bluuebunny/crossref_metadata_2025 huggingface dataset:
Hydrogeochemical Characterization and Identification of Factors Influencing Groundwater Quality in Coastal Aquifers, Case: La Yarada, Tacna, Peru
Authors: Chucuya Samuel , Vera Alissa , Pino-Vargas Edwin , Steenken André , Mahlknecht Jürgen , Montalván Isaac
Published: March 2022

The coastal aquifer La Yarada has anthropogenic and geogenic contamination that adversely affect the quality of groundwater for population and agricultural use. In this scenario, multivariate statistical methods were applied in 20 physicochemical and isotopic parameters of 53 groundwater pumping wells in October 2020, with the aim of characterizing the hydrogeochemical processes that dominate the groundwater of the coastal aquifer and the factors that cause them to optimize the effective management of water resources, delimiting areas affected by more than one salinization process. The samples were grouped into three clusters (C1, C2, and C3) with cluster analysis, the spatial distribution of C2 and C3 (reclassified in stiff diagrams), evidenced hydrogeochemical facies associated with the flow and recharge directions governed by the structural lineaments (NE-SO), favoring some areas more than others, arising different facies and hydrogeochemical processes. Factor analysis was applied from three different approaches: (1) main elements, (2) trace elements, and (3) physicochemical and isotopic parameters; exposing 6 distinguishable hydrogeochemical processes in the aquifer and factors that cause them: (i) salinization—marine intrusion, (ii) fertilizer leaching and dissolution of (Ca2+, Mg2+), (iii) wastewater mixture (NO3−), (iv) reducing conditions (Fe, Mn, Al), (v) contributions of (B, Sr), (vi) conservative mixtures and dissolution (As, F). It was validated with water quality indices (WQI) according to the national limits, delimiting 67 km2 parallel to the coast with “bad” to “very bad” quality for human consumption and unsuitable for irrigation according to the Wilcox diagram thus pre-treatment in this area is indispensable.
The Mediating Role of Resilience and Life Satisfaction in the Relationship between Stress and Burnout in Medical Students during the COVID-19 Pandemic
Authors: Duarte Ivone , Alves Ana , Coelho Ana , Ferreira Ana , Cabral Beatriz , Silva Bebiana , Peralta João , Silva Juliana , Domingues Pedro , Nunes Pedro , Serrão Carla , Santos Cristina
Published: March 2022

Following the WHO’s declaration of a public health emergency due to the COVID-19 outbreak, the subsequent quarantine and confinement measures that were adopted, including distance learning measures, were shown to have caused a significant deterioration in the mental health of medical students. The goal of this study was to explore the mediating role of resilience and life satisfaction in the relationship between perceived stress and burnout among medical students in the context of COVID-19. A transversal assessment was performed using an online questionnaire, to which 462 students responded. The instruments applied were the Perceived Stress Scale-10, the Resilience Scale-25 items, the Satisfaction with Life Scale (SWLS), and the Burnout Scale (Oldenburg Inventory). A regression model was estimated for each dimension of burnout. The results revealed that resilience and life satisfaction play a mediating role in the association between stress and the dimensions of burnout. This suggests that measures of promoting mental health based on resilience and improving perceptions of life should be implemented.
Myocardial Work Brings New Insights into Left Ventricular Remodelling in Cardio-Oncology Patients
Authors: Vaz Ferreira Vera , Mano Tania Branco , Cardoso Isabel , Coutinho Cruz Madalena , Moura Branco Luísa , Almeida-Morais Luís , Timóteo Ana , Galrinho Ana , Castelo Alexandra , Garcia Brás Pedro , Simão Diana , Sardinha Mariana , Gonçalves António , Cruz Ferreira Rui
Published: March 2022

Serial transthoracic echocardiographic (TTE) assessment of 2D left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) are the gold standard screening methods for cancer therapeutics-related cardiac dysfunction (CTRCD). Non-invasive left ventricular (LV) pressure-strain loop (PSL) provides a novel method of quantifying myocardial work (MW) with potential advantages to evaluate the impact of cardiotoxic treatments on heart function. We prospectively assessed breast cancer female patients undergoing cancer therapy through serial monitoring by 2D and 3D TTE. Patients were evaluated at T0, T1 and T2 (before, 4–6 and 12–14 months after starting therapy, respectively). Through PSL analysis, MW indices were calculated. A total of 122 patients, with a mean age of 54.7 years, who received treatment with anthracyclines (77.0%) and anti-HER2 (75.4%) were included. During a mean follow-up of 14.9 ± 9.3 months, LVEF and GLS were significantly diminished, and 29.5% developed CTRCD. All MW indices were significantly reduced at T1 compared with baseline and tended to return to baseline values at T2. Global work index and global work efficiency showed a more pronounced variation in patients with CTRCD. The presence of more than one cardiovascular risk factor, obesity and baseline left atrium volume were predictors of changes in MW parameters. In conclusion, breast cancer treatment was associated with LV systolic dysfunction as assessed by MW, with its peak at 4–6 months and a partial recovery afterwards. Assessment of myocardial deformation parameters allows a more detailed characterization of cardiac remodelling and could enhance patient screening and selection for cardioprotective therapeutics.
Differences in Body Mass Index Trajectories and Their Classification, Sociodemographic Characteristics, and Health Behaviors between People with and without Disabilities Using Korea Health Panel Survey Data
Authors: Song Yea-Li-A , Park Jae-Hyun
Published: March 2022

A high body mass index (BMI) is an important factor that negatively affects the health of people with disabilities. In particular, since the high BMI has a cumulative effect on the occurrence of complications such as cardiovascular disease, it is required to investigate the data through longitudinal studies rather than cross-sectional studies. Therefore, we conducted a longitudinal follow-up study to examine the differences in the BMI trajectories of people in South Korea with disabilities, as well as the sociodemographic characteristics and health behaviors that classify individual trajectories into clusters. Participants aged 40 to 79 years who responded to the Korea Health Panel Survey (KHPS) from 2009 to 2018, 283 people with physical disabilities or brain lesion disorders, and 849 people without disabilities, were extracted. We found that the differences in the initial BMI between clusters were larger in 60–79-year-old people with disabilities (men 22.5 kg/m2, 26.9 kg/m2; women 23.8 kg/m2, 28.1 kg/m2) than in those without disabilities (men 22.1 kg/m2, 23.3 kg/m2; women 24.8 kg/m2, 25.6 kg/m2). Also, logistic regression analysis showed that, among the people with disabilities, women (OR = 1.94), those who lived alone (OR = 2.36), and those who were economically inactive (OR = 1.78) were more likely to be classified into the higher BMI category than those who were not. To effectively manage the BMI, it would be better to focus on women with disabilities, people with disabilities living alone, and people who are economically inactive.
Youth Bullying and Suicide: Risk and Protective Factor Profiles for Bullies, Victims, Bully-Victims and the Uninvolved
Authors: Kwan Ching , Wong Clifford , Chen Zhansheng , Yip Paul S. F.
Published: March 2022

Bullying is closely associated with suicide. This study validates mixed evidence on whether young bullies, victims, bully-victims, and those uninvolved in bullying differ in suicidality, risk, protective factor profiles, and predictors of suicide. A total of 2004 Hong Kong adolescents and young adults completed the Hong Kong Online Survey on Youth Mental Health and Internet Usage in 2018. Bullies, victims, and bully victims, as opposed to the uninvolved, were found to possess higher tendencies of suicidal thoughts and behaviors. They had more distinct rather than overlapping risk and protective factor profiles yet shared psychological distress and diagnosis of a psychiatric disorder as common predictors of suicide. The results indicate that suicide screening assessments and training to detect common suicide predictors can benefit youngsters regardless of their bullying involvement. From the discussion, group-specific interventions include restorative justice approaches to promote reintegration and help-seeking among bullies, peer, and professional support programs geared towards lowering victim isolation and equipping gatekeepers such as teachers with skills to connect with both bullies and victims.
Toward an Anthropometric Pattern in Elite Male Handball
Authors: Leuciuc Florin Valentin , Petrariu Ileana , Pricop Gheorghe , Rohozneanu Dan Mihai , Popovici Ileana Monica
Published: March 2022

We investigated the anthropometric characteristics associated with specific handball skills in competition. The body anthropometric profiles differ significantly among the playing positions in handball due to the specific tasks. The aim of this study is to identify the anthropometric patterns for each playing position by collecting data from elite male handball players. To determine the anthropometric profile of the elite handball players for each playing position, we used descriptive statistics for every indicator in order to identify the optimal patterns for elite handball players from the top-four ranked teams at the most important competitions over a period of 18 years (2004–2021). Over time, the anthropometric indices evolved: the average height increased (from 190 to 192.6 cm) but less than weight increased (from 90.5 to 95.28 kg), and these affected the body mass index (increase from 25.2 to 25.67). The novelty of our study is that we identified an anthropometric pattern for each playing position and for all teams in elite male handball. Our study also covered a period of 18 years to give our results more accuracy and reliability.
I Trust You: Does This Matter in the Relationship between Sexual Harassment, Continuous Commitment and Intention to Leave among Young Female Healthcare Professionals?
Authors: Gharbi Hassane , Aliane Nadir , Sobaih Abu Elnasr E.
Published: March 2022

This research examines the direct influence of sexual harassment by superiors on subordinates’ young female trust in their superiors. The research also examines the mediating role of trust in the relationship between sexual harassment and continuous commitment as well as intention to leave. For this purpose, a pre-tested questionnaire survey was self-dropped and collected by the research team to young female professionals, who are in their early career (within five years of their career), in public hospitals in the cities of Tunis, Sfax and Sousse, Tunisia. The results were analyzed using SPSS and AMOS. The results of structural model, interestingly, showed no significant effect of sexual harassment by superiors on their subordinates’ trust. Hence, trust in superiors has no mediating role in the relationship between sexual harassment and continuous commitment as well as intention to leave. However, sexual harassment by superiors was found to directly and positively influence young female professionals’ intention to leave the job. Additionally, trust in superiors was found to negatively influence both young female professionals’ continuous commitment and their intention to leave. The results have certain theoretical and managerial implications, particularly in relation to young female professional in the healthcare sector, which is vital for Tunisia and every country.
The Association between ADHD and Environmental Chemicals—A Scoping Review
Authors: Moore Sonja , Paalanen Laura , Melymuk Lisa , Katsonouri Andromachi , Kolossa-Gehring Marike , Tolonen Hanna
Published: March 2022

The role of environmental chemicals in the etiology of attention deficit hyperactivity disorder (ADHD) has been of interest in recent research. This scoping review aims to summarize known or possible associations between ADHD and environmental exposures to substances selected as priority chemicals of the European Human Biomonitoring Initiative (HBM4EU). Literature searches were performed in PubMed to identify relevant publications. Only meta-analyses and review articles were included, as they provide more extensive evidence compared to individual studies. The collected evidence indicated that lead (Pb), phthalates and bisphenol A (BPA) are moderately to highly associated with ADHD. Limited evidence exists for an association between ADHD and polycyclic aromatic hydrocarbons (PAHs), flame retardants, mercury (Hg), and pesticides. The evidence of association between ADHD and cadmium (Cd) and per- and polyfluoroalkyl substances (PFASs) based on the identified reviews was low but justified further research. The methods of the individual studies included in the reviews and meta-analyses covered in the current paper varied considerably. Making precise conclusions in terms of the strength of evidence on association between certain chemicals and ADHD was not straightforward. More research is needed for stronger evidence of associations or the lack of an association between specific chemical exposures and ADHD.
PM2.5 Concentration Exposure over the Belt and Road Region from 2000 to 2020
Authors: Li Shenxin , Shafi Sedra , Zou Bin , Liu Jing , Xiong Ying , Muhammad Bilal
Published: March 2022

Ambient fine particulate matter (PM2.5) can cause respiratory and heart diseases, which have a great negative impact on human health. While, as a fast-developing region, the Belt and Road (B&R) has suffered serious air pollution, more detailed information has not been revealed. This study aims to investigate the evolutionary relationships between PM2.5 air pollution and its population-weighted exposure level (PWEL) over the B&R based on satellite-derived PM2.5 concentration and to identify the key regions for exposure control in the future. For this, the study focused on the B&R region, covering 51 countries, ranging from developed to least developed levels, extensively evaluated the different development levels of PM2.5 concentrations during 2000–2020 by spatial-temporal trend analysis and bivariate spatial correlation, then identified the key regions with high risk under different levels of Air Quality Guidelines (AQG). Results show that the overall PM2.5 and PWEL of PM2.5 concentration remained stable. Developing countries presented with the heaviest PM2.5 pollution and highest value of PWEL of PM2.5 concentration, while least developed countries presented with the fastest increase of both PM2.5 and PWEL of PM2.5 concentration. Areas with a high level and rapid increase PWEL of PM2.5 concentration were mainly located in the developing countries of India, Bangladesh, Nepal, and Pakistan, the developed country of Saudi Arabia, and least developed countries of Yemen and Myanmar. The key regions at high risk were mainly on the Indian Peninsula, Arabian Peninsula, coastal area of the Persian Gulf, northwestern China, and North China Plain. The findings of this research would be beneficial to identify the spatial distributions of PM2.5 concentration exposure and offer suggestions for formulating policies for the prevention and control PM2.5 air pollution at regional scale by the governments.
Effects of a Worksite-Based Self-Management Program in Traditional Retail Market Workers: Longitudinal Associations with Metabolic Parameters
Authors: Kim Yeon-Ha , Yoon Seong-Yong
Published: March 2022

(1) Background: This study explored the effects of a worksite-based self-management program on metabolic parameters in traditional retail market workers during a 3-year period. (2) Methods: Seventy traditional retail market workers who completed 3 years of follow-up were included in this study. The worksite-based self-management program was developed to help traditional retail market workers manage metabolic parameters themselves based on the following content: (I) using a metabolic syndrome action checklist, (II) counseling, (III) creating improvement action plans, and (IV) evaluating implemented improvements. (3) Results: The rates of implemented improvements showed success. Fasting blood sugar and triglycerides showed yearly reductions from baseline for 3 years, which eventually led to a decreased metabolic syndrome score and maintenance of metabolic parameters in the normal range for 3 years. (4) Conclusions: A worksite-based self-management program on metabolic parameters in traditional retail market workers was effective. It improved their intention to self-assess and cope their health problems and eventually decreased their metabolic syndrome score. It should be considered for the primary prevention of metabolic syndrome among traditional retail market workers.
The General Public’s Perceptions of How the COVID-19 Pandemic Has Impacted the Elderly and Individuals with Intellectual Disabilities
Authors: Dekker Maria R. , Frielink Noud , Hendriks Alexander H. C. , Embregts Petri J. C. M.
Published: March 2022

This study examined the general public’s perceptions of how the COVID-19 pandemic has impacted the elderly and people with intellectual disabilities as well how these perceptions relate to people’s level of familiarity and contact quality with these groups. A cross-sectional survey was administered to a sample of the Dutch population (n = 1458 and n = 1761, comprising questions related to the elderly and people with intellectual disabilities, respectively). The general public was found to be generally aware of the deleterious impact of the pandemic upon the elderly and people with intellectual disabilities. Specifically, the respondents reported that both groups’ quality of life, physical and mental health, and quality and frequency of social contact was lower than it was prior to COVID-19, in addition to perceiving them as lonelier and less self-reliant. Notably, the impact on the elderly was considered to be greater than that on people with intellectual disabilities. Furthermore, those who had no familiarity with people with intellectual disabilities in real life perceived the impact to be lower than those who had a greater degree of familiarity. These findings have important implications, both for increasing awareness of the pandemic’s negative impact on these vulnerable groups and in terms of sufficiently addressing their specific needs and concerns. The findings also underscore that, particularly during the COVID-19 pandemic, it is important to increase the visibility of groups who already relied more on help and support from others in society prior to the pandemic, such as the elderly and people with intellectual disabilities, via, among other things, self-advocacy, education, and enhanced intergroup contact, in order to be able to sufficiently address their needs during these challenging times.
Drug Lag and Associated Factors for Approved Drugs in Korea Compared with the United States
Authors: Cho Inhye , Han Euna
Published: March 2022

(1) Background: Drug lag, the delay between the first global regulatory approval and approval by the national health authorities in other countries, impacts the accessibility of drugs. Although the Korean pharmaceutical market has grown significantly, most of its innovative drugs for public health depend on imports from foreign pharmaceutical markets. (2) Methods: We extracted data from the official websites of the Korean Ministry of Food and Drug Safety (MFDS) and the US Food and Drug Administration. Information on new molecule entity drugs, approved as imported drugs by MFDS from 2000 to 2019, was extracted. Multivariate Cox proportional hazard models on drug approval were estimated. (3) Results: In total, 424 drugs were analyzed. Orphan drugs designated by MFDS were less likely to receive approval (HR = 0.731, 95% CI: 0.572–0.934). The drugs with Korean MAHs were less likely to obtain drug approval than those with MAHs of subsidiaries of multinational pharmaceutical companies (HR = 0.524, 95% CI: 0.371–0.738). In the analyses for non-orphan drugs (n = 37), oncology drugs that need local clinical study (HR = 0.247, 95% CI: 0.093–0.657) and drugs that need more patients in a local clinical study (HR = 0.993, 95% CI: 0.988–0.999) were less likely to receive approval, with longer drug lag. The higher number of clinical studies in Korea was associated with a shorter drug lag (HR = 2.133, 95% CI: 1.196–3.805). (4) Conclusions: Our findings imply that Korean pharmaceutical companies should augment their research capabilities for new drug development. Furthermore, consideration of orphan drugs used in rare diseases is needed for drug approval to ensure the availability of these drugs in the market without approval delays.
Screening Tests for Assessing Athletes at Risk of ACL Injury or Reinjury—A Scoping Review
Authors: Schweizer Noah , Strutzenberger Gerda , Franchi Martino V. , Farshad Mazda , Scherr Johannes , Spörri Jörg
Published: March 2022

Various tests are available to assess athletes for factors associated with their susceptibility and risk of anterior cruciate ligament (ACL) injury or reinjury; however, it is unclear which tests are clinically meaningful and what should be considered when using them. Therefore, the aim of this scoping review was to screen and summarize testing and to derive evidence-based recommendations for clinicians, practitioners and future research. Five databases were searched to identify studies addressing musculoskeletal morphology or functional-performance-related screening tests with a clear conceptual link or an evidence-based relationship to ACL (re)injury. A quality rating was carried out using the National Institutes of Health (NIH) Study-Quality Assessment Tool. Six different categories of common screening tests were identified: balance and postural control, gait- and running-related tests, joint laxity, joint morphology and anthropometrics, jump tests and strength tests. Predicting future injury in a complex, dynamic system based on a single screening test is methodologically challenging, which is also reflected in the highly controversial findings in the literature regarding potential associations between specific screening tests and the occurrence of ACL injuries and reinjuries. Nonetheless, various screening tests can provide clinically relevant information on ACL-(re)injury-related factors and help to provide tailored preventive measures. A selection of corresponding evidence-based recommendations is derived and presented in this scoping review.
Investigation of COVID-19 Vaccine Information Websites across Europe and Asia Using Automated Accessibility Protocols
Authors: Ara Jinat , Sik-Lanyi Cecilia
Published: March 2022

Websites content accessibility guidelines (WCAG) ensure that websites should be perceivable, understandable, navigable, and interactive. During the SARS-CoV-2 pandemic, the importance of accessible websites and online content grew throughout the world. Therefore, in this study, we examined COVID-19-related official government websites. This research covered 21 government websites, with 13 websites from European countries and 8 websites from Asian countries, to evaluate their accessibility following WCAG 2.0 and WCAG 2.1 guidelines. The overall goal of this study was to identify the frequent accessibility problems that might help the website owners to identify the shortcomings of their websites. The target websites were evaluated in two steps: in step-1, evaluation was performed through four automatic web accessibility testing tools such as Mauve++, Nibbler, WAVE, and WEB accessibility tools; in step-2, evaluation went through human observation, such as system usability testing and expert testing. The automatic evaluation results showed that few of the websites were accessible; a significant number of websites were not accessible for people with disabilities. In addition, system usability testing found some complexity in website organization, short explanations, and outdated information. The expert testing suggested improving the color of the websites, organization of links, buttons, and font size. This study might be helpful for associated authorities to improve the quality of the websites in the future.
Genetic Diversity of Antimicrobial Resistance and Key Virulence Features in Two Extensively Drug-Resistant Acinetobacter baumannii Isolates
Authors: Marazzato Massimiliano , Scribano Daniela , Sarshar Meysam , Brunetti Francesca , Fillo Silvia , Fortunato Antonella , Lista Florigio , Palamara Anna Teresa , Zagaglia Carlo , Ambrosi Cecilia
Published: March 2022

In recent decades, Acinetobacter baumannii emerged as a major infective menace in healthcare settings due to scarce therapeutic options to treat infections. Therefore, undertaking genome comparison analyses of multi-resistant A. baumannii strains could aid the identification of key bacterial determinants to develop innovative anti-virulence approaches. Following genome sequencing, we performed a molecular characterization of key genes and genomic comparison of two A. baumannii strains, #36 and #150, with selected reference genomes. Despite a different antibiotic resistance gene content, the analyzed strains showed a very similar antibiogram profile. Interestingly, the lack of some important virulence determinants (i.e., bap, ata and omp33–36) did not abrogate their adhesive abilities to abiotic and biotic surfaces, as reported before; indeed, strains retained these capacities, although to a different extent, suggesting the presence of distinct vicarious genes. Conversely, secretion systems, lipopolysaccharide (LPS), capsule and iron acquisition systems were highly similar to A. baumannii reference strains. Overall, our analyses increased our knowledge on A. baumannii genomic content and organization as well as the genomic events occurring in nosocomial isolates to better fit into changing healthcare environments.
Sleep Quality and Its Associations with Physical and Mental Health-Related Quality of Life among University Students: A Cross-Sectional Study
Authors: Carpi Matteo , Cianfarani Claudia , Vestri Annarita
Published: March 2022

The association between sleep problems and quality of life has been well documented and the COVID-19 pandemic seemingly had an impact on both sleep quality and health-related quality of life (HRQoL). However, recent evidence about this relationship among university students is limited. The aims of this study are to investigate the prevalence of poor sleep quality and insomnia and to explore the associations between these outcomes, perceived stress, and HRQoL among Italian university students. An anonymous questionnaire comprising the Pittsburgh Sleep Quality Index, the Insomnia Severity Index, the Short Form-12 health survey, and the Perceived Stress Scale was administered to a convenience sample of 1279 students (1119 females and 160 males, mean age: 23.4 ± 2.5 years) attending one of the largest Italian universities. A total of 65% of the participants showed poor sleep quality, whereas 55% reported insomnia symptoms. Students reporting poor sleep quality and insomnia obtained higher perceived stress scores and lower physical and mental HRQoL scores. Controlling for health-related variables and perceived stress, hierarchical regression analyses showed that sleep quality components added a significant contribution to the prediction of both physical (ΔR2 = 0.1) and mental (ΔR2 = 0.02) HRQoL. As a whole, these findings confirm the relevance of sleep for university students’ well-being and might inform the development of health promotion interventions for this population.
Cytokine and Chemokine Receptor Patterns of Human Malignant Melanoma Cell Lines
Authors: Koroknai Viktoria , Szász István , Jámbor Krisztina , Balázs Margit
Published: March 2022

Cytokine and chemokine receptors can promote tumor progression, invasion, and metastasis development by inducing different intracellular signaling pathways. The aim of this study was to determine the cytokine and chemokine receptor gene expression patterns in human melanoma cell lines. We found a large set of cytokine and chemokine receptor genes that were significantly differentially expressed between melanoma cell lines that originated from different subtypes of primary melanomas as well as cell lines that originated from melanoma metastases. The relative expressions of two receptor genes (CCR2 and TNFRSF11B) were positively correlated with the invasive potential of the cell lines, whereas a negative correlation was observed for the TNFRSF14 gene expression. We also found a small set of receptor genes that exhibited a significantly decreased expression in association with a BRAFV600E mutation. Based on our results, we assume that the analyzed cytokine and chemokine receptor collection may provide potential to distinguish the different subtypes of melanomas, helping us to understand the biological behavior of BRAFV600E-mutated melanoma cells.
Untargeted LC-MS/MS Metabolomics Study on the MCF-7 Cell Line in the Presence of Valproic Acid
Authors: Estrada-Pérez Alan Rubén , Rosales-Hernández Martha Cecilia , García-Vázquez Juan Benjamín , Bakalara Norbert , Fromager Benedicte , Correa-Basurto José
Published: March 2022

To target breast cancer (BC), epigenetic modulation could be a promising therapy strategy due to its role in the genesis, growth, and metastases of BC. Valproic acid (VPA) is a well-known histone deacetylase inhibitor (HDACi), which due to its epigenetic focus needs to be studied in depth to understand the effects it might elicit in BC cells. The aim of this work is to contribute to exploring the complete pharmacological mechanism of VPA in killing cancer cells using MCF-7. LC-MS/MS metabolomics studies were applied to MCF-7 treated with VPA. The results show that VPA promote cell death by altering metabolic pathways principally pentose phosphate pathway (PPP) and 2′deoxy-α-D-ribose-1-phosphate degradation related with metabolites that decrease cell proliferation and cell growth, interfere with energy sources and enhance reactive oxygen species (ROS) levels. We even suggest that mechanisms such as ferropoptosis could be involved due to deregulation of L-cysteine. These results suggest that VPA has different pharmacological mechanisms in killing cancer cells including apoptotic and nonapoptotic mechanisms, and due to the broad impact that HDACis have in cells, metabolomic approaches are a great source of information to generate new insights for this type of molecule.
Malnutrition and Dietary Habits Alter the Immune System Which May Consequently Influence SARS-CoV-2 Virulence: A Review
Authors: Foolchand Ashmika , Ghazi Terisha , Chuturgoon Anil A.
Published: March 2022

COVID-19, resulting from the SARS-CoV-2 virus, is a major pandemic that the world is fighting. SARS-CoV-2 primarily causes lung infection by attaching to the ACE2 receptor on the alveolar epithelial cells. However, the ACE2 receptor is also present in intestinal epithelial cells, suggesting a link between nutrition, virulence and clinical outcomes of COVID-19. Respiratory viral infections perturb the gut microbiota. The gut microbiota is shaped by our diet; therefore, a healthy gut is important for optimal metabolism, immunology and protection of the host. Malnutrition causes diverse changes in the immune system by repressing immune responses and enhancing viral vulnerability. Thus, improving gut health with a high-quality, nutrient-filled diet will improve immunity against infections and diseases. This review emphasizes the significance of dietary choices and its subsequent effects on the immune system, which may potentially impact SARS-CoV-2 vulnerability.
A Redox-Silent Analogue of Tocotrienol May Break the Homeostasis of Proteasomes in Human Malignant Mesothelioma Cells by Inhibiting STAT3 and NRF1
Authors: Ishii Kyota , Fusegi Momoka , Mori Tatsuki , Teshima Kosuke , Ninomiya Nanako , Kohno Kakeru , Sato Ayami , Ishida Tatsuya , Miyakoshi Yuichi , Yano Tomohiro
Published: March 2022

6-O-Carboxypropyl-alpha-tocotrienol (α-T3E) is a multi-target redox-silent analogue of tocotrienol that exhibits cytotoxicity against many cancer cells, including malignant mesothelioma (MM) cells. α-T3E has several molecular targets to effectively induce cytotoxicity against MM cells; however, the mechanisms underlying this cytotoxicity remain unclear. In the present study, we demonstrated that the α-T3E-dependent disruption of the homeostasis of proteasomes strongly induced endoplasmic reticulum (ER) stress, which resulted in effective cytotoxicity against MM cells. The α-T3E-dependent disruption of the homeostasis of proteasomes depended on decreases in proteasome subunits via the inactivation of signal transducer and activator of transcription 3 (STAT3) and nuclear factor erythroid 2 related factor-1 (NRF1), which inhibited protease activity, such as chymotrypsin-like activity, in proteasomes. The α-T3E-dependent inhibition of this activity also induced severe ER stress and ultimately resulted in effective cytotoxicity against MM cells with chemoresistance. The present results indicate that α-T3E acts as an effective anti-mesothelioma agent by disrupting the homeostasis of proteasomes through the simultaneous inactivation of STAT3 and NRF1.
DNA Hydroxymethylation in Smoking-Associated Cancers
Authors: Besaratinia Ahmad , Caceres Amanda , Tommasi Stella
Published: March 2022

5-hydroxymethylcytosine (5-hmC) was first detected in mammalian DNA five decades ago. However, it did not take center stage in the field of epigenetics until 2009, when ten-eleven translocation 1 (TET1) was found to oxidize 5-methylcytosine to 5-hmC, thus offering a long-awaited mechanism for active DNA demethylation. Since then, a remarkable body of research has implicated DNA hydroxymethylation in pluripotency, differentiation, neural system development, aging, and pathogenesis of numerous diseases, especially cancer. Here, we focus on DNA hydroxymethylation in smoking-associated carcinogenesis to highlight the diagnostic, therapeutic, and prognostic potentials of this epigenetic mark. We describe the significance of 5-hmC in DNA demethylation, the importance of substrates and cofactors in TET-mediated DNA hydroxymethylation, the regulation of TETs and related genes (isocitrate dehydrogenases, fumarate hydratase, and succinate dehydrogenase), the cell-type dependency and genomic distribution of 5-hmC, and the functional role of 5-hmC in the epigenetic regulation of transcription. We showcase examples of studies on three major smoking-associated cancers, including lung, bladder, and colorectal cancers, to summarize the current state of knowledge, outstanding questions, and future direction in the field.
Salidroside, 8(E)-Nuezhenide, and Ligustroside from Ligustrum japonicum Fructus Inhibit Expressions of MMP-2 and -9 in HT 1080 Fibrosarcoma
Authors: Kim Hojun , Kong Chang-Suk , Seo Youngwan
Published: March 2022

A phenyl ethanoid, salidroside (SAL), and two secoiridoids, 8(E)-nuezhenide (NZD) and ligustroside (LIG), were isolated from fruits of Ligustrumjaponicum, used as traditional folk medicine, and their chemical structures were elucidated by the comparison of spectral data with published literature. Matrix metalloproteinases (MMPs) are major enzymes that play crucial roles in the metastasis and invasive behavior of tumors. In particular, MMP-2 and MMP-9, regulated by the MAPK signaling pathways, including p38, ERK and JNK, are known to play a key role in the degradation of the basement membrane. In the present study, the effects of SAL, NZD and LIG on the expression of MMP-2 and -9 were examined in phorbol 12-myristate 13-acetate (PMA)-induced HT 1080 cells. All the compounds significantly lowered the amount of MMP-2 and MMP-9 released, as determined by gelatin zymography and ELISA. In addition, the mRNA and protein expression levels of MMP-2 and MMP-9 were significantly suppressed, as measured by RT-PCR and Western blotting. According to the Western blotting assay, SAL and LIG effectively reduced the expression of MMP-2 in a dose-dependent manner. NZD lowered the expression of MMP-9 in a similar way. The phosphorylation of p38, ERK and JNK was also significantly suppressed by these compounds. These findings suggest that all the compounds regulate the release and expression of MMP-2 and MMP-9 via MAPK signaling pathways.
Identification of Surface Antigens That Define Human Pluripotent Stem Cell-Derived PRRX1+Limb-Bud-like Mesenchymal Cells
Authors: Yamada Daisuke , Takao Tomoka , Nakamura Masahiro , Kitano Toki , Nakata Eiji , Takarada Takeshi
Published: March 2022

Stem cell-based therapies and experimental methods rely on efficient induction of human pluripotent stem cells (hPSCs). During limb development, the lateral plate mesoderm (LPM) produces limb-bud mesenchymal (LBM) cells that differentiate into osteochondroprogenitor cells and form cartilage tissues in the appendicular skeleton. Previously, we generated PRRX1-tdTomato reporter hPSCs to establish the protocol for inducing the hPSC-derived PRRX1+ LBM-like cells. However, surface antigens that assess the induction efficiency of hPSC-derived PRRX1+ LBM-like cells from LPM have not been identified. Here, we used PRRX1-tdTomato reporter hPSCs and found that high pluripotent cell density suppressed the expression of PRRX1 mRNA and tdTomato after LBM-like induction. RNA sequencing and flow cytometry suggested that PRRX1-tdTomato+ LBM-like cells are defined as CD44high CD140Bhigh CD49f−. Importantly, other hPSC lines, including four human induced pluripotent stem cell lines (414C2, 1383D2, HPS1042, HPS1043) and two human embryonic stem cell lines (SEES4, SEES7), showed the same results. Thus, an appropriate cell density of hPSCs before differentiation is a prerequisite for inducing the CD44high CD140Bhigh CD49f− PRRX1+ LBM-like cells.
COVID-19 Pandemic: Escape of Pathogenic Variants and MHC Evolution
Authors: Pontarotti Pierre , Paganini Julien
Published: March 2022

We propose a new hypothesis that explains the maintenance and evolution of MHC polymorphism. It is based on two phenomena: the constitution of the repertoire of naive T lymphocytes and the evolution of the pathogen and its impact on the immune memory of T lymphocytes. Concerning the latter, pathogen evolution will have a different impact on reinfection depending on the MHC allomorph. If a mutation occurs in a given region, in the case of MHC allotypes, which do not recognize the peptide in this region, the mutation will have no impact on the memory repertoire. In the case where the MHC allomorph binds to the ancestral peptides and not to the mutated peptide, that individual will have a higher chance of being reinfected. This difference in fitness will lead to a variation of the allele frequency in the next generation. Data from the SARS-CoV-2 pandemic already support a significant part of this hypothesis and following up on these data may enable it to be confirmed. This hypothesis could explain why some individuals after vaccination respond less well than others to variants and leads to predict the probability of reinfection after a first infection depending upon the variant and the HLA allomorph.
Prodrug-Based Targeting Approach for Inflammatory Bowel Diseases Therapy: Mechanistic Study of Phospholipid-Linker-Cyclosporine PLA2-Mediated Activation
Authors: Markovic Milica , Abramov-Harpaz Karina , Regev Clil , Ben-Shabat Shimon , Aponick Aaron , Zimmermann Ellen M. , Miller Yifat , Dahan Arik
Published: March 2022

Therapeutics with activity specifically at the inflamed sites throughout the gastrointestinal tract (GIT) would be a major advance in our therapeutic approach to inflammatory bowel disease (IBD). We aimed to develop the prodrug approach that can allow such site-specific drug delivery. Currently, using cyclosporine as a drug of choice in IBD is limited to the most severe cases due to substantial systemic toxicities and narrow therapeutic index of this drug. Previously, we synthesized a series of a phospholipid-linker-cyclosporine (PLC) prodrugs designed to exploit the overexpression of phospholipase A2 (PLA2) in the inflamed intestinal tissues, as the prodrug-activating enzyme. Nevertheless, the extent and rate of prodrug activation differed significantly. In this study we applied in-vitro and modern in-silico tools based on molecular dynamics (MD) simulation, to gain insight into the dynamics and mechanisms of the PLC prodrug activation. We aimed to elucidate the reason for the significant activation change between different linker lengths in our prodrug design. Our work reveals that the PLC conjugate with the 12-carbon linker length yields the optimal prodrug activation by PLA2 in comparison to shorter linker length (6-carbons). This optimized length efficiently allows cyclosporine to be released from the prodrug to the active pocket of PLA2. This newly developed mechanistic approach, presented in this study, can be applied for future prodrug optimization to accomplish optimal prodrug activation and drug targeting in various conditions that include overexpression of PLA2.
BdGUCD1 and Cyclic GMP Are Required for Responses of Brachypodium distachyon to Fusarium pseudograminearum in the Mechanism Involving Jasmonate
Authors: Duszyn Maria , Świeżawska-Boniecka Brygida , Skorupa Monika , Jaworski Krzysztof , Szmidt-Jaworska Adriana
Published: March 2022

Guanosine 3′,5′-cyclic monophosphate (cGMP) is an important signaling molecule in plants. cGMP and guanylyl cyclases (GCs), enzymes that catalyze the synthesis of cGMP from GTP, are involved in several physiological processes and responses to environmental factors, including pathogen infections. Using in vitro analysis, we demonstrated that recombinant BdGUCD1 is a protein with high guanylyl cyclase activity and lower adenylyl cyclase activity. In Brachypodium distachyon, infection by Fusarium pseudograminearum leads to changes in BdGUCD1 mRNA levels, as well as differences in endogenous cGMP levels. These observed changes may be related to alarm reactions induced by pathogen infection. As fluctuations in stress phytohormones after infection have been previously described, we performed experiments to determine the relationship between cyclic nucleotides and phytohormones. The results revealed that inhibition of cellular cGMP changes disrupts stress phytohormone content and responses to pathogen. The observations made here allow us to conclude that cGMP is an important element involved in the processes triggered as a result of infection and changes in its levels affect jasmonic acid. Therefore, stimuli-induced transient elevation of cGMP in plants may play beneficial roles in priming an optimized response, likely by triggering the mechanisms of feedback control.
Plant Secondary Metabolites as Defense Tools against Herbivores for Sustainable Crop Protection
Authors: Divekar Pratap Adinath , Narayana Srinivasa , Divekar Bhupendra Adinath , Kumar Rajeev , Gadratagi Basana Gowda , Ray Aishwarya , Singh Achuit Kumar , Rani Vijaya , Singh Vikas , Singh Akhilesh Kumar , Kumar Amit , Singh Rudra Pratap , Meena Radhe Shyam , Behera Tusar Kanti
Published: March 2022

Plants have evolved several adaptive strategies through physiological changes in response to herbivore attacks. Plant secondary metabolites (PSMs) are synthesized to provide defensive functions and regulate defense signaling pathways to safeguard plants against herbivores. Herbivore injury initiates complex reactions which ultimately lead to synthesis and accumulation of PSMs. The biosynthesis of these metabolites is regulated by the interplay of signaling molecules comprising phytohormones. Plant volatile metabolites are released upon herbivore attack and are capable of directly inducing or priming hormonal defense signaling pathways. Secondary metabolites enable plants to quickly detect herbivore attacks and respond in a timely way in a rapidly changing scenario of pest and environment. Several studies have suggested that the potential for adaptation and/or resistance by insect herbivores to secondary metabolites is limited. These metabolites cause direct toxicity to insect pests, stimulate antixenosis mechanisms in plants to insect herbivores, and, by recruiting herbivore natural enemies, indirectly protect the plants. Herbivores adapt to secondary metabolites by the up/down regulation of sensory genes, and sequestration or detoxification of toxic metabolites. PSMs modulate multi-trophic interactions involving host plants, herbivores, natural enemies and pollinators. Although the role of secondary metabolites in plant-pollinator interplay has been little explored, several reports suggest that both plants and pollinators are mutually benefited. Molecular insights into the regulatory proteins and genes involved in the biosynthesis of secondary metabolites will pave the way for the metabolic engineering of biosynthetic pathway intermediates for improving plant tolerance to herbivores. This review throws light on the role of PSMs in modulating multi-trophic interactions, contributing to the knowledge of plant-herbivore interactions to enable their management in an eco-friendly and sustainable manner.
Balancing Damage via Non-Photochemical Quenching, Phenolic Compounds and Photorespiration in Ulva prolifera Induced by Low-Dose and Short-Term UV-B Radiation
Authors: Zhong Yi , Xu Jinhui , Zhao Xinyu , Qu Tongfei , Guan Chen , Hou Chengzong , Tang Xuexi , Wang Ying
Published: March 2022

The Yellow Sea green tide (YSGT) is the world’s largest transregional macroalgal blooms, and the causative species Ulva prolifera (U. prolifera) suffers from ultraviolet-b radiation (UVBR) during the floating migration process. Previous study confirmed that U. prolifera displayed a wide variety of physiological responses characterized as acclimation to UVBR, while the response mechanisms against low-dose and short-term radiation (LDSTR) are not clear. A study with photosynthetically active radiation (PAR) and UVBR was designed: normal light (NL: 72 μmol photons m−2 s−1), NL+0.3 (UVBR: 0.3 W·m−2), and NL+1.6 (UVBR: 1.6 W·m−2). The results showed that high-dose UVBR inhibited photosynthesis in thalli, especially under long-term exposure, while a variety of physiological responses were observed under LDSTR. The inhibition of photosynthesis appeared to be ameliorated by the algae under LDSTR. Further analysis showed that U. prolifera achieved balancing damage by means of non-photochemical quenching (NPQ), accumulation of phenolic compounds coupled with the ASA-GSH cycle involved in the antioxidant process and enhanced photorespiratory metabolism under LDSTR. This study provides new insights into the balancing damage mechanisms of U. prolifera under LDSTR, enabling the thalli to adapt to the light conditions during the long duration and distance involved in floating migration.