bluuebunny/crossref_metadata_2025 huggingface dataset:
Google Trend Analysis and Paradigm Shift of Online Education Platforms during the COVID-19 Pandemic
Authors: Kansal Ashwani Kumar , Gautam Jyoti , Chintalapudi Nalini , Jain Shivani , Battineni Gopi
Published: May 2021

Objective: The largest pandemic in history, the COVID-19 pandemic, has been declared a doomsday globally. The second wave spreading worldwide has devastating consequences in every sector of life. Several measures to contain and curb its infection have forged significant challenges for the education community. With an estimated 1.6 billion learners, the closure of schools and other educational institutions has impacted more than 90% of students worldwide from the elementary to tertiary level. Methods: In a view to studying impacts on student’s fraternity, this article aims at addressing alternative ways of educating—more specifically, online education—through the analysis of Google trends for the past year. The study analyzed the platforms of online teaching and learning systems that have been enabling remote learning, thereby limiting the impact on the education system. Thorough text analysis is performed on an existing dataset from Kaggle to retrieve insight on the clustering of words that are more often looked at during this pandemic to find the general patterns of their occurrence. Findings: The results show that the coronavirus patients are the most trending patterns in word search clustering, with the education system being at the control and preventive measures to bring equilibrium in the system of education. There has been significant growth in online platforms in the last year. Existing assets of educational establishments have effectively converted conventional education into new-age online education with the help of virtual classes and other key online tools in this continually fluctuating scholastic setting. The effective usage of teaching tools such as Microsoft Teams, Zoom, Google Meet, and WebEx are the most used online platforms for the conduction of classes, and whiteboard software tools and learning apps such as Vedantu, Udemy, Byju’s, and Whitehat Junior have been big market players in the education system over the pandemic year, especially in India. Conclusions: The article helps to draw a holistic approach of ongoing online teaching-learning methods during the lockdown and also highlights changes that took place in the conventional education system amid the COVID pandemic to overcome the persisting disruption in academic activities and to ensure correct perception towards the online procedure as a normal course of action in the new educational system. To fill in the void of classroom learning and to minimize the virus spread over the last year, digital learning in various schools and colleges has been emphasized, leading to a significant increase in the usage of whiteboard software platforms.
A New Multiplatform Model for Outpatient Prenatal and Postpartum Care in a Cohort of COVID-19-Affected Obstetric Patients
Authors: Gutiérrez Mar Muñoz-Chápuli , Durán-Vila Ana , Ruiz-Labarta Javier , Payá-Martínez Pilar , Pintado Recarte Pilar , Bujan Julia , Ortega Miguel A. , De León-Luis Juan
Published: May 2021

Spain was one of the epicenters of the first wave of the COVID-19 pandemic. We describe in this article the design and results of a new telephone-and-telematic multiplatform model of systematic prenatal and postpartum follow-up for COVID-19-affected women implemented in a tertiary reference hospital in Madrid. We included patients with RT-PCR-confirmed COVID-19 during pregnancy or delivery from 10 March 2020 to 15 December 2020. We had a total of 211 obstetric patients: 148 (70.1%) were tested at the onset of suspicious clinical manifestations and 62 (29.4%) were tested in the context of routine screening. Of all the patients, 60 women (28.4%) were asymptomatic and 97 (46%) presented mild symptoms. Fifty-one women (24.2%) were admitted to our hospital for specific treatment because of moderate or severe symptoms. We had no missed cases and a good adherence. The mean number of calls per patient was 2.3. We performed 55 in-person visits. We analyzed the complexity of our program over time, showing a two-wave-like pattern. One patient was identified as needing hospitalization and we did not record major morbidity. Telemedicine programs are a strong and reproducible tool to reach to pregnant population affected by COVID-19, to assess its symptoms and severity, and to record for pregnancy-related symptoms both in an outpatient regime and after discharge from hospital.
Contribution of Solid Food to Achieve Individual Nutritional Requirement during a Continuous 438 km Mountain Ultramarathon in Female Athlete
Authors: Ishihara Kengo , Inamura Naho , Tani Asuka , Shima Daisuke , Kuramochi Ai , Nonaka Tsutomu , Oneda Hiroshi , Nakamura Yasuyuki
Published: May 2021

Background: Races and competitions over 100 miles have recently increased. Limited information exists about the effect of multiday continuous endurance exercise on blood glucose control and appropriate intake of food and drink in a female athlete. The present study aimed to examine the variation of blood glucose control and its relationship with nutritional intake and running performance in a professional female athlete during a 155.7 h ultramarathon race with little sleep. Methods: We divided the mountain course of 438 km into 33 segments by timing gates and continuously monitored the participant’s glucose profile throughout the ultramarathon. The running speed in each segment was standardized to the scheduled required time-based on three trial runs. Concurrently, the accompanying runners recorded the participant’s food and drink intake. Nutrient, energy, and water intake were then calculated. Results: Throughout the ultramarathon of 155.7 h, including 16.0 h of rest and sleep, diurnal variation had almost disappeared with the overall increase in blood glucose levels (25–30 mg/dL) compared with that during resting (p < 0.0001). Plasma total protein and triglyceride levels were decreased after the ultramarathon. The intake of protein and fat directly or indirectly contributed to maintaining blood glucose levels and running speed as substrates for gluconeogenesis or as alternative sources of energy when the carbohydrate intake was at a lower recommended limit. The higher amounts of nutrient intakes from solid foods correlated with a higher running pace compared with those from liquids and gels to supply carbohydrates, protein, and fat. Conclusion: Carbohydrate, protein, and fat intake from solid foods contributed to maintaining a fast pace with a steady, mild rise in blood glucose levels compared with liquids and gels when female runner completed a multiday continuous ultramarathon with little sleep.
Are Healthcare Workers at an Increased Risk for Obstructive Respiratory Diseases Due to Cleaning and Disinfection Agents? A Systematic Review and Meta-Analysis
Authors: Romero Starke Karla , Friedrich Sophie , Schubert Melanie , Kämpf Daniel , Girbig Maria , Pretzsch Anna , Nienhaus Albert , Seidler Andreas
Published: May 2021

Several reviews have reported an increased risk of obstructive respiratory diseases in workers exposed to cleaning or disinfection agents, but they have focused mainly on professional cleaners. Cleaning and disinfecting are frequently performed activities by healthcare workers. We conducted a systematic review with meta-analysis to quantify the risk of obstructive respiratory diseases in healthcare workers exposed to cleaning and disinfection agents. We searched the Medline and Embase databases until 4 February 2021 to find adequate primary studies. Two independent reviewers screened the titles/abstracts and the full texts of the studies, as well as performing data extraction and quality assessment. The literature search yielded 9432 records, and 8 studies were found through a hand search. After screening, 14 studies were included in the review. All had a high risk of bias, and most studies dealt with nurses, asthma, and hyperresponsiveness (BHR)-related symptoms. Only one study investigated COPD. The meta-analysis estimated an increased risk of new-onset asthma for nurses (Effect size (ES) = 1.67; 95% CI 1.11–2.50) compared with other occupations and found an increase in the risk of new-onset asthma for nurses exposed to cleaning and disinfecting surfaces (ES = 1.43; 95% CI 1.09–1.89) and instruments (ES = 1.34; 95% CI 1.09–1.65). Exposure to specific chemicals such as bleach and glutaraldehyde (GA) increased the risk of asthma in nurses (bleach ES = 2.44; 95% CI 1.56–3.82; GA ES = 1.91, 95% CI 1.35–2.70). A higher risk for BHR-related symptoms was observed for nurses exposed to cleaning surfaces (ES = 1.44; 95% CI 1.18–1.78). Although the overall evidence was rated as low, the limitations found in this review hint at a potential underestimation of the real risk. These findings highlight the need for reinforced prevention practices with regard to healthcare workers. Similar research investigating these associations among other healthcare workers such as rescue service and nursing home personnel is needed.
Rapid Review on COVID-19, Work-Related Aspects, and Age Differences
Authors: Bellotti Lara , Zaniboni Sara , Balducci Cristian , Grote Gudela
Published: May 2021

The COVID-19 pandemic significantly impacted the labor market and multiple aspects of work and workers’ life. The present rapid review analyzes this impact considering the effects that COVID-19 pandemic had on employment and work-related aspects across different age groups. A comprehensive literature search was performed on scientific contributions published between 2019 and March 2021, resulting in 36 papers pertinent to the scope of this review. Findings were grouped according to different topics, all linked to age: occupational risk, implications on the labor market (i.e., job loss and reemployment, job insecurity, turnover intentions and retirement, and healthcare workers’ return-to-work phase), remote work, and key individual and organizational resources and strategies. Overall, the review revealed variability across age groups in the impact this pandemic had on employment and several work-related aspects (i.e., occupational risk, remote work). Findings supported an age-differential effect of normative history-graded events such as the current pandemic, highlighting different responses and consequences depending on workers’ age.
Parental Nonstandard Work Schedules and Child Development: Evidence from Dual-Earner Families in Hong Kong
Authors: Kim Minseop
Published: May 2021

With the emergence of 24/7 economies, the practice of working nonstandard schedules has become increasingly common. This trend raises a concern about how parental nonstandard work schedules affect child development outcomes. Using data from dual-earner families with young children (age 5–6) in Hong Kong, this study examined the association between parental work schedules and child development. It also examined under what conditions parental nonstandard work schedules affect child development, with a focus on the moderating role of family income. Results showed that paternal nonstandard work schedules were negatively associated with overall child development. This association was particularly salient among low-income families. By contrast, maternal nonstandard work schedules were not associated with child development outcomes. These findings suggest that it is important to equip parents, in particular low-income fathers, to address challenges resulting from their nonstandard work schedules.
Associations between Parent–Child Communication on Sexual Health and Drug Use and Use of Drugs during Sex among Urban Black Youth
Authors: Boyd Donte T. , Opara Ijeoma , Quinn Camille R. , Waller Bernadine , Ramos S. Raquel , Duncan Dustin T.
Published: May 2021

Black youth and their families living in urban settings may experience unique stressors that contribute to underlying issues due to the environmental context. Such factors may exacerbate and promote drug use and engagement in risky sexual behaviors, unknowingly. Little is known about how family factors, peer pressure, condom use, and other related factors are associated with substance use and engaging in sexual behaviors while on drugs among urban African American youth aged 12–22 (N = 638). We used regression models to examine associations between parental bonding, parent–adolescent sexual health communication, condom use, peer pressure on substance use, and having sex while on drugs. Multivariate results indicated that parental bonding was statistically significant and associated with drug use (OR: 1.36, 95%CI: 1.36). Our study highlights that parental bonding plays a critical role in youth using drugs while living in urban environments.
Cannabis Policy Changes and Adolescent Cannabis Use: Evidence from Europe
Authors: Benedetti Elisa , Resce Giuliano , Brunori Paolo , Molinaro Sabrina
Published: May 2021

Cannabis accounts for the largest share of the illicit drug market, with a high prevalence of use even among adolescents. To tackle this longstanding problem, many kinds of reforms to national cannabis control policies have been implemented in Europe, but their effectiveness is still unclear. This paper analyses the association between selected categories of cannabis policy reforms and changes in perceived cannabis availability and patterns of use among adolescents. Data from 20 European countries across 15 years were drawn from a novel database of the European school Survey Project on Alcohol and other Drugs (ESPAD). Our analysis is based on a Difference-in-Differences design, which application is allowed by the fact that only thirteen out of the twenty countries included implemented policy changes. The results suggest that selected categories of reforms influence the availability and prevalence of cannabis use. In particular, some forms of restrictive intervention reduce the general prevalence of use and more liberal reforms seem linked to an increase in the share of students initiating use of cannabis. We find no evidence of an effect of policy changes on the share of frequent users, which are presumably those more likely to develop use-related health consequences.
Scaling up Action Schools! BC: How Does Voltage Drop at Scale Affect Student Level Outcomes? A Cluster Randomized Controlled Trial
Authors: Nettlefold Lindsay , Naylor Patti-Jean , Macdonald Heather M. , McKay Heather A.
Published: May 2021

Action Schools! BC (AS! BC) was scaled-up from an efficacy trial to province-wide delivery across 11 years (2004–2015). In this study we: (1) describe strategies that supported implementation and scale-up; (2) evaluate implementation (teachers’ physical activity (PA) delivery) and student’s PA and cardiorespiratory fitness (CRF) within a cluster randomized controlled trial during years 2 and 3 of scale-up; and (3) assess relationships between teacher-level implementation and student-level outcomes. We classified implementation strategies as process, capacity-building or scale-up strategies. Elementary schools (n = 30) were randomized to intervention (INT; 16 schools; 747 students) or usual practice (UP; 14 schools; 782 students). We measured teachers’ PA delivery (n = 179) using weekly logs; students’ PA by questionnaire (n = 30 schools) and accelerometry (n = 9 schools); and students’ CRF by 20-m shuttle run (n = 25 schools). INT teachers delivered more PA than UP teachers in year 1 (+33.8 min/week, 95% CI 12.7, 54.9) but not year 2 (+18.8 min/week, 95% CI −0.8, 38.3). Unadjusted change in CRF was 36% and 27% higher in INT girls and boys, respectively, compared with their UP peers (year 1; effect size 0.28–0.48). Total PA delivered was associated with change in children’s self-reported MVPA (year 1; r = 0.17, p = 0.02). Despite the ‘voltage drop’, scaling-up school-based PA models is feasible and may enhance children’s health. Stakeholders must conceive of new ways to effectively sustain scaled-up health promoting interventions if we are to improve the health of students at a population level. Clinical Trials registration: NCT01412203.
Pupils’ Motivational and Emotional Responses to Pedagogies of Affect in Physical Education in Scottish Secondary Schools
Authors: Lamb Cara A. , Teraoka Eishin , Oliver Kimberly L. , Kirk David
Published: May 2021

This paper reports on the findings of two studies concerned with pupils’ motivational and emotional responses to pedagogies of affect in physical education in Scottish secondary schools. Pedagogies of affect explicitly focus on learning in the affective domain, or what is known in Scotland’s Curriculum for Excellence (CfE) as ‘personal qualities’. Personal qualities include motivation, confidence and self-esteem, determination and resilience, responsibility and leadership, respect and tolerance, and communication. In one study, led by Teraoka, the researchers explored the ways in which pupils responded, through focus group interviews based on Self-Determination Theory, to teachers who claimed to value and be committed to teaching explicitly for affective learning outcomes. In another study, led by Lamb, the researchers investigated the impact of an activist intervention on girls’ experiences of physical education, through their conversations in focus group discussions. Both studies reveal that pupils responded favorably, both in motivation and emotion, to pedagogies of affect in physical education, and that these responses offer a promising basis for future developments.
Reliability, Validity, and Feasibility of the Frail-VIG Index
Authors: Torné Anna , Puigoriol Emma , Zabaleta-del-Olmo Edurne , Zamora-Sánchez Juan-José , Santaeugènia Sebastià , Amblàs-Novellas Jordi
Published: May 2021

The study aimed to assess the reliability of the scores, evidence of validity, and feasibility of the Frail-VIG index. A validation study mixing hospitalized and community-dwelling older people was designed. Intraclass correlation coefficient (ICC) was used to assess the inter-rater agreement and the reliability. The construct validity of the Frail-VIG index with respect to the Frailty Phenotype (FP) was evaluated by calculating the area under the receiver operating characteristic curve (AUC-ROC). Convergent validity with the Clinical Frailty Scale (CFS) was assessed using Pearson’s correlation coefficients. The feasibility was evaluated by calculating the average time required to administer the Frail-VIG index and the percentage of unanswered responses. A sample of 527 older people (mean age of 81.61, 56.2% female) was included. The inter-rater agreement and test–retest reliability were very strong: 0.941 (95% CI, 0.890 to 0.969) and 0.976 (95% CI, 0.958 to 0.986), respectively. Results indicated adequate convergent validity of the Frail-VIG index with respect to the FP, AUC-ROC 0.704 (95% CI, 0.622 to 0.786), and a moderate to strong positive correlation between the Frail-VIG index and CFS (r = 0.635, 95% CI, 0.54 to 0.71). The Frail-VIG index administration required an average of 5.01 min, with only 0.34% of unanswered responses. The Frail-VIG index is a reliable, feasible, and valid instrument to assess the degree of frailty in hospitalized and community-dwelling older people.
Reasons for Low Protection of Vulnerable Workers from COVID-19—Results from the Quantitative and Qualitative Study on Working Life in Latvia
Authors: Matisāne Linda , Paegle Linda , Eglīte Maija , Akūlova Lāsma , Linde Asnate Anna , Vanadziņš Ivars , Mietule Iveta , Lonska Jeļena , Litavniece Lienīte , Arbidāne Iluta , Rozentāle Sarmīte , Grīntāle Ieva
Published: May 2021

Several individual factors like older age and chronic diseases have been linked with more severe symptoms often leading to hospitalization and higher mortality from COVID-19. Part of adults with such factors is still active in the workforce. The objective of the study was to identify measures taken by the employer to protect them and to investigate reasons for low protection of vulnerable workers during the 1st wave of the COVID-19 pandemic. Answers from 1000 workers collected via web-survey and results from 10 focus group discussions were analyzed. Only 31.5% of respondents mentioned that their employer had identified existing vulnerable groups and offered specific measures to protect them. Moving vulnerable workers away from the workplace was the most frequent measure (e.g., transfer to the back-office without contact with clients, telework, paid vacations, paid downtime). Most employers do not see elderly workers and workers with chronic diseases as risk groups, thus are not specifically protecting them. Instead, several employers have included workers critical for business continuity in their risk group. Others had not taken measures because of the lack of information due to general data protection regulation. Poor communication and lack of interest of employers to ask their workers if they need special protection is the topic to be addressed at the national level.
Physical Activity and the Quality of Life of Female Students of Universities in Poland
Authors: Kotarska Katarzyna , Paczyńska-Jędrycka Małgorzata , Sygit Katarzyna , Kmieć Kamila , Czerw Aleksandra , Nowak Maria Alicja
Published: May 2021

Physical activity increases human health potential and has an impact on achieving a higher quality of life in society. The aim of our research was to determine the relationship between a physically active lifestyle and the quality of life of female students in the context of demographic and social factors (major, age, marital status, professional activity). The research was conducted among a group of 285 women studying physical culture and social sciences in Poznań and Szczecin (Poland). Average age: 22.7 ± 4.90. The standardized World Health Organization Quality of Life—BREF (WHQOL-BREF) questionnaire was used to assess the quality of life of female students, and the original survey technique was used to study the lifestyle of people undertaking physical activity in the context of socio-demographic factors. Nonparametric statistics were applied in the analyses of the results. The effect size was calculated for each test: E2R for the Kruskal–Wallis H test, Glass rank biserial correlation (rg) for the Mann–Whitney U test, and Cramér′s V for the χ2 test. The value of p ≤0.05 was assumed to be a significant difference. In the study, it was shown that a higher overall quality of life and health satisfaction, as well as better results in the physical, psychological, and environmental domains, were achieved by female students who assessed their lifestyle as physically active in comparison to those physically inactive. Higher scores of overall quality of life and satisfaction with health were found among female students of physical education and people participating in physical recreation, who also achieved better results in the environmental domain. Female students aged 23–25 had a higher quality of life in the physical, psychological, and social domains. Having a partner or spouse had a positive effect on the quality of life of female students defined by the social domain. A higher overall quality of life and satisfaction with health were characteristic of people who were employed. In the search of factors positively influencing the quality of life of society, it seems necessary to promote a physically active lifestyle among students. The observed differences in the quality of life and health satisfaction of female students of selected majors require targeted programs and interventions that improve the quality of their lives at various stages of their studies. Such activities increase the health potential of the individual and society, not only in the biological, but also psychosocial dimension.
Measuring and Quantifying Impacts of Environmental Parameters on Airborne Particulate Matter in Under-Viaducts Spaces in Wuhan, China
Authors: Yin Lihua , Hang Tian , Qin Fanfan , Lin Xueting , Han Yiwen
Published: May 2021

Particulate pollution caused by urban traffic emissions has become a significant public hazard. Many urban roads of under-viaduct spaces (UVSs) have become concentrated areas of particulate pollution. This study aims to explore the effects of landscape parameters on particulate matter in UVSs in Wuhan, China. We selected 14 types of UVS sections and nine potential environmental parameters to monitor four types of particulate matter (PM1.0, PM2.5, PM10, and TSP). Finally, linear regression analysis was employed to quantify the relative contributions of environmental parameters to the reduction in the concentration of the four types of particulate matter in the summer and winter. The results showed that particulate matter concentrations exhibit spatial and seasonal differences in UVSs. A single landscape parameter was correlated with particulate matter concentration, while compound environmental parameters had significant effects on the particulate matter concentration in UVSs. Meteorological factors and greening structures had a dominant impact on the particulate matter concentrations in summer and winter, respectively. Therefore, adjusting and optimizing the environmental parameters could reduce particulate pollution in UVSs and could have practical significance for the planning and design of UVSs.
Cascaded Attention DenseUNet (CADUNet) for Road Extraction from Very-High-Resolution Images
Authors: Li Jing , Liu Yong , Zhang Yindan , Zhang Yang
Published: May 2021

The use of very-high-resolution images to extract urban, suburban and rural roads has important application value. However, it is still a problem to effectively extract the road area occluded by roadside tree canopy or high-rise buildings to maintain the integrity of the extracted road area, the smoothness of the sideline and the connectivity of the road network. This paper proposes an innovative Cascaded Attention DenseUNet (CADUNet) semantic segmentation model by embedding two attention modules, such as global attention and core attention modules, in the DenseUNet framework. First, a set of cascaded global attention modules are introduced to obtain the contextual information of the road; secondly, a set of cascaded core attention modules are embedded to ensure that the road information is transmitted to the greatest extent among the dense blocks in the network, and further assist the global attention module in acquiring multi-scale road information, thereby improving the connectivity of the road network while restoring the integrity of the road area shaded by the tree canopy and high-rise buildings. Based on binary cross entropy, an adaptive loss function is proposed for network parameter tuning. Experiments on the Massachusetts road dataset and the DeepGlobe-CVPR 2018 road dataset show that this semantic segmentation model can effectively extract the road area shaded by tree canopy and improve the connectivity of the road network.
Correction: Hu et al. Profiles of Long Non-Coding RNAs and mRNA Expression in Human Macrophages Regulated by Interleukin-27. Int. J. Mol. Sci. 2019, 20, 6207
Authors: Hu Xiaojun , Goswami Suranjana , Qiu Ju , Chen Qian , Laverdure Sylvain , Sherman Brad T. , Imamichi Tomozumi
Published: May 2021

The authors wish to make the following corrections to this paper [...]
Pathophysiological Association of Endothelial Dysfunction with Fatal Outcome in COVID-19
Authors: Maruhashi Tatsuya , Higashi Yukihito
Published: May 2021

The outbreak of coronavirus disease 2019 (COVID-19) caused by the betacoronavirus SARS-CoV-2 is now a worldwide challenge for healthcare systems. Although the leading cause of mortality in patients with COVID-19 is hypoxic respiratory failure due to viral pneumonia and acute respiratory distress syndrome, accumulating evidence has shown that the risk of thromboembolism is substantially high in patients with severe COVID-19 and that a thromboembolic event is another major complication contributing to the high morbidity and mortality in patients with COVID-19. Endothelial dysfunction is emerging as one of the main contributors to the pathogenesis of thromboembolic events in COVID-19. Endothelial dysfunction is usually referred to as reduced nitric oxide bioavailability. However, failures of the endothelium to control coagulation, inflammation, or permeability are also instances of endothelial dysfunction. Recent studies have indicated the possibility that SARS-CoV-2 can directly infect endothelial cells via the angiotensin-converting enzyme 2 pathway and that endothelial dysfunction caused by direct virus infection of endothelial cells may contribute to thrombotic complications and severe disease outcomes in patients with COVID-19. In this review, we summarize the current understanding of relationships between SARS-CoV-2 infection, endothelial dysfunction, and pulmonary and extrapulmonary complications in patients with COVID-19.
CLCA1 Regulates Airway Mucus Production and Ion Secretion Through TMEM16A
Authors: Centeio Raquel , Ousingsawat Jiraporn , Schreiber Rainer , Kunzelmann Karl
Published: May 2021

TMEM16A, a Ca2+-activated chloride channel (CaCC), and its regulator, CLCA1, are associated with inflammatory airway disease and goblet cell metaplasia. CLCA1 is a secreted protein with protease activity that was demonstrated to enhance membrane expression of TMEM16A. Expression of CLCA1 is particularly enhanced in goblet cell metaplasia and is associated with various lung diseases. However, mice lacking expression of CLCA1 showed the same degree of mucous cell metaplasia and airway hyperreactivity as asthmatic wild-type mice. To gain more insight into the role of CLCA1, we applied secreted N-CLCA1, produced in vitro, to mice in vivo using intratracheal instillation. We observed no obvious upregulation of TMEM16A membrane expression by CLCA1 and no differences in ATP-induced short circuit currents (Iscs). However, intraluminal mucus accumulation was observed by treatment with N-CLCA1 that was not seen in control animals. The effects of N-CLCA1 were augmented in ovalbumin-sensitized mice. Mucus production induced by N-CLCA1 in polarized BCi-NS1 human airway epithelial cells was dependent on TMEM16A expression. IL-13 upregulated expression of CLCA1 and enhanced mucus production, however, without enhancing purinergic activation of Isc. In contrast to polarized airway epithelial cells and mouse airways, which express very low levels of TMEM16A, nonpolarized airway cells express large amounts of TMEM16A protein and show strong CaCC. The present data show an only limited contribution of TMEM16A to airway ion secretion but suggest a significant role of both CLCA1 and TMEM16A for airway mucus secretion.
The Protective Effects of EMF-LTE against DNA Double-Strand Break Damage In Vitro and In Vivo
Authors: Jin Hee , Kim Kyuri , Park Ga-Young , Kim Minjeong , Lee Hae-June , Jeon Sangbong , Kim Ju Hwan , Kim Hak Rim , Lim Kyung-Min , Lee Yun-Sil
Published: May 2021

With the rapid growth of the wireless communication industry, humans are extensively exposed to electromagnetic fields (EMF) comprised of radiofrequency (RF). The skin is considered the primary target of EMFs given its outermost location. Recent evidence suggests that extremely low frequency (ELF)-EMF can improve the efficacy of DNA repair in human cell-lines. However, the effects of EMF-RF on DNA damage remain unknown. Here, we investigated the impact of EMF-long term evolution (LTE, 1.762 GHz, 8 W/kg) irradiation on DNA double-strand break (DSB) using the murine melanoma cell line B16 and the human keratinocyte cell line HaCaT. EMF-LTE exposure alone did not affect cell viability or induce apoptosis or necrosis. In addition, DNA DSB damage, as determined by the neutral comet assay, was not induced by EMF-LTE irradiation. Of note, EMF-LTE exposure can attenuate the DNA DSB damage induced by physical and chemical DNA damaging agents (such as ionizing radiation (IR, 10 Gy) in HaCaT and B16 cells and bleomycin (BLM, 3 μM) in HaCaT cells and a human melanoma cell line MNT-1), suggesting that EMF-LTE promotes the repair of DNA DSB damage. The protective effect of EMF-LTE against DNA damage was further confirmed by attenuation of the DNA damage marker γ-H2AX after exposure to EMF-LTE in HaCaT and B16 cells. Most importantly, irradiation of EMF-LTE (1.76 GHz, 6 W/kg, 8 h/day) on mice in vivo for 4 weeks reduced the γ-H2AX level in the skin tissue, further supporting the protective effects of EMF-LTE against DNA DSB damage. Furthermore, p53, the master tumor-suppressor gene, was commonly upregulated by EMF-LTE irradiation in B16 and HaCaT cells. This finding suggests that p53 plays a role in the protective effect of EMF-LTE against DNA DSBs. Collectively, these results demonstrated that EMF-LTE might have a protective effect against DNA DSB damage in the skin, although further studies are necessary to understand its impact on human health.
Fibrinolysis in Platelet Thrombi
Authors: Kanji Rahim , Gue Ying X. , Memtsas Vassilios , Gorog Diana A.
Published: May 2021

The extent and duration of occlusive thrombus formation following an arterial atherothrombotic plaque disruption may be determined by the effectiveness of endogenous fibrinolysis. The determinants of endogenous fibrinolysis are the subject of much research, and it is now broadly accepted that clot composition as well as the environment in which the thrombus was formed play a significant role. Thrombi with a high platelet content demonstrate significant resistance to fibrinolysis, and this may be attributable to an augmented ability for thrombin generation and the release of fibrinolysis inhibitors, resulting in a fibrin-dense, stable thrombus. Additional platelet activators may augment thrombin generation further, and in the case of coronary stenosis, high shear has been shown to strengthen the attachment of the thrombus to the vessel wall. Neutrophil extracellular traps contribute to fibrinolysis resistance. Additionally, platelet-mediated clot retraction, release of Factor XIII and resultant crosslinking with fibrinolysis inhibitors impart structural stability to the thrombus against dislodgment by flow. Further work is needed in this rapidly evolving field, and efforts to mimic the pathophysiological environment in vitro are essential to further elucidate the mechanism of fibrinolysis resistance and in providing models to assess the effects of pharmacotherapy.
Energy-Dependent Endocytosis Is Responsible for Skin Penetration of Formulations Based on a Combination of Indomethacin Nanoparticles and l-Menthol in Rat and Göttingen Minipig
Authors: Otake Hiroko , Yamaguchi Mizuki , Ogata Fumihiko , Deguchi Saori , Yamamoto Naoki , Sasaki Hiroshi , Kawasaki Naohito , Nagai Noriaki
Published: May 2021

We previously designed a Carbopol gel formulation (N-IND/MEN) based on a combination of indomethacin solid nanoparticles (IND-NPs) and l-menthol, and we reported that the N-IND/MEN showed high transdermal penetration. However, the detailed mechanism for transdermal penetration of IND-NPs was not clearly defined. In this study, we investigated whether endocytosis in the skin tissue of rat and Göttingen minipig is related to the transdermal penetration of IND-NPs using pharmacological inhibitors of endocytosis. The pharmacological inhibitors used in this study are as follows: 54 µM nystatin, a caveolae-mediated endocytosis (CavME) inhibitor; 40 µM dynasore, a clathrin-mediated endocytosis (CME) inhibitor; and 2 µM rottlerin, a micropinocytosis (MP) inhibitor. The N-IND/MEN was prepared by a bead mill method, and the particle size of solid indomethacin was 79–216 nm. In both rat and Göttingen minipig skin, skin penetration of approximately 80% IND-NPs was limited by the stratum corneum (SC), although the penetration of SC was improved by the combination of l-menthol. On the other hand, the treatment of nystatin and dynasore decreased the transdermal penetration of indomethacin in rats and Göttingen minipigs treated with N-IND/MEN. Moreover, in addition to nystatin and dynasore, rottlerin attenuated the transdermal penetration of IND-NPs in the Göttingen minipigs’ skin. In conclusion, we found that l-menthol enhanced the SC penetration of IND-NPs. In addition, this study suggests that the SC-passed IND-NPs are absorbed into the skin tissue by energy-dependent endocytosis (CavME, CME, and/or MP pathways) on the epidermis under the SC, resulting in an enhancement in transdermal penetration of IND-NPs. These findings provide significant information for the design of nanomedicines in transdermal formulations.
Nanoscale Surface Topography Modulates hIAPP Aggregation Pathways at Solid–Liquid Interfaces
Authors: Hanke Marcel , Yang Yu , Ji Yuxin , Grundmeier Guido , Keller Adrian
Published: May 2021

The effects that solid–liquid interfaces exert on the aggregation of proteins and peptides are of high relevance for various fields of basic and applied research, ranging from molecular biology and biomedicine to nanotechnology. While the influence of surface chemistry has received a lot of attention in this context, the role of surface topography has mostly been neglected so far. In this work, therefore, we investigate the aggregation of the type 2 diabetes-associated peptide hormone hIAPP in contact with flat and nanopatterned silicon oxide surfaces. The nanopatterned surfaces are produced by ion beam irradiation, resulting in well-defined anisotropic ripple patterns with heights and periodicities of about 1.5 and 30 nm, respectively. Using time-lapse atomic force microscopy, the morphology of the hIAPP aggregates is characterized quantitatively. Aggregation results in both amorphous aggregates and amyloid fibrils, with the presence of the nanopatterns leading to retarded fibrillization and stronger amorphous aggregation. This is attributed to structural differences in the amorphous aggregates formed at the nanopatterned surface, which result in a lower propensity for nucleating amyloid fibrillization. Our results demonstrate that nanoscale surface topography may modulate peptide and protein aggregation pathways in complex and intricate ways.
Glycosylation in Axonal Guidance
Authors: Mutalik Sampada P. , Gupton Stephanie L.
Published: May 2021

How millions of axons navigate accurately toward synaptic targets during development is a long-standing question. Over decades, multiple studies have enriched our understanding of axonal pathfinding with discoveries of guidance molecules and morphogens, their receptors, and downstream signalling mechanisms. Interestingly, classification of attractive and repulsive cues can be fluid, as single guidance cues can act as both. Similarly, guidance cues can be secreted, chemotactic cues or anchored, adhesive cues. How a limited set of guidance cues generate the diversity of axonal guidance responses is not completely understood. Differential expression and surface localization of receptors, as well as crosstalk and spatiotemporal patterning of guidance cues, are extensively studied mechanisms that diversify axon guidance pathways. Posttranslational modification is a common, yet understudied mechanism of diversifying protein functions. Many proteins in axonal guidance pathways are glycoproteins and how glycosylation modulates their function to regulate axonal motility and guidance is an emerging field. In this review, we discuss major classes of glycosylation and their functions in axonal pathfinding. The glycosylation of guidance cues and guidance receptors and their functional implications in axonal outgrowth and pathfinding are discussed. New insights into current challenges and future perspectives of glycosylation pathways in neuronal development are discussed.
Pseudoephedrine—Benefits and Risks
Authors: Głowacka Krystyna , Wiela-Hojeńska Anna
Published: May 2021

Pseudoephedrine (PSE) is a drug with a long history of medical use; it is helpful in treating symptoms of the common cold and flu, sinusitis, asthma, and bronchitis. Due to its central nervous system (CNS) stimulant properties and structural similarity to amphetamine, it is also used for non-medical purposes. The substance is taken as an appetite reducer, an agent which eliminates drowsiness and fatigue, to improve concentration and as a doping agent. Due to its easier availability, it is sometimes used as a substitute for amphetamine or methamphetamine. Pseudoephedrine is also a substrate (precursor) used in the production of these drugs. Time will tell whether legal restrictions on the sale of this drug will reduce the scale of the problem associated with its misuse.
A Fructan Exohydrolase from Maize Degrades Both Inulin and Levan and Co-Exists with 1-Kestotriose in Maize
Authors: Wu Silin , Greiner Steffen , Ma Chongjian , Zhong Jiaxin , Huang Xiaojia , Rausch Thomas , Zhao Hongbo
Published: May 2021

Enzymes with fructan exohydrolase (FEH) activity are present not only in fructan-synthesizing species but also in non-fructan plants. This has led to speculation about their functions in non-fructan species. Here, a cell wall invertase-related Zm-6&1-FEH2 with no “classical” invertase motif was identified in maize. Following heterologous expression in Pichia pastoris and in Nicotiana benthamiana leaves, the enzyme activity of recombinant Zm-6&1-FEH2 displays substrate specificity with respect to inulin and levan. Subcellular localization showed Zm-6&1-FEH2 exclusively localized in the apoplast, and its expression profile was strongly dependent on plant development and in response to drought and abscisic acid. Furthermore, formation of 1-kestotriose, an oligofructan, was detected in vivo and in vitro and could be hydrolyzed by Zm-6&1-FEH2. In summary, these results support that Zm-6&1-FEH2 enzyme from maize can degrade both inulin-type and levan-type fructans, and the implications of the co-existence of Zm-6&1-FEH2 and 1-kestotriose are discussed.
Dysregulation of miR-15a-5p, miR-497a-5p and miR-511-5p Is Associated with Modulation of BDNF and FKBP5 in Brain Areas of PTSD-Related Susceptible and Resilient Mice
Authors: Maurel Oriana Maria , Torrisi Sebastiano Alfio , Barbagallo Cristina , Purrello Michele , Salomone Salvatore , Drago Filippo , Ragusa Marco , Leggio Gian Marco
Published: May 2021

Post-traumatic stress disorder (PTSD) is a neuropsychiatric disorder occurring in susceptible individuals following a traumatic event. Understanding the mechanisms subserving trauma susceptibility/resilience is essential to develop new effective treatments. Increasing evidence suggests that non-coding RNAs, such as microRNAs (miRNAs), may play a prominent role in mediating trauma susceptibility/resilience. In this study, we evaluated the transcriptional expression of two key PTSD-related genes (FKBP5 and BDNF) and the relative targeting miRNAs (miR-15a-5p, miR-497a-5p, miR-511-5p, let-7d-5p) in brain areas of PTSD-related susceptible and resilient mice identified through our recently developed mouse model of PTSD (arousal-based individual screening (AIS) model). We observed lower transcript levels of miR-15a-5p, miR-497a-5p, and miR-511a-5p in the hippocampus and hypothalamus of susceptible mice compared to resilient mice, suggesting that the expression of these miRNAs could discriminate the two different phenotypes of stress-exposed mice. These miRNA variations could contribute, individually or synergically, to the inversely correlated transcript levels of FKBP5 and BDNF. Conversely, in the medial prefrontal cortex, downregulation of miR-15a-5p, miR-511-5p, and let-7d-5p was observed both in susceptible and resilient mice, and not accompanied by changes in their mRNA targets. Furthermore, miRNA expression in the different brain areas correlated to stress-induced behavioral scores (arousal score, avoidance-like score, social memory score and PTSD-like score), suggesting a linear connection between miRNA-based epigenetic modulation and stress-induced phenotypes. Pathway analysis of a miRNA network showed a statistically significant enrichment of molecular processes related to PTSD and stress. In conclusion, our results indicate that PTSD susceptibility/resilience might be shaped by brain-area-dependent modulation of miRNAs targeting FKBP5, BDNF, and other stress-related genes.
Multi-Omics Perspective Reveals the Different Patterns of Tumor Immune Microenvironment Based on Programmed Death Ligand 1 (PD-L1) Expression and Predictor of Responses to Immune Checkpoint Blockade across Pan-Cancer
Authors: Huang Kaitang , Hu Meiling , Chen Jiayun , Wei Jinfen , Qin Jingxin , Lin Shudai , Du Hongli
Published: May 2021

Immune checkpoint inhibitor (ICI) therapies have shown great promise in cancer treatment. However, the intra-heterogeneity is a major barrier to reasonably classifying the potential benefited patients. Comprehensive heterogeneity analysis is needed to solve these clinical issues. In this study, the samples from pan-cancer and independent breast cancer datasets were divided into four tumor immune microenvironment (TIME) subtypes based on tumor programmed death ligand 1 (PD-L1) expression level and tumor-infiltrating lymphocyte (TIL) state. As the combination of the TIL Z score and PD-L1 expression showed superior prediction of response to ICI in multiple data sets compared to other methods, we used the TIL Z score and PD-L1 to classify samples. Therefore, samples were divided by combined TIL Z score and PD-L1 to identify four TIME subtypes, including type I (3.24%), type II (43.24%), type III (6.76%), and type IV (46.76%). Type I was associated with favorable prognosis with more T and DC cells, while type III had the poorest condition and composed a higher level of activated mast cells. Furthermore, TIME subtypes exhibited a distinct genetic and transcriptional feature: type III was observed to have the highest mutation rate (77.92%), while co-mutations patterns were characteristic in type I, and the PD-L1 positive subgroup showed higher carbohydrates, lipids, and xenobiotics metabolism compared to others. Overall, we developed a robust method to classify TIME and analyze the divergence of prognosis, immune cell composition, genomics, and transcriptomics patterns among TIME subtypes, which potentially provides insight for classification of TIME and a referrable theoretical basis for the screening benefited groups in the ICI immunotherapy.
Glucose Metabolism in Burns—What Happens?
Authors: Badoiu Silviu Constantin , Miricescu Daniela , Stanescu-Spinu Iulia-Ioana , Ripszky Totan Alexandra , Badoiu Silvia Elena , Costagliola Michel , Greabu Maria
Published: May 2021

Severe burns represent an important challenge for patients and medical teams. They lead to profound metabolic alterations, trigger a systemic inflammatory response, crush the immune defense, impair the function of the heart, lungs, kidneys, liver, etc. The metabolism is shifted towards a hypermetabolic state, and this situation might persist for years after the burn, having deleterious consequences for the patient’s health. Severely burned patients lack energy substrates and react in order to produce and maintain augmented levels of glucose, which is the fuel “ready to use” by cells. In this paper, we discuss biological substances that induce a hyperglycemic response, concur to insulin resistance, and determine cell disturbance after a severe burn. We also focus on the most effective agents that provide pharmacological modulations of the changes in glucose metabolism.