A research gap also appears to exist in estimating the prevalence of depression among farming populations outside of the US. Assessment for bias at the study level revealed challenges in reporting of key study design elements, as well as potential for selection bias in the majority of studies.
Firefighters Are More Physically Active On-Duty Compared to Off-Duty
Authors: Barry Allison M. , Lyman Katie L. , Dicks Nathan D. , McGeorge Christi R. , Carper Michael J. , Walch Tanis J.
Published: December 2020

Physical inactivity, coupled with increasing obesity levels, in firefighters plays a key role in aggregated cardiovascular events. The purpose of this study was to investigate device-measured physical activity (PA) for firefighters while on- and off-duty to have a clearer understanding of their overall PA level. Methods: Twenty-nine career firefighters participated in this non-experimental, within-subjects study by wearing an accelerometer to assess PA intensities and step-count. Obesity was classified using body mass index (BMI). Dependent t-tests were used to examine mean differences in PA intensities when on- and off-duty. Pearson product-moment correlations were used to assess the association between PA intensities when on and off-duty. Results: According to the World Health Organization BMI categorizations, 20 firefighters were overweight, 9 were obese, and, thus, none were normal weight. Only light PA (LPA) was statistically significant (p = 0.026) for on- and off-duty days with a small-to-medium effect size (d = 0.47), meaning that on average, firefighters performed more minutes of LPA when on-duty compared to off. There was a significant difference between on- (9060.2 ± 2636.4) and off-duty (7495.3 ± 2835.8) daily step counts (p = 0.011). Conclusion: As the results demonstrate, there is a dire need for increased PA levels in firefighters while on- and off-duty.
Accelerated Spatial Fibrin Growth and Impaired Contraction of Blood Clots in Patients with Rheumatoid Arthritis
Authors: Peshkova Alina D. , Evdokimova Tatiana A. , Sibgatullin Timur B. , Ataullakhanov Fazoil I. , Litvinov Rustem I. , Weisel John W.
Published: December 2020

Rheumatoid arthritis (RA) is an autoimmune disease associated with thrombotic complications. To elucidate pathogenic mechanisms, hemostatic disorders in RA were correlated with other laboratory and clinical manifestations. Hemostasis was assessed using relatively new complementary tests, the spatial growth of a plasma clot (Thrombodynamics assay), and contraction of whole blood clots. Platelet functionality was assessed with flow cytometry that quantified the expression of P-selectin and the fibrinogen-binding capacity of platelets before and after activation with a thrombin receptor-activating peptide. Parameters of fibrin clot growth and the kinetics of contraction of blood clots were significantly altered in patients with RA compared to the control group. In Thrombodynamics measurements, an increase in the clot growth rate, size, and optical density of plasma clots altogether indicated chronic hypercoagulability. The rate and extent of blood clot contraction in patients with RA was significantly reduced and associated with platelet dysfunction revealed by an impaired response to activation. Changes in the parameters of clot growth and contraction correlated with the laboratory signs of systemic inflammation, including hyperfibrinogenemia. These results confirm the pathogenic role of hemostatic disorders in RA and support the validity of fibrin clot growth and the blood clot contraction assay as indicators of a (pro)thrombotic state.
Trypanosoma cruzi Modulates PIWI-Interacting RNA Expression in Primary Human Cardiac Myocytes during the Early Phase of Infection
Authors: Rayford Kayla J. , Cooley Ayorinde , Arun Ashutosh , Rachakonda Girish , Kleschenko Yulia , Villalta Fernando , Pratap Siddharth , Lima Maria F. , Nde Pius N.
Published: December 2020

Trypanosoma cruzi dysregulates the gene expression profile of primary human cardiomyocytes (PHCM) during the early phase of infection through a mechanism which remains to be elucidated. The role that small non-coding RNAs (sncRNA) including PIWI-interacting RNA (piRNA) play in regulating gene expression during the early phase of infection is unknown. To understand how T. cruzi dysregulate gene expression in the heart, we challenged PHCM with T. cruzi trypomastigotes and analyzed sncRNA, especially piRNA, by RNA-sequencing. The parasite induced significant differential expression of host piRNAs, which can target and regulate the genes which are important during the early infection phase. An average of 21,595,866 (88.40%) of clean reads mapped to the human reference genome. The parasite induced 217 unique piRNAs that were significantly differentially expressed (q ≥ 0.8). Of these differentially expressed piRNAs, 6 were known and 211 were novel piRNAs. In silico analysis showed that some of the dysregulated known and novel piRNAs could target and potentially regulate the expression of genes including NFATC2, FOS and TGF-β1, reported to play important roles during T. cruzi infection. Further evaluation of the specific functions of the piRNAs in the regulation of gene expression during the early phase of infection will enhance our understanding of the molecular mechanism of T. cruzi pathogenesis. Our novel findings constitute the first report that T. cruzi can induce differential expression of piRNAs in PHCM, advancing our knowledge about the involvement of piRNAs in an infectious disease model, which can be exploited for biomarker and therapeutic development.
Insights into Cardiac IKs (KCNQ1/KCNE1) Channels Regulation
Authors: Wu Xiaoan , Larsson H. Peter
Published: December 2020

The delayed rectifier potassium IKs channel is an important regulator of the duration of the ventricular action potential. Hundreds of mutations in the genes (KCNQ1 and KCNE1) encoding the IKs channel cause long QT syndrome (LQTS). LQTS is a heart disorder that can lead to severe cardiac arrhythmias and sudden cardiac death. A better understanding of the IKs channel (here called the KCNQ1/KCNE1 channel) properties and activities is of great importance to find the causes of LQTS and thus potentially treat LQTS. The KCNQ1/KCNE1 channel belongs to the superfamily of voltage-gated potassium channels. The KCNQ1/KCNE1 channel consists of both the pore-forming subunit KCNQ1 and the modulatory subunit KCNE1. KCNE1 regulates the function of the KCNQ1 channel in several ways. This review aims to describe the current structural and functional knowledge about the cardiac KCNQ1/KCNE1 channel. In addition, we focus on the modulation of the KCNQ1/KCNE1 channel and its potential as a target therapeutic of LQTS.
Differential Co-Expression Analyses Allow the Identification of Critical Signalling Pathways Altered during Tumour Transformation and Progression
Authors: Savino Aurora , Provero Paolo , Poli Valeria
Published: December 2020

Biological systems respond to perturbations through the rewiring of molecular interactions, organised in gene regulatory networks (GRNs). Among these, the increasingly high availability of transcriptomic data makes gene co-expression networks the most exploited ones. Differential co-expression networks are useful tools to identify changes in response to an external perturbation, such as mutations predisposing to cancer development, and leading to changes in the activity of gene expression regulators or signalling. They can help explain the robustness of cancer cells to perturbations and identify promising candidates for targeted therapy, moreover providing higher specificity with respect to standard co-expression methods. Here, we comprehensively review the literature about the methods developed to assess differential co-expression and their applications to cancer biology. Via the comparison of normal and diseased conditions and of different tumour stages, studies based on these methods led to the definition of pathways involved in gene network reorganisation upon oncogenes’ mutations and tumour progression, often converging on immune system signalling. A relevant implementation still lagging behind is the integration of different data types, which would greatly improve network interpretability. Most importantly, performance and predictivity evaluation of the large variety of mathematical models proposed would urgently require experimental validations and systematic comparisons. We believe that future work on differential gene co-expression networks, complemented with additional omics data and experimentally tested, will considerably improve our insights into the biology of tumours.
Restraint Stress in Mice Alters Set of 25 miRNAs Which Regulate Stress- and Depression-Related mRNAs
Authors: Solich Joanna , Kuśmider Maciej , Faron-Górecka Agata , Pabian Paulina , Dziedzicka-Wasylewska Marta
Published: December 2020

In the present study, we aim to identify the effect of restrain stress (RS) on the expression of miRNAs in mouse serum. We used three genotypes of animals (mice with knock-out of the gene-encoding norepinephrine transporter, NET-KO; C57BL/6J, and SWR/J) which had previously been shown to display different sensitivity to RS, and focused on miRNAs which were altered by RS in the serum of all three genotypes. An analysis of miRNAs expression allowed for the identification of a set of 25 differentially expressed miRNAs; 10 were down-regulated compared to an appropriate control group of animals, while 15 were up-regulated. The application of DIANA-miRPath v. 3.0 allowed for the identification of selected pathways (KEGG) and Gene Ontology (GO) categories that were significantly controlled by these miRNAs, while miRWalk v. 3.0—the platform that used the machine learning based algorithm, TaRPmiR—was used to find their targets. The results indicate that 25 miRNAs, identified as altered upon RS in three genotypes of mice, are responsible for regulation of mRNA-encoding proteins that are key for the main hypotheses of depression; therefore, they may help to understand the link between stress and depression at the molecular level.
Experimental Pulmonary Tuberculosis in the Absence of Detectable Brain Infection Induces Neuroinflammation and Behavioural Abnormalities in Male BALB/c Mice
Authors: Lara-Espinosa Jacqueline V. , Santana-Martínez Ricardo A. , Maldonado Perla D. , Zetter Mario , Becerril-Villanueva Enrique , Pérez-Sánchez Gilberto , Pavón Lenin , Mata-Espinosa Dulce , Barrios-Payán Jorge , López-Torres Manuel O. , Marquina-Castillo Brenda , Hernández-Pando Rogelio
Published: December 2020

Tuberculosis (TB) is a chronic infectious disease in which prolonged, non-resolutive inflammation of the lung may lead to metabolic and neuroendocrine dysfunction. Previous studies have reported that individuals coursing pulmonary TB experience cognitive or behavioural changes; however, the pathogenic substrate of such manifestations have remained unknown. Here, using a mouse model of progressive pulmonary TB, we report that, even in the absence of brain infection, TB is associated with marked increased synthesis of both inflammatory and anti-inflammatory cytokines in discrete brain areas such as the hypothalamus, the hippocampal formation and cerebellum accompanied by substantial changes in the synthesis of neurotransmitters. Moreover, histopathological findings of neurodegeneration and neuronal death were found as infection progressed with activation of p38, JNK and reduction in the BDNF levels. Finally, we perform behavioural analysis in infected mice throughout the infection, and our data show that the cytokine and neurochemical changes were associated with a marked onset of cognitive impairment as well as depressive- and anxiety-like behaviour. Altogether, our results suggest that besides pulmonary damage, TB is accompanied by an extensive neuroinflammatory and neurodegenerative state which explains some of the behavioural abnormalities found in TB patients.
P27 Protects Neurons from Ischemic Damage by Suppressing Oxidative Stress and Increasing Autophagy in the Hippocampus
Authors: Kim Woosuk , Kwon Hyun Jung , Jung Hyo Young , Hahn Kyu Ri , Yoon Yeo Sung , Hwang In Koo , Choi Soo Young , Kim Dae Won
Published: December 2020

p27Kip1 (p27), a well-known cell regulator, is involved in the regulation of cell death and survival. In the present study, we observed the effects of p27 against oxidative stress induced by H2O2 in HT22 cells and transient ischemia in gerbils. Tat (trans-acting activator of transcription) peptide and p27 fusion proteins were prepared to facilitate delivery into cells and across the blood-brain barrier. The tat-p27 fusion protein, rather than its control protein Control-p27, was delivered intracellularly in a concentration and incubation time-dependent manner and showed its activity in HT22 cells. The localization of the delivered Tat-p27 protein was also confirmted in the HT22 cells and hippocampus in gerbils. In addition, the optimal concentration (5 μM) of Tat-p27 was determined to protect neurons from cell death induced by 1 mM H2O2. Treatment with 5 μM Tat-p27 significantly ameliorated H2O2-induced DNA fragmentation and the formation of reactive oxygen species (ROS) in HT22 cells. Tat-p27 significantly mitigated the increase in locomotor activity a day after ischemia and neuronal damage in the hippocampal CA1 region. It also reduced the ischemia-induced membrane phospholipids and ROS formation. In addition, Tat-p27 significantly increased microtubule-associated protein 1A/1B light chain 3A/3B expression and ameliorated the H2O2 or ischemia-induced increases of p62 and decreases of beclin-1 in the HT22 cells and hippocampus. These results suggest that Tat-p27 protects neurons from oxidative or ischemic damage by reducing ROS-induced damage and by facilitating the formation of autophagosomes in hippocampal cells.
Prognostic Significance of COX-2 Overexpression in BRAF-Mutated Middle Eastern Papillary Thyroid Carcinoma
Authors: Parvathareddy Sandeep Kumar , Siraj Abdul K. , Annaiyappanaidu Padmanaban , Al-Sobhi Saif S. , Al-Dayel Fouad , Al-Kuraya Khawla S.
Published: December 2020

The cyclooxygenase-2 (COX-2)–prostaglandin E2 (PGE2) pathway has been implicated in carcinogenesis, with BRAF mutation shown to promote PGE2 synthesis. This study was conducted to evaluate COX-2 expression in a large cohort of Middle Eastern papillary thyroid carcinoma (PTC), and further evaluate the prognostic significance of COX-2 expression in strata of BRAF mutation status. BRAF mutation analysis was performed using Sanger sequencing, and COX-2 expression was evaluated immunohistochemically using tissue microarray (TMA). COX-2 overexpression, noted in 43.2% (567/1314) of cases, was significantly associated with poor prognostic markers such as extra-thyroidal extension, lymph-node metastasis, and higher tumor stage. COX-2 was also an independent predictor of poor disease-free survival (DFS). Most notably, the association of COX-2 expression with DFS differed by BRAF mutation status. COX-2 overexpression was associated with poor DFS in BRAF-mutant but not BRAF wild-type PTCs, with a multivariate-adjusted hazard ratio of 2.10 (95% CI = 1.52–2.92; p < 0.0001) for COX-2 overexpressed tumors in BRAF-mutant PTC. In conclusion, the current study shows that COX-2 plays a key role in prognosis of PTC patients, especially in BRAF-mutated tumors. Our data suggest the potential therapeutic role of COX-2 inhibition in patients with BRAF-mutated PTC.
Alzheimer’s, Parkinson’s Disease and Amyotrophic Lateral Sclerosis Gene Expression Patterns Divergence Reveals Different Grade of RNA Metabolism Involvement
Authors: Garofalo Maria , Pandini Cecilia , Bordoni Matteo , Pansarasa Orietta , Rey Federica , Costa Alfredo , Minafra Brigida , Diamanti Luca , Zucca Susanna , Carelli Stephana , Cereda Cristina , Gagliardi Stella
Published: December 2020

Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders characterized by a progressive degeneration of the central or peripheral nervous systems. A central role of the RNA metabolism has emerged in these diseases, concerning mRNAs processing and non-coding RNAs biogenesis. We aimed to identify possible common grounds or differences in the dysregulated pathways of AD, PD, and ALS. To do so, we performed RNA-seq analysis to investigate the deregulation of both coding and long non-coding RNAs (lncRNAs) in ALS, AD, and PD patients and controls (CTRL) in peripheral blood mononuclear cells (PBMCs). A total of 293 differentially expressed (DE) lncRNAs and 87 mRNAs were found in ALS patients. In AD patients a total of 23 DE genes emerged, 19 protein coding genes and four lncRNAs. Through Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses, we found common affected pathways and biological processes in ALS and AD. In PD patients only five genes were found to be DE. Our data brought to light the importance of lncRNAs and mRNAs regulation in three principal neurodegenerative disorders, offering starting points for new investigations on deregulated pathogenic mechanisms.
Albanol B from Mulberries Exerts Anti-Cancer Effect through Mitochondria ROS Production in Lung Cancer Cells and Suppresses In Vivo Tumor Growth
Authors: Phan Thanh Nam , Kim Okwha , Ha Manh Tuan , Hwangbo Cheol , Min Byung-Sun , Lee Jeong-Hyung
Published: December 2020

Albanol B (ABN-B), an arylbenzofuran derivative isolated from mulberries, has been shown to have anti-Alzheimer’s disease, anti-bacterial and antioxidant activities. The aim of this study was to investigate the anti-cancer effect of this compound against lung cancer cells. The results show that ABN-B inhibited the proliferation of four human lung cancer cell lines (A549, BZR, H1975, and H226) and induced apoptosis, based on the cleavage of caspase-7 and PARP (poly (ADP-ribose) polymerase), as well as the downregulation of Bcl-2. ABN-B also induced cell cycle arrest at G2/M by down-regulating the expression of CKD1 (cyclin-dependent kinase 1) and cyclin B1, but up-regulating p21 (cyclin-dependent kinase inhibitor 1) expression. Notably, ABN-B increased the production of mitochondrial reactive oxygen species (ROS); however, treatment with mito-TEMPO (a specific mitochondrial antioxidant) blocked ABN-B-induced cell cycle arrest at G2/M and apoptosis, as well as the up-regulation of p21 and down-regulation of CDK1 and cyclin B1 induced by ABN-B. At the molecular level, ABN-B-induced mitochondrial ROS production increased the phosphorylation levels of AKT (protein kinase B) and ERK1/2 (extracellular signal-regulated kinase 1/2), while the inhibition of these kinases blocked the ABN-B-induced up-regulation of p21 and down-regulation of CDK1 and cyclin B1. Moreover, ABN-B significantly suppressed tumor growth in Ex-3LL (Lewis lung carcinoma) tumor-bearing mice. Taken together, these results suggest that ABN-B can exert an anti-cancer effect by inducing apoptosis and cell cycle arrest at G2/M through mitochondrial ROS production in lung cancer cells.
Molecular Features and Clinical Management of Hereditary Gynecological Cancers
Authors: Ueki Arisa , Hirasawa Akira
Published: December 2020

Hereditary gynecological cancers are caused by several inherited genes. Tumors that arise in the female reproductive system, such as ovaries and the uterus, overlap with hereditary cancers. Several hereditary cancer-related genes are important because they might lead to therapeutic targets. Treatment of hereditary cancers should be updated in line with the advent of various new methods of evaluation. Next-generation sequencing has led to rapid, economical genetic analyses that have prompted a concomitant and significant paradigm shift with respect to hereditary cancers. Molecular tumor profiling is an epochal method for determining therapeutic targets. Clinical treatment strategies are now being designed based on biomarkers based on tumor profiling. Furthermore, the National Comprehensive Cancer Network (NCCN) guidelines significantly changed the genetic testing process in 2020 to initially consider multi-gene panel (MGP) evaluation. Here, we reviewed the molecular features and clinical management of hereditary gynecological malignancies, such as hereditary breast and ovarian cancer (HBOC), and Lynch, Li–Fraumeni, Cowden, and Peutz–Jeghers syndromes. We also reviewed cancer-susceptible genes revealed by MGP tests.
The Lipid Paradox as a Metabolic Checkpoint and Its Therapeutic Significance in Ameliorating the Associated Cardiovascular Risks in Rheumatoid Arthritis Patients
Authors: Behl Tapan , Kaur Ishnoor , Sehgal Aayush , Zengin Gokhan , Brisc Ciprian , Brisc Mihaela Cristina , Munteanu Mihai Alexandru , Nistor-Cseppento Delia Carmen , Bungau Simona
Published: December 2020

While the most common manifestations associated with rheumatoid arthritis (RA) are synovial damage and inflammation, the systemic effects of this autoimmune disorder are life-threatening, and are prevalent in 0.5–1% of the population, mainly associated with cardiovascular disorders (CVDs). Such effects have been instigated by an altered lipid profile in RA patients, which has been reported to correlate with CV risks. Altered lipid paradox is related to inflammatory burden in RA patients. The review highlights general lipid pathways (exogenous and endogenous), along with the changes in different forms of lipids and lipoproteins in RA conditions, which further contribute to elevated risks of CVDs like ischemic heart disease, atherosclerosis, myocardial infarction etc. The authors provide a deep insight on altered levels of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TGs) in RA patients and their consequence on the cardiovascular health of the patient. This is followed by a detailed description of the impact of anti-rheumatoid therapy on the lipid profile in RA patients, comprising DMARDs, corticosteroids, anti-TNF agents, anti-IL-6 agents, JAK inhibitors and statins. Furthermore, this review elaborates on the prospects to be considered to optimize future investigation on management of RA and treatment therapies targeting altered lipid paradigms in patients.
N-Heterocycles Scaffolds as Quorum Sensing Inhibitors. Design, Synthesis, Biological and Docking Studies
Authors: Fuentes-Gutiérrez Alfredo , Curiel-Quesada Everardo , Correa-Basurto José , Martínez-Muñoz Alberto , Reyes-Arellano Alicia
Published: December 2020

Quorum sensing is a communication system among bacteria to sense the proper time to express their virulence factors. Quorum sensing inhibition is a therapeutic strategy to block bacterial mechanisms of virulence. The aim of this study was to synthesize and evaluate new bioisosteres of N-acyl homoserine lactones as Quorum sensing inhibitors in Chromobacterium violaceum CV026 by quantifying the specific production of violacein. Five series of compounds with different heterocyclic scaffolds were synthesized in good yields: thiazoles, 16a–c, thiazolines 17a–c, benzimidazoles 18a–c, pyridines 19a–c and imidazolines 32a–c. All 15 compounds showed activity as Quorum sensing inhibitors except 16a. Compounds 16b, 17a–c, 18a, 18c, 19c and 32b exhibited activity at concentrations of 10 µM and 100 µM, highlighting the activity of benzimidazole 18a (IC50 = 36.67 µM) and 32b (IC50 = 85.03 µM). Pyridine 19c displayed the best quorum sensing inhibition activity (IC50 = 9.66 µM). Molecular docking simulations were conducted for all test compounds on the Chromobacterium violaceum CviR protein to gain insight into the process of quorum sensing inhibition. The in-silico data reveal that all 15 the compounds have higher affinity for the protein than the native AHL ligand (1). A strong correlation was found between the theoretical and experimental results.
Hydrogen Peroxide-Preconditioned Human Adipose-Derived Stem Cells Enhance the Recovery of Oligodendrocyte-Like Cells after Oxidative Stress-Induced Damage
Authors: Garrido-Pascual Patricia , Alonso-Varona Ana , Castro Begoña , Burón María , Palomares Teodoro
Published: December 2020

Oxidative stress associated with neuroinflammation is a key process involved in the pathophysiology of neurodegenerative diseases, and therefore, has been proposed as a crucial target for new therapies. Recently, the therapeutic potential of human adipose-derived stem cells (hASCs) has been investigated as a novel strategy for neuroprotection. These cells can be preconditioned by exposing them to mild stress in order to improve their response to oxidative stress. In this study, we evaluate the therapeutic potential of hASCs preconditioned with low doses of H2O2 (called HC016 cells) to overcome the deleterious effect of oxidative stress in an in vitro model of oligodendrocyte-like cells (HOGd), through two strategies: i, the culture of oxidized HOGd with HC016 cell-conditioned medium (CM), and ii, the indirect co-culture of oxidized HOGd with HC016 cells, which had or had not been exposed to oxidative stress. The results demonstrated that both strategies had reparative effects, oxidized HC016 cell co-culture being the one associated with the greatest recovery of the damaged HOGd, increasing their viability, reducing their intracellular reactive oxygen species levels and promoting their antioxidant capacity. Taken together, these findings support the view that HC016 cells, given their reparative capacity, might be considered an important breakthrough in cell-based therapies.
Fox Hunting in Wild Apples: Searching for Novel Genes in Malus Sieversii
Authors: Wisniewski Michael , Artlip Timothy , Liu Jia , Ma Jing , Burchard Erik , Norelli John , Dardick Christopher
Published: December 2020

Malus sieversii is considered the progenitor of modern apple (Malus pumila) cultivars and to represent a valuable source of genetic diversity. Despite the importance of M. sieversii as a source of disease resistance, stress tolerance, and novel fruit traits, little is known about gene function and diversity in M. sieversii. Notably, a publicly annotated genome sequence for this species is not available. In the current study, the FOX (Full-length cDNA OvereXpressing) gene hunting system was used to construct a library of transgenic lines of Arabidopsis in which each transgenic line overexpresses a full-length gene obtained from a cDNA library of the PI619283 accession of M. sieversii. The cDNA library was constructed from mRNA obtained from bark tissues collected in late fall–early winter, a time at which many abiotic stress-adaptative genes are expressed. Over 4000 apple FOX Arabidopsis lines have been established from the pool of transgenic seeds and cDNA inserts corresponding to various Gene Ontology (GO) categories have been identified. A total of 160 inserts appear to be novel, with no or limited homology to M. pumila, Arabidopsis, or poplar. Over 1300 lines have also been screened for freezing resistance. The constructed library of transgenic lines provides a valuable genetic resource for exploring gene function and diversity in Malus sieversii. Notably, no such library of t-DNA lines currently exists for any Malus species.
Three-Dimensional Cell Culture Models to Investigate Oral Carcinogenesis: A Scoping Review
Authors: Chitturi Suryaprakash Ravi Teja , Kujan Omar , Shearston Kate , Farah Camile S.
Published: December 2020

Three-dimensional (3-D) cell culture models, such as spheroids, organoids, and organotypic cultures, are more physiologically representative of the human tumor microenvironment (TME) than traditional two-dimensional (2-D) cell culture models. They have been used as in vitro models to investigate various aspects of oral cancer but, to date, have not be widely used in investigations of the process of oral carcinogenesis. The aim of this scoping review was to evaluate the use of 3-D cell cultures in oral squamous cell carcinoma (OSCC) research, with a particular emphasis on oral carcinogenesis studies. Databases (PubMed, Scopus, and Web of Science) were systematically searched to identify research applying 3-D cell culture techniques to cells from normal, dysplastic, and malignant oral mucosae. A total of 119 studies were included for qualitative analysis including 53 studies utilizing spheroids, 62 utilizing organotypic cultures, and 4 using organoids. We found that 3-D oral carcinogenesis studies had been limited to just two organotypic culture models and that to date, spheroids and organoids had not been utilized for this purpose. Spheroid culture was most frequently used as a tumorosphere forming assay and the organoids cultured from human OSCCs most often used in drug sensitivity testing. These results indicate that there are significant opportunities to utilize 3-D cell culture to explore the development of oral cancer, particularly as the physiological relevance of these models continues to improve.
Potential for Protein Kinase Pharmacological Regulation in Flaviviridae Infections
Authors: Blázquez Ana-Belén , Saiz Juan-Carlos
Published: December 2020

Protein kinases (PKs) are enzymes that catalyze the transfer of the terminal phosphate group from ATP to a protein acceptor, mainly to serine, threonine, and tyrosine residues. PK catalyzed phosphorylation is critical to the regulation of cellular signaling pathways that affect crucial cell processes, such as growth, differentiation, and metabolism. PKs represent attractive targets for drugs against a wide spectrum of diseases, including viral infections. Two different approaches are being applied in the search for antivirals: compounds directed against viral targets (direct-acting antivirals, DAAs), or against cellular components essential for the viral life cycle (host-directed antivirals, HDAs). One of the main drawbacks of DAAs is the rapid emergence of drug-resistant viruses. In contrast, HDAs present a higher barrier to resistance development. This work reviews the use of chemicals that target cellular PKs as HDAs against virus of the Flaviviridae family (Flavivirus and Hepacivirus), thus being potentially valuable therapeutic targets in the control of these pathogens.
Mechanism of Action of Atypical Antipsychotic Drugs in Mood Disorders
Authors: Grinchii Daniil , Dremencov Eliyahu
Published: December 2020

Atypical antipsychotic drugs were introduced in the early 1990s. Unlike typical antipsychotics, which are effective only against positive symptoms of schizophrenia, atypical antipsychotics are effective against negative and cognitive symptoms as well. Furthermore, they are effective not only in psychotic but also in affective disorders, on their own or as adjuncts to antidepressant drugs. This review presents the neural mechanisms of currently existing atypical antipsychotics and putative antipsychotics currently being investigated in preclinical and clinical studies and how these relate to their effectiveness in mood disorders such as depression, anxiety, and post-traumatic stress disorder (PTSD). Typical antipsychotics act almost exclusively on the dopamine system. Atypical drugs, however, modulate serotonin (5-HT), norepinephrine, and/or histamine neurotransmission as well. This multimodal mechanism of action putatively underlies the beneficial effect of atypical antipsychotics in mood and anxiety disorders. Interestingly, novel experimental drugs having dual antipsychotic and antidepressant therapeutic potential, such as histamine, adenosine, and trace amine-associated receptors (TAAR) ligand, are also characterized by a multimodal stimulatory effect on central 5-HT, norepinephrine, and/or histamine transmission. The multimodal stimulatory effect on central monoamine neurotransmission may be thus primarily responsible for the combined antidepressant and antipsychotic therapeutic potential of certain central nervous system (CNS) drugs.
Isoflurane Potentiation of GABAA Receptors Is Reduced but Not Eliminated by the β3(N265M) Mutation
Authors: Lor Chong , Perouansky Misha , Pearce Robert A.
Published: December 2020

Background: Mice carrying the GABAA receptor β3(N265M) point mutation, which renders receptors incorporating β3-subunits insensitive to many general anesthetics, have been used experimentally to link modulation of different receptor subtypes to distinct behavioral endpoints. Remarkably, however, the effect of the mutation on the susceptibility to modulation by isoflurane (a standard reference agent for inhalational vapors) has never been tested directly. Therefore, we compared the modulation by isoflurane of expressed α5β3(N265M)γ2L receptors with their wild type counterparts. Methods: Using whole-cell electrophysiological recording and rapid solution exchange techniques, we tested the effects of isoflurane at concentrations ranging from 80 μM to 320 μM on currents activated by 1 μM GABA. We measured drug modulation of wild-type α5β3γ2L GABAA receptors and their counterparts harboring the β3(N265M) mutation. Results: Currents elicited by GABA were enhanced two- to four-fold by isoflurane, in a concentration-dependent manner. Under the same conditions, receptors incorporating the β3(N265M) mutation were enhanced by approximately 1.5- to two-fold; i.e., modulation by isoflurane was attenuated by approximately one-half. Direct activation by isoflurane was also present in mutant receptors but also attenuated. Conclusions: In contrast to the complete insensitivity of β3(N265M) mutant receptors to etomidate and propofol, the mutation has only a partial effect on receptor modulation by isoflurane. Therefore, the persistence of isoflurane effects in mutant mice does not exclude a possible contribution of β3-GABAA receptors.
Clinicopathologic Analysis of Cathepsin B as a Prognostic Marker of Thyroid Cancer
Authors: Kim Eun-Kyung , Song Min-Jeong , Jang Ho Hee , Chung Yoo Seung
Published: December 2020

Thyroid cancer incidence has increased worldwide; however, investigations of thyroid cancer-related factors as potential prognosis markers remain insufficient. Secreted proteins from the cancer secretome are regulators of several molecular mechanisms and are, thereby, ideal candidates for potential markers. We aimed to identify a specific factor for thyroid cancer by analyzing the secretome from normal thyroid cells, papillary thyroid cancer (PTC) cells, and anaplastic thyroid cancer cells using mass spectrometry (MS). Cathepsin B (CTSB) showed highest expression in PTC cells compared to other cell lines, and CTSB levels in tumor samples were higher than that seen in normal tissue. Further, among thyroid cancer patients, increased CTSB expression was related to higher risk of lymph node metastasis (LNM) and advanced N stage. Overexpression of CTSB in thyroid cancer cell lines activated cell migration by increasing the expression of vimentin and Snail, while its siRNA-mediated silencing inhibited cell migration by decreasing vimentin and Snail expression. Mechanistically, CTSB-associated enhanced cell migration and upregulation of vimentin and Snail occurred via increased phosphorylation of p38. As our results suggest that elevated CTSB in thyroid cancer induces the expression of metastatic proteins and thereby leads to LNM, CTSB may be a good and clinically relevant prognostic marker.
Tyrosine Phosphorylation of the Kv2.1 Channel Contributes to Injury in Brain Ischemia
Authors: Song Min-Young , Hwang Ji Yeon , Bae Eun Ji , Kim Saesbyeol , Kang Hye-Min , Kim Yong Jun , Park Chan , Park Kang-Sik
Published: December 2020

In brain ischemia, oxidative stress induces neuronal apoptosis, which is mediated by increased activity of the voltage-gated K+ channel Kv2.1 and results in an efflux of intracellular K+. The molecular mechanisms underlying the regulation of Kv2.1 and its activity during brain ischemia are not yet fully understood. Here this study provides evidence that oxidant-induced apoptosis resulting from brain ischemia promotes rapid tyrosine phosphorylation of Kv2.1. When the tyrosine phosphorylation sites Y124, Y686, and Y810 on the Kv2.1 channel are mutated to non-phosphorylatable residues, PARP-1 cleavage levels decrease, indicating suppression of neuronal cell death. The tyrosine residue Y810 on Kv2.1 was a major phosphorylation site. In fact, cells mutated Y810 were more viable in our study than were wild-type cells, suggesting an important role for this site during ischemic neuronal injury. In an animal model, tyrosine phosphorylation of Kv2.1 increased after ischemic brain injury, with an observable sustained increase for at least 2 h after reperfusion. These results demonstrate that tyrosine phosphorylation of the Kv2.1 channel in the brain may play a critical role in regulating neuronal ischemia and is therefore a potential therapeutic target in patients with brain ischemia.
A Plasma Proteomic Signature of Skeletal Muscle Mitochondrial Function
Authors: Zampino Marta , Tanaka Toshiko , Ubaida-Mohien Ceereena , Fantoni Giovanna , Candia Julián , Semba Richard D. , Ferrucci Luigi
Published: December 2020

Although mitochondrial dysfunction has been implicated in aging, physical function decline, and several age-related diseases, an accessible and affordable measure of mitochondrial health is still lacking. In this study we identified the proteomic signature of muscular mitochondrial oxidative capacity in plasma. In 165 adults, we analyzed the association between concentrations of plasma proteins, measured using the SOMAscan assay, and skeletal muscle maximal oxidative phosphorylation capacity assessed as post-exercise phosphocreatine recovery time constant (τPCr) by phosphorous magnetic resonance spectroscopy. Out of 1301 proteins analyzed, we identified 87 proteins significantly associated with τPCr, adjusting for age, sex, and phosphocreatine depletion. Sixty proteins were positively correlated with better oxidative capacity, while 27 proteins were correlated with poorer capacity. Specific clusters of plasma proteins were enriched in the following pathways: homeostasis of energy metabolism, proteostasis, response to oxidative stress, and inflammation. The generalizability of these findings would benefit from replication in an independent cohort and in longitudinal analyses.