bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between Interferon-Lambda-3 rs12979860, TLL1 rs17047200 and DDR1 rs4618569 Variant Polymorphisms with the Course and Outcome of SARS-CoV-2 Patients
Authors: Agwa Sara H. A. , Kamel Marwa Mostafa , Elghazaly Hesham , Abd Elsamee Aya M. , Hafez Hala , Girgis Samia Abdo , Ezz Elarab Hoda , Ebeid Fatma S. E. , Sayed Safa Matbouly , Sherif Lina , Matboli Marwa
Published: May 2021

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection provides a critical host-immunological challenge. Aim: We explore the effect of host-genetic variation in interferon-lambda-3 rs12979860, Tolloid Like–1 (TLL1) rs17047200 and Discoidin domain receptor 1(DDR1) rs4618569 on host response to respiratory viral infections and disease severity that may probe the mechanistic approach of allelic variation in virus-induced inflammatory responses. Methods: 141 COVID-19 positive patients and 100 healthy controls were tested for interferon-lambda-3 rs12979860, TLL1 rs17047200 and DDR1 rs4618569 polymorphism by TaqMan probe-based genotyping. Different genotypes were assessed regarding the COVID-19 severity and prognosis. Results: There were statistically significant differences between the studied cases and control group with regard to the presence of comorbidities, total leucocytic count, lymphocytic count, CRP, serum LDH, ferritin and D-dimer (p < 0.01). The CC genotype of rs12979860 cytokine, the AA genotype of TLL1 rs17047200 and the AA genotype of the rs4618569 variant of DDR1 showed a higher incidence of COVID-19 compared to the others. There were significant differences between the rs4618569 variant of DDR and the outcome of the disease, with the highest mortality in AG genotype 29 (60.4%) in comparison to 16 (33.3%) and 3 (6.2%) in the AA and GG genotypes, respectively (p = 0.007*), suggesting that the A allele is associated with a poor outcome in the disease. Conclusion: Among people who carry C and A alleles of SNPs IFN-λ rs12979860 and TLL1 rs17047200, respectively, the AG genotype of the DDR1 rs4618569 variant is correlated with a COVID-19 poor outcome. In those patients, the use of anti-IFN-λ 3, TLL1 and DDR1 therapy may be promising for personalized translational clinical practice.
Circulating RNA in Kidney Cancer: What We Know and What We Still Suppose
Authors: Cinque Alessandra , Vago Riccardo , Trevisani Francesco
Published: May 2021

Renal cancer represents the 7th most common tumor worldwide, affecting 400,000 people annually. This malignancy, which is the third most frequent cancer among urological diseases, displays a completely different prognosis if the tumor is detected in the early stages or advance phases. Unfortunately, more than 50% of renal cancers are discovered incidentally, with a consistent percentage of cases where the tumor remains clinically silent till the metastatic process is established. In day-to-day clinical practice, no available predictive biomarkers exist, and the existent imaging diagnostic techniques harbor several gaps in terms of diagnosis and prognosis. In the last decade, many efforts have been reported to detect new predictive molecular biomarkers using liquid biopsies, which are less invasive in comparison to renal biopsy. However, until now, there has been no clear evidence that a liquid biopsy biomarker could be relevant to the creation of a precise and tailored medical management in these oncological patients, even though circulating RNA biomarkers remain among the most promising. Given the idea that liquid biopsies will play a future key role in the management of these patients, in the present review, we summarize the current state of circulating RNA (miRNA, lncRNAs, and circRNAs) as possible biomarkers of renal cancer presence and aggressiveness in patients.
The Full-Length Transcriptome Sequencing and Identification of Na+/H+ Antiporter Genes in Halophyte Nitraria tangutorum Bobrov
Authors: Zhu Liming , Lu Lu , Yang Liming , Hao Zhaodong , Chen Jinhui , Cheng Tielong
Published: May 2021

Nitraria tangutorum Bobrov is a halophyte that is resistant to salt and alkali and is widely distributed in northwestern China. However, its genome has not been sequenced, thereby limiting studies on this particular species. For species without a reference genome, the full-length transcriptome is a convenient and rapid way to obtain reference gene information. To better study N. tangutorum, we used PacBio single-molecule real-time technology to perform full-length transcriptome analysis of this halophyte. In this study, a total of 21.83 Gb of data were obtained, and 198,300 transcripts, 51,875 SSRs (simple sequence repeats), 55,574 CDS (coding sequence), and 74,913 lncRNAs (long non-coding RNA) were identified. In addition, using this full-length transcriptome, we identified the key Na+/H+ antiporter (NHX) genes that maintain ion balance in plants and found that these are induced to express under salt stress. The results indicate that the full-length transcriptome of N. tangutorum can be used as a database and be utilized in elucidating the salt tolerance mechanism of N. tangutorum.
How Accurate and Precise Can We Measure the Posture and the Energy Expenditure Component of Sedentary Behaviour with One Sensor?
Authors: Kuster Roman P. , Grooten Wilhelmus J. A. , Blom Victoria , Baumgartner Daniel , Hagströmer Maria , Ekblom Örjan
Published: May 2021

Sedentary behaviour is an emergent public health topic, but there is still no method to simultaneously measure both components of sedentary behaviour—posture and energy expenditure—with one sensor. This study investigated the accuracy and precision of measuring sedentary time when combining the proprietary processing of a posture sensor (activPAL) with a new energy expenditure algorithm and the proprietary processing of a movement sensor (ActiGraph) with a published posture algorithm. One hundred office workers wore both sensors for an average of 7 days. The activPAL algorithm development used 38 and the subsequent independent method comparison 62 participants. The single sensor sedentary estimates were compared with Bland–Atman statistics to the Posture and Physical Activity Index, a combined measurement with both sensors. All single-sensor methods overestimated sedentary time. However, adding the algorithms reduced the overestimation from 129 to 21 (activPAL) and from 84 to 7 min a day (ActiGraph), with far narrower 95% limits of agreements. Thus, combining the proprietary data with the algorithms is an easy way to increase the accuracy and precision of the single sensor sedentary estimates and leads to sedentary estimates that are more precise at the individual level than those of the proprietary processing are at the group level.
The Moderating Effect of Community-Level Deprivation on the Association between Individual Characteristics and Smoking Behavior among Chinese Adults: A Cross-Level Study
Authors: Chen Nan , Kim Chang-Gyeong
Published: May 2021

China joined the World Health Organization (WHO) Framework Convention on Tobacco Control in 2006; however, the overall Chinese smoking rate is still high. The aim of this study is to provide new evidence for the direct effects of community-level deprivation, and the effects of interactions between community-level deprivation and individual characteristics, on smoking intensity, by using cross-sectional data from the 2015 China Health and Nutrition Survey (CHNS). The results show that there is a strong association between community-level deprivation and individual smoking intensity, and that community deprivation moderates the relationship between individual perceived stress and smoking intensity. The findings imply that adequate interventions should be conducted in the context of deprived neighborhoods, and should consider differences between levels of individual perceived stress and between sexes, especially focusing on highly stressed women who live in deprived communities.
Adolescents’ Exposure to Online Risks: Gender Disparities and Vulnerabilities Related to Online Behaviors
Authors: Savoia Elena , Harriman Nigel Walsh , Su Max , Cote Tyler , Shortland Neil
Published: May 2021

In the last decade, readily available electronic devices have created unprecedented opportunities for teens to access a wide variety of information and media–both positive and negative–on the internet. Despite the increasing number of initiatives taking place worldwide intended to assess and mitigate the online risks encountered by children and adolescents, there is still a need for a better understanding of how adolescents use the internet and their susceptibility to exposure to risks in the online space. We conducted a cross-sectional online survey of a convenience sample of 733 8th and 9th grade students in Utah. The survey contained eight questions regarding students’ exposure to three types of online risk scenarios: content risk, contact risk, and criminal risk. Independent variables included students’ online behaviors, use of social media and private messaging apps, and adult supervision of online activities. Logistic and negative binomial regression models indicated that gender, social media use, and chatting with strangers were associated with exposure to multiple risky online scenarios. Our results provide critical information to educators involved in the development of initiatives focusing on the reduction of youth online risk by identifying correlates of risky online events, allowing them to tailor their initiatives to meet the needs of potentially vulnerable populations.
Impacts of Social Participation on Self-Rated Health of Aging Women in China: With a Mediating Role of Caring for Grandchildren
Authors: Tian Shuliu , Xu Lei , Wu Xiangling
Published: May 2021

Population aging is a global challenge and the degree of population aging is continuing to deepen in China. Under the active aging policy framework by WHO, great importance has been attached to aging women and participation is emphasized for the well-being of the elderly. This study aimed to investigate the relation between social participation and self-rated health status of aging women in China and whether caring for grandchildren mediated such an association. Adopting data from the 2018 China Health and Retirement Longitudinal Study (CHARLS), this study used Oprobit regression, propensity score matching (PSM), and instrument variable regression to estimate the effects. The result showed that there was a positive association between social participation and self-rated health among aging women in China, and social activities that directly made contributions to others had the most significant impacts on self-rated health. Furthermore, the mediator analysis confirmed that caring for grandchildren played a role between social participation and self-rated health. In conclusion, to deal with population aging challenges, the society should recognize the value of intergenerational care for aging women and the government need to strengthen policy supports to guarantee platforms and opportunities for the elderly to participate in social activities.
Translation and Cross-Cultural Adaptation of Quality of Life Scale in Patients with Onychomycosis
Authors: Silva-Neves Vasco , Caramelo Ana , Alves Paulo , Pais-Vieira Carla , Minton Alexandra Palmer , Rodríguez-Leboeuf Ana María , Pais-Vieira Miguel
Published: May 2021

(1) Background: Onychomycosis (OM) is a fungal nail infection, considered a risk factor for diabetic foot ulcers. It is associated with changes in quality of life, in terms of pain, self-confidence and self-esteem. The aim was to translate and adapt the OM quality of life questionnaire “OnyCOE-tTM–Quality Of Life Questionnaire Onychomycosis (Nail Fungal Condition)”. (2) Methods: This study followed the guidelines proposed by Beaton et al. (2000), where two English to Portuguese translations were performed and, after an expert consensus, a common version was obtained. This was followed by two back-translations. The expert committee achieved semantic equivalence, idioms and concepts. The pre-test was applied to 49 people. The final version and processed data were sent to the authors. (3) Results: We adapted terms semantically, modified statements syntactically, altering items from interrogative to affirmative. (4) Conclusions: The translated version of the “Quality of life–Onychomycosis” questionnaire suggested that it can be used for further studies to test validity and reliability in this population.
Salivary Antibodies against Multiple Environmental Pathogens Found in Individuals Recreating at an Iowa Beach
Authors: Augustine Swinburne A. J. , Eason Tarsha N. , Wade Tim , Griffin Shannon M. , Sams Elizabeth , Simmons Kaneatra , Ramudit Malini , Oshima Kevin , Dufour Alfred
Published: May 2021

Detecting environmental exposures and mitigating their impacts are growing global public health challenges. Antibody tests show great promise and have emerged as fundamental tools for large-scale exposure studies. Here, we apply, demonstrate and validate the utility of a salivary antibody multiplex immunoassay in measuring antibody prevalence and immunoconversions to six pathogens commonly found in the environment. The study aimed to assess waterborne infections in consenting beachgoers recreating at an Iowa riverine beach by measuring immunoglobulin G (IgG) antibodies against select pathogens in serially collected saliva samples. Results showed that nearly 80% of beachgoers had prior exposures to at least one of the targeted pathogens at the beginning of the study. Most of these exposures were to norovirus GI.1 (59.41%), norovirus GII.4 (58.79%) and Toxoplasma gondii (22.80%) and over half (56.28%) of beachgoers had evidence of previous exposure to multiple pathogens. Of individuals who returned samples for each collection period, 6.11% immunoconverted to one or more pathogens, largely to noroviruses (GI.1: 3.82% and GII.4: 2.29%) and T. gondii (1.53%). Outcomes of this effort illustrate that the multiplex immunoassay presented here serves as an effective tool for evaluating health risks by providing valuable information on the occurrence of known and emerging pathogens in population surveillance studies.
Exploring Regional Advanced Manufacturing and Its Driving Factors: A Case Study of the Guangdong–Hong Kong–Macao Greater Bay Area
Authors: Dou Zixin , Sun Yanming , Wang Tao , Wan Huiyin , Fan Shiqi
Published: May 2021

This study aims to analyze the development trend of the manufacturing industry of the Guangdong–Hong Kong–Macao Greater Bay Area (from 2008 to 2018) by constructing an evaluation system. On the basis of push–pull–mooring theory, we analyze these factors by using an entropy and cluster model. The results show the following: (1) Technological development had an obvious spatial distribution pattern of core regional radiation, while others did not. (2) Economic development was based on the city’s existing industrial development system, while environmental development depended on governmental policies. (3) Compared with the environmental factor, the development trends of the economic and technological factors were more similar. Lastly, we provide four strategies for the development of the manufacturing industry in different cities.
The Relationship between E-Health Literacy and Health-Promoting Behaviors in Nursing Students: A Multiple Mediation Model
Authors: Kim Sunghee , Oh Jihyun
Published: May 2021

The availability of a wide range of online health-related information on the internet has made it an increasingly popular source of health information, particularly for people in their 20s. This study aimed to explore possible multistep and indirect pathways of association between e-health literacy and health-promoting behaviors through social media use for health information, online health information-seeking behaviors, and self-care agency among nursing students. The study included 558 nursing students from three different universities in South Korea. Data were collected using structured questionnaires from 2 August to 29 August, 2019. The results show that e-health literacy had a significant direct effect on health-promoting behaviors through the three mediators. Moreover, the overall model explained 46% of the total variance in health-promoting behaviors. Based on these findings, it is necessary to introduce interventions that improve e-health literacy and develop a strategy to promote healthy behaviors. It is also necessary to develop programs to improve e-health literacy competency in nursing students. Moreover, health interventions that improve health-promoting behaviors should be developed, and research to evaluate the effect of the interventions should be conducted.
Speaking Softly and Listening Hard: The Process of Involving Young Voices from a Culturally and Linguistically Diverse School in Child Health Research
Authors: Samir Nora , Diaz Antonio Mendoza , Hodgins Michael , Matic Simone , Bawden Samira , Khoury Jessica , Eapen Valsamma , Lingam Raghu
Published: May 2021

The involvement of young people in the planning of research continues to be rare, particularly for young people from culturally and linguistically diverse communities. This paper describes our experience in establishing a Youth Research Advisory Group (YRAG) in South West Sydney (SWS), including barriers and successful strategies. One hundred and fifteen students between school Years 7 and 12 (ages 11–18) took part in at least one of five sessions between 2019 and 2021. In total, we carried out 26 YRAG sessions, with between five and 30 students in each. Sessions focused on mapping the health priorities of the participants and co-developing research project proposals related to their health priorities. Our work with students revealed that their main areas of concern were mental health and stress. This led to material changes in our research strategy, to include “Mental Health” as a new research stream and co-develop new mental health-related projects with the students. Important strategies that enabled our research included maintaining flexibility to work seamlessly with organisational and individual preferences, and ensuring our processes were directed by the schools and—most importantly—the students themselves. Strategies such as maintaining an informal context, responding rapidly to student preference, and regularly renegotiating access enabled us to engage with the students to deepen our understanding of their experiences.
Effects of Animal-Assisted Therapy on Gait Performance, Respiratory Function, and Psychological Variables in Patients Post-Stroke
Authors: An Ho-Jung , Park Shin-Jun
Published: May 2021

Background: Animal-assisted therapy using dogs is being administered to patients post-stroke for the purpose of recovering psychological and physical activity. Objective: This study was conducted to confirm the effect of animal-assisted therapy using dogs on gait performance, pulmonary function, and psychological variables in patients post-stroke. All outcomes were analyzed using two-way repeated-measure analysis. Methods: In total, 30 post-stroke patients were divided into an experimental group (gait training by animal-assisted activity, n = 15) and a control group (gait training, n = 15). Gait performance (cadence, gait speed, stride length, symmetric index), respiratory pulmonary function (forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), peak expiratory flow (PEF), maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP)), and psychological variables (rehabilitation motivation and depression assessment) were measured before and after eight weeks of intervention. Results: Gait performance, respiratory pulmonary function, and psychological variables significantly increased in the experimental group compared to the control group. Conclusion: Based on this study, it was found that animal-assisted therapy using dogs is an effective intervention for recovery of psychological and physical activity in patients post-stroke.
Ocean Literacy and Surfing: Understanding How Interactions in Coastal Ecosystems Inform Blue Space User’s Awareness of the Ocean
Authors: Fox Natalie , Marshall Jamie , Dankel Dorothy Jane
Published: May 2021

Intergovernmental policy is targeting public ocean literacy to help achieve the societal changes needed to reach a sustainable ocean agenda within a 10-year timeframe. To create a culture of care for the ocean, which is under threat from Anthropocentric pressures, informed ocean citizens are central to upholding meaningful actions and best practices. This research focuses on recreational ocean users, specifically surfers and how their blue space activities may inform understanding of ocean processes and human-ocean interconnections. The Ocean Literacy Principles were used to assess ocean awareness through surfing interactions. An online survey questionnaire was completed by 249 participants and reduced to a smaller sample focus group. Qualitative and quantitative data were triangulated to develop further understanding of surfer experiences, using the social-ecological systems framework to model surfing outcomes. The results found that surfers indeed receive ocean literacy benefits, specifically three out of the seven Ocean Literacy Principles and that ocean literacy is a direct benefit many surfers in the sample group receive. By identifying synergies between the Ocean Literacy Principles, variables within coastal ecosystems and user (surfer) interactions, this research offers novel insight into opportunities for integrating ocean sustainability strategies through blue space activity mechanisms and coastal community engagement.
Effect of a Simulation-Based Handover Education Program for Nursing Students: A Quasi-Experimental Design
Authors: Lee Da-Hye , Lim Eun-Ju
Published: May 2021

Nursing handover facilitates the continuity of nursing and ensures patient safety and quality of care. This study aimed to evaluate the effectiveness of a handover education program by assessing handover knowledge, self-efficacy, and handover performance competency. A group pretest–post-test quasi-experimental design was used. Thirty 4th-year Korean nursing students participated in a handover education program comprising a lecture and simulation training using a high-fidelity simulator. The average level of handover knowledge was 4.63 ± 1.61 before the program and 5.83 ± 0.95 after (t = −3.71, p = 0.001). Meanwhile, the average self-efficacy score was 3.35 ± 0.57 before the program and 3.90 ± 0.60 after (t = −5.65, p < 0.001). Further, the average handover performance competency was 1.75 ± 0.25 before the program and 2.37 ± 0.21 after (t = −12.08, p < 0.001). The simulation-based handover education intervention was effective in improving knowledge, self-efficacy, and performance competency of nursing students. This intervention can provide an effective method of improving nursing students’ handover skills prior to entering clinical practice.
Empowerment and Employee Well-Being: A Mediation Analysis Study
Authors: Marin-Garcia Juan A. , Bonavia Tomas
Published: May 2021

This study examines the relationship between structural and psychological empowerment and its effects on employees’ psychological, physical, and social well-being. Despite the quantity of previously published works, empirical evidence about these relationships in the workplace is scarce. We developed a mediation model in which structural empowerment predicts employee well-being via psychological empowerment. We based our study on the EU-27 data from the 6th European Working Conditions Survey (EWCS). Data were collected from a questionnaire administered face-to-face to a random sample of employees and the self-employed representative of the working population in the European Union (number of valid responses in this study: 23,468). The effects of the relationships among the variables considered were evaluated using Partial Least Squares (PLS). Results indicate that structural empowerment was positively related to psychological empowerment, which was positively related to job satisfaction, work engagement, and social well-being. The expected relationships for work stress and physical well-being were not found.
Minimum Clearance Distance in Fall Arrest Systems with Energy Absorber Lanyards
Authors: Carrión Elena Ángela , Ferrer Belén , Monge Juan Francisco , Saez Pedro Ignacio , Pomares Juan Carlos , González Antonio
Published: May 2021

Accidents due to falls from height are one of the main causes of death in workplaces. Fall arrest systems (FAS) are designed to arrest the fall safely without injuring the accident victim. Their main mission is to restrain the body so as to prevent it from hitting the ground, generating forces and accelerations in the arrest process that are not harmful. A lack of empirical evidence and scant technical information provided by manufacturers regarding minimum clearance distance (MCD) below anchorage makes it necessary to study the safety distances required in the use of Energy Absorber Lanyards (EAL). This paper aims to determine the MCD below anchorage to arrest a fall using an EAL without hitting the ground. The real deformation of EAL when stopping a fall is studied. Ten EAL models distributed internationally by six manufacturers were chosen. Dynamic behavior tests were performed on the samples. Using image processing the total elongation of the equipment (elastic plus plastic) is obtained. The main conclusions are that maximum plastic elongation could be reduced by 29%. The method described in EN 355: 2002 underestimates elongation by up to 70% for some equipment 20% of EAL’s exceed the maximum arrest force (Fm) allowed in EN 355. The MCD data provided by manufacturers is not reliable. The data provided by manufacturers are incomplete. It is recommended that quality control for EAL’s be strengthened to ensure that products launched onto the market meet the requirement of EN355. The findings of this study recommended increasing MCD distance longer than that calculated according to EN355, at less than 1 m.
Examining Controlling Styles of Significant Others and Their Implications for Motivation, Boredom and Burnout in Young Swimmers
Authors: Alvarez Octavio , Tormo-Barahona Lluis , Castillo Isabel , Moreno-Murcia Juan Antonio
Published: May 2021

The aim of the study was to examine the controlling style in two contexts of social influence: the team (i.e., coach and teammates) and the family (i.e., father and mother), as well as the mediational role of motivation (autonomous, controlled, and amotivation) and its relationship with boredom and burnout in young swimmers. To this end, 267 swimmers (140 girls and 127 boys) between 12 and 18 years of age (M = 14.26; SD = 1.61) were assessed. The results showed that in the team context, coaches’ controlling style directly promoted controlled motivation and boredom in their swimmers, and indirectly influenced burnout through the mediating role of swimmers’ controlled motivation. Teammates’ controlling style was directly associated with controlled motivation, amotivation, and burnout, and indirectly associated with boredom and burnout through the mediating role of amotivation. Regarding the family context, the father’s controlling style showed direct associations with controlled motivation and burnout, and indirect associations with boredom through the mediating role of swimmers’ controlled motivation. Finally, the associations of the mother’s controlling style with all the variables studied were neutralized by the father’s controlling interpersonal style. This study emphasizes the differentiating role of significant others when displaying controlling styles, and it confirms that the controlling style has a significant relationship with maladaptive sport practice experiences.
Supramolecular Chromatographic Separation of C60 and C70 Fullerenes: Flash Column Chromatography vs. High Pressure Liquid Chromatography
Authors: Mekapothula Subbareddy , Wonanke A. D. Dinga , Addicoat Matthew A. , Boocock David J. , Wallis John D. , Cave Gareth W. V.
Published: May 2021

A silica-bound C-butylpyrogallol[4]arene chromatographic stationary phase was prepared and characterised by thermogravimetric analysis, scanning electron microscopy, NMR and mass spectrometry. The chromatographic performance was investigated by using C60 and C70 fullerenes in reverse phase mode via flash column and high-pressure liquid chromatography (HPLC). The resulting new stationary phase was observed to demonstrate size-selective molecular recognition as postulated from our in-silico studies. The silica-bound C-butylpyrogallol[4]arene flash and HPLC stationary phases were able to separate a C60- and C70-fullerene mixture more effectively than an RP-C18 stationary phase. The presence of toluene in the mobile phase plays a significant role in achieving symmetrical peaks in flash column chromatography.
Striated Preferentially Expressed Protein Kinase (SPEG) in Muscle Development, Function, and Disease
Authors: Luo Shiyu , Rosen Samantha M. , Li Qifei , Agrawal Pankaj B.
Published: May 2021

Mutations in striated preferentially expressed protein kinase (SPEG), a member of the myosin light chain kinase protein family, are associated with centronuclear myopathy (CNM), cardiomyopathy, or a combination of both. Burgeoning evidence suggests that SPEG plays critical roles in the development, maintenance, and function of skeletal and cardiac muscles. Here we review the genotype-phenotype relationships and the molecular mechanisms of SPEG-related diseases. This review will focus on the progress made toward characterizing SPEG and its interacting partners, and its multifaceted functions in muscle regeneration, triad development and maintenance, and excitation-contraction coupling. We will also discuss future directions that are yet to be investigated including understanding of its tissue-specific roles, finding additional interacting proteins and their relationships. Understanding the basic mechanisms by which SPEG regulates muscle development and function will provide critical insights into these essential processes and help identify therapeutic targets in SPEG-related disorders.
BRAF Inhibitors Induce Feedback Activation of RAS Pathway in Thyroid Cancer Cells
Authors: Bonaldi Elisa , Gargiuli Chiara , De Cecco Loris , Micali Arianna , Rizzetti Maria Grazia , Greco Angela , Borrello Maria Grazia , Minna Emanuela
Published: May 2021

BRAFV600E is the most frequent oncogenic mutation identified in papillary thyroid cancer (PTC). In PTC patients who do not respond to standard treatment, BRAF inhibitors are currently tested as alternative strategies. However, as observed for other targeted therapies, patients eventually develop drug resistance. The mechanisms of BRAF inhibitors response are still poorly understood in a thyroid cancer (TC) context. In this study, we investigated in BRAFV600E mutated TC cell lines the effects of Vemurafenib and Dabrafenib, two BRAF inhibitors currently used in a clinical setting. We assessed cell proliferation, and the expression and activity of the thyroid function related transporter NIS following the treatment with BRAF inhibitors. In addition, we investigated the global gene expression by microarray, the relevant modulated biological processes by gene set enrichment analysis (GSEA), and TC specific gene signatures related to MAPK pathway activation, thyroid differentiation, and transcriptional profile associated with BRAFV600E or RAS mutation. We found that both inhibitors induce antiproliferative and redifferentiative effects on TC cells, as well as a rewiring of the MAPK pathway related to RAS signaling. Our results suggest a possible mechanism of drug response to the BRAF inhibitors Vemurafenib or Dabrafenib, supporting very recent findings in TC patients treated with targeted therapies.
Comparative Study of the Genetic and Biochemical Variability of Polyscias filicifolia (Araliaceae) Regenerants Obtained by Indirect and Direct Somatic Embryogenesis as a Source of Triterpenes
Authors: Śliwińska Anita A. , Białek Agnieszka , Orłowska Renata , Mańkowski Dariusz , Sykłowska-Baranek Katarzyna , Pietrosiuk Agnieszka
Published: May 2021

Polyscias filicifolia (Araliaceae) is broadly used in traditional medicine in Southeast Asia due to its antimicrobial, immunomodulating and cytotoxic activities. The main groups of compounds responsible for pharmacological effects are believed to be oleanolic triterpene saponins. However, Polyscias plants demonstrate relatively slow growth in natural conditions, which led to applying a developing sustainable source of plant material via primary (PSE), secondary (DSE) and direct somatic embryogenesis from DSE (TSE). The AFLP and metAFLP genotyping resulted in 1277 markers, amplified by a total of 24 pairs of selective primers. Only 3.13% of the markers were polymorphic. The analysis of variance showed that the PSE and TSE regenerants differed only in terms of root number, while the DSE plantlets differed for all studied morphological characteristics. Further, the chemical analysis revealed that oleanolic acid (439.72 µg/g DW), ursolic acid (111.85 µg/g DW) and hederagenin (19.07 µg/g DW) were determined in TSE regenerants. Our results indicate that direct somatic embryogenesis ensures the production of homogeneous plant material, which can serve as a potential source of triterpene compounds. Plants obtained via somatic embryogenesis could also be reintroduced into the natural environment to protect and preserve its biodiversity.
Do Autophagy Enhancers/ROS Scavengers Alleviate Consequences of Mild Mitochondrial Dysfunction Induced in Neuronal-Derived Cells?
Authors: Damri Odeya , Natur Sarya , Agam Galila
Published: May 2021

Mitochondrial function is at the nexus of pathways regulating synaptic-plasticity and cellular resilience. The involvement of brain mitochondrial dysfunction along with increased reactive oxygen species (ROS) levels, accumulating mtDNA mutations, and attenuated autophagy is implicated in psychiatric and neurodegenerative diseases. We have previously modeled mild mitochondrial dysfunction assumed to occur in bipolar disorder (BPD) using exposure of human neuronal cells (SH-SY5Y) to rotenone (an inhibitor of mitochondrial-respiration complex-I) for 72 and 96 h, which exhibited up- and down-regulation of mitochondrial respiration, respectively. In this study, we aimed to find out whether autophagy enhancers (lithium, trehalose, rapamycin, and resveratrol) and/or ROS scavengers [resveratrol, N-acetylcysteine (NAC), and Mn-Tbap) can ameliorate neuronal mild mitochondrial dysfunction. Only lithium (added for the last 24/48 h of the exposure to rotenone for 72/96 h, respectively) counteracted the effect of rotenone on most of the mitochondrial respiration parameters (measured as oxygen consumption rate (OCR)). Rapamycin, resveratrol, NAC, and Mn-Tbap counteracted most of rotenone’s effects on OCR parameters after 72 h, possibly via different mechanisms, which are not necessarily related to their ROS scavenging and/or autophagy enhancement effects. The effect of lithium reversing rotenone’s effect on OCR parameters is compatible with lithium’s known positive effects on mitochondrial function and is possibly mediated via its effect on autophagy. By-and-large it may be summarized that some autophagy enhancers/ROS scavengers alleviate some rotenone-induced mild mitochondrial changes in SH-SY5Y cells.
Fc-Receptor Targeted Therapies for the Treatment of Myasthenia gravis
Authors: Keller Christian W. , Pawlitzki Marc , Wiendl Heinz , Lünemann Jan D.
Published: May 2021

Myasthenia gravis (MG) is an autoimmune disease in which immunoglobulin G (IgG) antibodies (Abs) bind to acetylcholine receptors (AChR) or to functionally related molecules in the postsynaptic membrane at the neuromuscular junction. IgG crystallizable fragment (Fc)-mediated effector functions, such as antibody-dependent complement deposition, contribute to disease development and progression. Despite progress in understanding Ab-mediated disease mechanisms, immunotherapy of MG remained rather unspecific with corticosteroids and maintenance with immunosuppressants as first choice drugs for most patients. More specific therapeutic IgG Fc-based platforms that reduce serum half-life or effector functions of pathogenic MG-related Abs are currently being developed, tested in clinical trials or have recently been successfully translated into the clinic. In this review, we illustrate mechanisms of action and clinical efficacies of emerging Fc-mediated therapeutics such as neonatal Fc receptor (FcRn)-targeting agents. Furthermore, we evaluate prospects of therapies targeting classical Fc receptors that have shown promising therapeutic efficacy in other antibody-mediated conditions. Increased availability of Fc- and Fc receptor-targeting biologics might foster the development of personalized immunotherapies with the potential to induce sustained disease remission in patients with MG.
Curcumin-Loaded Nanoparticles Impair the Pro-Tumor Activity of Acid-Stressed MSC in an In Vitro Model of Osteosarcoma
Authors: Di Pompo Gemma Di , Cortini Margherita , Palomba Roberto , Di Francesco Valentina Di , Bellotti Elena , Decuzzi Paolo , Baldini Nicola , Avnet Sofia
Published: May 2021

In the tumor microenvironment, mesenchymal stromal cells (MSCs) are key modulators of cancer cell behavior in response to several stimuli. Intratumoral acidosis is a metabolic trait of fast-growing tumors that can induce a pro-tumorigenic phenotype in MSCs through the activation of the NF-κB-mediated inflammatory pathway, driving tumor clonogenicity, invasion, and chemoresistance. Recent studies have indicated that curcumin, a natural ingredient extracted from Curcuma longa, acts as an NF-κB inhibitor with anti-inflammatory properties. In this work, highly proliferating osteosarcoma cells were used to study the ability of curcumin to reduce the supportive effect of MSCs when stimulated by acidosis. Due to the poor solubility of curcumin in biological fluids, we used spherical polymeric nanoparticles as carriers (SPN-curc) to optimize its uptake by MSCs. We showed that SPN-curc inhibited the release of inflammatory cytokines (IL6 and IL8) by acidity-stimulated MSCs at a higher extent than by free curcumin. SPN-curc treatment was also successful in blocking tumor stemness, migration, and invasion that were driven by the secretome of acid-stressed MSCs. Overall, these data encourage the use of lipid–polymeric nanoparticles encapsulating NF-κB inhibitors such as curcumin to treat cancers whose progression is stimulated by an activated mesenchymal stroma.
How Neural Crest Transcription Factors Contribute to Melanoma Heterogeneity, Cellular Plasticity, and Treatment Resistance
Authors: Wessely Anja , Steeb Theresa , Berking Carola , Heppt Markus Vincent
Published: May 2021

Cutaneous melanoma represents one of the deadliest types of skin cancer. The prognosis strongly depends on the disease stage, thus early detection is crucial. New therapies, including BRAF and MEK inhibitors and immunotherapies, have significantly improved the survival of patients in the last decade. However, intrinsic and acquired resistance is still a challenge. In this review, we discuss two major aspects that contribute to the aggressiveness of melanoma, namely, the embryonic origin of melanocytes and melanoma cells and cellular plasticity. First, we summarize the physiological function of epidermal melanocytes and their development from precursor cells that originate from the neural crest (NC). Next, we discuss the concepts of intratumoral heterogeneity, cellular plasticity, and phenotype switching that enable melanoma to adapt to changes in the tumor microenvironment and promote disease progression and drug resistance. Finally, we further dissect the connection of these two aspects by focusing on the transcriptional regulators MSX1, MITF, SOX10, PAX3, and FOXD3. These factors play a key role in NC initiation, NC cell migration, and melanocyte formation, and we discuss how they contribute to cellular plasticity and drug resistance in melanoma.
The Amino Acid Transporter Mct10/Tat1 Is Important to Maintain the TSH Receptor at Its Canonical Basolateral Localization and Assures Regular Turnover of Thyroid Follicle Cells in Male Mice
Authors: Venugopalan Vaishnavi , Al-Hashimi Alaa , Weber Jonas , Rehders Maren , Qatato Maria , Wirth Eva K. , Schweizer Ulrich , Heuer Heike , Verrey François , Brix Klaudia
Published: May 2021

Cathepsin K-mediated thyroglobulin proteolysis contributes to thyroid hormone (TH) liberation, while TH transporters like Mct8 and Mct10 ensure TH release from thyroid follicles into the blood circulation. Thus, thyroid stimulating hormone (TSH) released upon TH demand binds to TSH receptors of thyrocytes, where it triggers Gαq-mediated short-term effects like cathepsin-mediated thyroglobulin utilization, and Gαs-mediated long-term signaling responses like thyroglobulin biosynthesis and thyrocyte proliferation. As reported recently, mice lacking Mct8 and Mct10 on a cathepsin K-deficient background exhibit excessive thyroglobulin proteolysis hinting towards altered TSH receptor signaling. Indeed, a combination of canonical basolateral and non-canonical vesicular TSH receptor localization was observed in Ctsk−/−/Mct8−/y/Mct10−/− mice, which implies prolonged Gαs-mediated signaling since endo-lysosomal down-regulation of the TSH receptor was not detected. Inspection of single knockout genotypes revealed that the TSH receptor localizes basolaterally in Ctsk−/− and Mct8−/y mice, whereas its localization is restricted to vesicles in Mct10−/− thyrocytes. The additional lack of cathepsin K reverses this effect, because Ctsk−/−/Mct10−/− mice display TSH receptors basolaterally, thereby indicating that cathepsin K and Mct10 contribute to TSH receptor homeostasis by maintaining its canonical localization in thyrocytes. Moreover, Mct10−/− mice displayed reduced numbers of dead thyrocytes, while their thyroid gland morphology was comparable to wild-type controls. In contrast, Mct8−/y, Mct8−/y/Mct10−/−, and Ctsk−/−/Mct8−/y/Mct10−/− mice showed enlarged thyroid follicles and increased cell death, indicating that Mct8 deficiency results in altered thyroid morphology. We conclude that vesicular TSH receptor localization does not result in different thyroid tissue architecture; however, Mct10 deficiency possibly modulates TSH receptor signaling for regulating thyrocyte survival.
Accelerated and Improved Vascular Maturity after Transplantation of Testicular Tissue in Hydrogels Supplemented with VEGF- and PDGF-Loaded Nanoparticles
Authors: Del Vento Federico , Poels Jonathan , Vermeulen Maxime , Ucakar Bernard , Giudice Maria Grazia , Kanbar Marc , des Rieux Anne , Wyns Christine
Published: May 2021

Avascular transplantation of frozen–thawed testicular tissue fragments represents a potential future technique for fertility restoration in boys with cancer. A significant loss of spermatogonia was observed in xeno-transplants of human tissue most likely due to the hypoxic period before revascularization. To reduce the effect of hypoxia–reoxygenation injuries, several options have already been explored, like encapsulation in alginate hydrogel and supplementation with nanoparticles delivering a necrosis inhibitor (NECINH) or VEGF. While these approaches improved short-term (5 days) vascular surfaces in grafts, neovessels were not maintained up to 21 days; i.e., the time needed for achieving vessel stabilization. To better support tissue grafts, nanoparticles loaded with VEGF, PDGF and NECINH were developed. Testicular tissue fragments from 4–5-week-old mice were encapsulated in calcium-alginate hydrogels, either non-supplemented (control) or supplemented with drug-loaded nanoparticles (VEGF-nanoparticles; VEGF-nanoparticles + PDGF-nanoparticles; NECINH-nanoparticles; VEGF-nanoparticles + NECINH-nanoparticles; and VEGF-nanoparticles + PDGF-nanoparticles + NECINH-nanoparticles) before auto-transplantation. Grafts were recovered after 5 or 21 days for analyses of tissue integrity (hematoxylin–eosin staining), spermatogonial survival (immuno-histo-chemistry for promyelocytic leukemia zinc finger) and vascularization (immuno-histo-chemistry for α-smooth muscle actin and CD-31). Our results showed that a combination of VEGF and PDGF nanoparticles increased vascular maturity and induced a faster maturation of vascular structures in grafts.
Facile Synthesis and Characterization of Palm CNF-ZnO Nanocomposites with Antibacterial and Reinforcing Properties
Authors: Supramaniam Janarthanan , Low Darren Yi Sern , Wong See Kiat , Tan Loh Teng Hern , Leo Bey Fen , Goh Bey Hing , Darji Dazylah , Mohd Rasdi Fatimah Rubaizah , Chan Kok Gan , Lee Learn Han , Tang Siah Ying
Published: May 2021

Cellulose nanofibers (CNF) isolated from plant biomass have attracted considerable interests in polymer engineering. The limitations associated with CNF-based nanocomposites are often linked to the time-consuming preparation methods and lack of desired surface functionalities. Herein, we demonstrate the feasibility of preparing a multifunctional CNF-zinc oxide (CNF-ZnO) nanocomposite with dual antibacterial and reinforcing properties via a facile and efficient ultrasound route. We characterized and examined the antibacterial and mechanical reinforcement performances of our ultrasonically induced nanocomposite. Based on our electron microscopy analyses, the ZnO deposited onto the nanofibrous network had a flake-like morphology with particle sizes ranging between 21 to 34 nm. pH levels between 8–10 led to the formation of ultrafine ZnO particles with a uniform size distribution. The resultant CNF-ZnO composite showed improved thermal stability compared to pure CNF. The composite showed potent inhibitory activities against Gram-positive (methicillin-resistant Staphylococcus aureus (MRSA)) and Gram-negative Salmonella typhi (S. typhi) bacteria. A CNF-ZnO-reinforced natural rubber (NR/CNF-ZnO) composite film, which was produced via latex mixing and casting methods, exhibited up to 42% improvement in tensile strength compared with the neat NR. The findings of this study suggest that ultrasonically-synthesized palm CNF-ZnO nanocomposites could find potential applications in the biomedical field and in the development of high strength rubber composites.
The E3 Ubiquitin-Protein Ligase RNF4 Promotes TNF-α-Induced Cell Death Triggered by RIPK1
Authors: Shimada Tatsuya , Kudoh Yuki , Noguchi Takuya , Kagi Tomohiro , Suzuki Midori , Tsuchida Mei , Komatsu Hiromu , Takahashi Miki , Hirata Yusuke , Matsuzawa Atsushi
Published: May 2021

Receptor-interacting protein kinase 1 (RIPK1) is a key component of the tumor necrosis factor (TNF) receptor signaling complex that regulates both pro- and anti-apoptotic signaling. The reciprocal functions of RIPK1 in TNF signaling are determined by the state of the posttranslational modifications (PTMs) of RIPK1. However, the underlying mechanisms associated with the PTMs of RIPK1 are unclear. In this study, we found that RING finger protein 4 (RNF4), a RING finger E3 ubiquitin ligase, is required for the RIPK1 autophosphorylation and subsequent cell death. It has been reported that RNF4 negatively regulates TNF-α-induced activation of the nuclear factor-κB (NF-κB) through downregulation of transforming growth factor β-activated kinase 1 (TAK1) activity, indicating the possibility that RNF4-mediated TAK1 suppression results in enhanced sensitivity to cell death. However, interestingly, RNF4 was needed to induce RIPK1-mediated cell death even in the absence of TAK1, suggesting that RNF4 can promote RIPK1-mediated cell death without suppressing the TAK1 activity. Thus, these observations reveal the existence of a novel mechanism whereby RNF4 promotes the autophosphorylation of RIPK1, which provides a novel insight into the molecular basis for the PTMs of RIPK1.