bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between Smoking during Pregnancy and Short Root Anomaly in Offspring
Authors: Sagawa Yuki , Ogawa Takuya , Matsuyama Yusuke , Nakagawa Kang Junka , Yoshizawa Araki Miyu , Unnai Yasuda Yuko , Tumurkhuu Tsasan , Ganburged Ganjargal , Bazar Amarsaikhan , Tanaka Toshihiro , Fujiwara Takeo , Moriyama Keiji
Published: November 2021

Short root anomaly (SRA) is a dental anomaly with short dental roots and its pathogenesis is poorly understood. This study investigated the association between maternal smoking during pregnancy and SRA in offspring. A survey was conducted on 558 children aged 8–16 years from two public schools in Ulaanbaatar, Mongolia. SRA was diagnosed using cases with a root-crown ratio of maxillary central incisors of ≤1.0. A questionnaire survey was conducted to assess maternal lifestyle habits. Multiple logistic regression was used to analyse the association between maternal smoking during pregnancy and SRA in offspring after adjusting for possible confounders. The prevalence of SRA in these children was 14.2%. Children whose mothers smoked from pregnancy to date were found to be 4.95 times (95% confidence interval [CI]: 1.65–14.79) more likely to have SRA than those whose mothers never smoked, after adjusting for possible confounders. Additionally, children whose mothers had been exposed to passive smoking during pregnancy were found to be 1.86 times (95% CI: 1.02–3.40) more likely to have SRA than those whose mothers had not been exposed to passive smoke. Our population-based study suggests that maternal and passive smoking exposure during pregnancy can affect tooth root formation in children.
Efficacy of a Standardised Patient Simulation Programme for Chronicity and End-of-Life Care Training in Undergraduate Nursing Students
Authors: Escribano Silvia , Cabañero-Martínez María José , Fernández-Alcántara Manuel , García-Sanjuán Sofía , Montoya-Juárez Rafael , Juliá-Sanchis Rocío
Published: November 2021

Background: Standardised patient simulations seem to be useful for improving the communication skills of health sciences students. However, it is important to define the effectiveness of these types of interventions in complex scenarios linked to disease chronicity and end-of-life contexts. Methods: A quasi-experimental study with pre- and post-intervention measures was carried out in a single group. A total of 161 nursing students completed different assessment instruments to measure their attitudes towards communication (Attitude Toward Communication Scale), self-efficacy (Self-Efficacy of Communication Skills, SE-12), and communication skills (Health Professionals Communication Skills Scale, EHC-PS) before and after simulation training with standardised patients. The objective of the program was to train students in non-technical skills for complex situations involving chronicity and end-of-life care. It comprised eight sessions lasting 2.5 h each. Results: The results showed notable baseline gender differences in attitudes towards communication and in the informative communication dimension, with women obtaining higher scores. The participants’ self-efficacy and communication skills significantly improved after completing the intervention, with no significant differences being found for the attitudes towards communication variable. Conclusion: The standardised patient simulation programme for complex scenarios related to chronicity and end-of-life contexts improved communication self-efficacy and communication skills in these nursing students. In future work it will be important to analyse the influence of gender and attitudes towards communication as variables in the learning of communication skills in nursing students.
Effect of Oral Health Education Using a Mobile App (OHEMA) on the Oral Health and Swallowing-Related Quality of Life in Community-Based Integrated Care of the Elderly: A Randomized Clinical Trial
Authors: Ki Ji-Yun , Jo Se-Rim , Cho Kyung-Sook , Park Jung-Eun , Cho Ja-Won , Jang Jong-Hwa
Published: November 2021

This study investigated the effect of oral health education using a mobile app (OHEMA) on the oral health and swallowing-related quality of life (SWAL-QoL) of the elderly population in a community-based integrated care project (CICP). Forty elderly individuals in the CICP were randomized into intervention and control groups. OHEMA provided information on customized oral health care management, oral exercises, and intraoral and extraoral massage methods for 50 min/session, once a week, for 6 weeks. Pre- and post-intervention surveys assessed the unstimulated salivary flow rate, subjective oral dryness, tongue pressure, and SWAL-QoL, which were analyzed using ANCOVA and repeated measures ANOVA. In the intervention group, tongue pressure increased significantly from pre- (17.75) to post-intervention (27.24) (p < 0.001), and subjective oral dryness decreased from pre- (30.75) to post-intervention (18.50). The unstimulated salivary flow rate had a higher mean score in the intervention group (7.19) than in the control group (5.04) (p < 0.001). The SWAL-QoL significantly improved from pre- (152.10) to post-intervention (171.50) in the intervention group (p < 0.001) but did not change significantly in the control group (p > 0.05). OHEMA appears to be a useful tool for oral health education for the elderly as it improved the SWAL-QoL, with increased tongue pressure and reduced oral dryness.
Have China’s Pilot Free Trade Zones Improved Green Total Factor Productivity?
Authors: Ma Qingshan , Zhang Yuanmeng , Yang Kexin , He Lingyun
Published: November 2021

Free trade zones (FTZ) are designated areas for promoting trade openness and investment facilitation. In China, FTZs are also regarded as “green areas” in which planning actions and institutional innovations are implemented, and there is a commitment to promoting urban green and healthy development. Given that green total factor productivity (GTFP) is an important measure of a city’s health and green performance, this study exploits the difference-in-differences method to explore the impact of pilot FTZs on urban GTFP in 280 cities in China for the period between 2005 and 2017. The results show that the green areas positively contributed to the growth of GTFP. Moreover, the outcome holds with robustness tests. Statistically, the positive effect emerged in cities during the first three years after introducing the initiative, with the effect disappearing afterward. It also had a strong positive impact in the central and western regions and in large and medium-sized cities, while the influence remained insignificant in the remaining areas in China. Furthermore, the paper also reveals that the promotion of foreign direct investment and industrial structure upgrading are the primary channels through which the positive relationship between pilot FTZs and GTFP is established.
Protective Factors for LGBTI+ Youth Wellbeing: A Scoping Review Underpinned by Recognition Theory
Authors: Ceatha Nerilee , Koay Aaron C. C. , Buggy Conor , James Oscar , Tully Louise , Bustillo Marta , Crowley Des
Published: November 2021

Considerable research has been undertaken regarding the mental health inequalities experienced by lesbian, gay, bisexual, transgender and intersex (LGBTI+) youth as a consequence of societal and individual prejudice, stigma and discrimination. Far less research has focussed on protective factors that promote wellbeing for this population. A scoping review was conducted using a six-stage methodological framework, and is reported in accordance with the PRISMA-ScR statement. This explored the extent, range and nature of the peer-reviewed, published, academic literature on what is known about the protective factors that promote LGBTI+ youth wellbeing. Six databases were systematically searched applying Population–Concept–Context key inclusion criteria, complemented by contact with authors to identify additional sources, reference checks and hand searches. Ninety-six individual research records were identified and analysed, drawing from Honneth’s Recognition Theory. Interpersonal relations with parents (n = 40), peers (n = 32) and providers (n = 22) were associated with indicators of enhanced wellbeing, as were LGBTI+ community relations (n = 32). Importantly, online (n = 10), faith (n = 10) and cultural (n = 5) communities were potentially protective. Content and thematic analysis highlighted the importance of Gay–Straight Alliances (GSAs) (n = 23) offering powerful protective opportunities through intersecting interpersonal, community and legal forms of recognition. GSAs enhance allyship by peers and providers (n = 21), facilitate access to LGBTI+ community networks (n = 11) and co-exist alongside inclusive policies (n = 12), curricular (n = 5) and extracurricular activities (n = 1). This scoping review underscores the need to move beyond the predominant focus on risk factors for LGBTI+ youth, which subsequently inform protectionist approaches. It concludes with an appeal to develop mechanisms to apply recognitive justice to policy, practice and, importantly, future research directions. This emphasises the salience of enhanced understandings of inclusion, which is rights-based, universally available and of potential benefit to all.
Teaching Urology to Undergraduates: A Prospective Survey of What General Practitioners Need to Know
Authors: Borque-Fernando Ángel , Redondo-Redondo Cristina , Orna-Montesinos Concepción , Esteban Luis Mariano , Denizón-Arranz Sophia , Tejero-Sánchez Arlanza , García-Ruiz Ramiro , Sanchez-Zalabardo José Manuel , Gracia-Romero Jesús , Monreal-Híjar Antonio , Gil-Sanz María Jesús , Sanz Gerardo , Sanz-Pozo Mónica , Romero-Fernández Francisco
Published: November 2021

Background: Higher education training in Medicine has considerably evolved in recent years. One of its main goals has been to ensure the training of students as future adequately qualified general practitioners (GPs). Tools need to be developed to evaluate and improve the teaching of Urology at the undergraduate level. Our objective is to identify the knowledge and skills needed in Urology for the real clinical practice of GPs. Methods: An anonymous self-administered survey was carried out among GPs of Primary Care and Emergencies which sought to evaluate urological knowledge and necessary urological skills. The results of the survey were exported and descriptive statistics were performed using IBM SPSS Statistics version 19.0. Results and limitations: A total of 127 answers were obtained, in which ‘Urological infections’, ‘Renal colic’, ‘PSA levels and screening for prostate cancer’, ‘Benign prostatic hyperplasia’, ‘Hematuria’, ‘Scrotal pain’, ‘Prostate cancer diagnosis’, ‘Bladder cancer diagnosis’, ‘Urinary incontinence’, and ‘Erectile dysfunction’ were rated as Very high or High formative requirements (>75%). Regarding urological skills, ‘Abdominal examination’, ‘Interpretation of urinalysis’, ‘Digital rectal examination’, ‘Genital examination’, and ‘Transurethral catheterization’ were assessed as needing Very high or High training in more than 80% of the surveys. The relevance of urological pathology in clinical practice was viewed as Very high or High in more than 80% of the responses. Conclusions: This study has shown helpful results to establish a differentiated prioritization of urological knowledge and skills in Primary Care and Emergencies. Efforts should be aimed at optimizing the teaching in Urology within the Degree of Medicine which consistently ensures patients’ proper care by future GPs.
The Prevalence of Use of Various Post-Exercise Recovery Methods after Training among Elite Endurance Athletes
Authors: Bezuglov Eduard , Lazarev Artemii , Khaitin Vladimir , Chegin Sergey , Tikhonova Aleksandra , Talibov Oleg , Gerasimuk Dagmara , Waśkiewicz Zbigniew
Published: November 2021

There is now compelling evidence of the effectiveness of a range of post-exercise recovery techniques, including extended nights of sleep, cold water immersion, massage, and compression garments. Currently, limited information is available on post-exercise recovery methods used by elite endurance athletes. Therefore, this study investigated the actual methods of recovery used in this group of athletes. Google Forms were used to collect information on the recovery methods used by elite endurance track and field athletes (n = 153, 61.4% men, 38.6% women; average age: 22.7 ± 4.6 years). The most used methods of recovery were sauna bathing (96.7%), massage (86.9%), daytime nap (81.0%), and long night sleep (at least 9h) (61.4%). Recovery methods with proven effectiveness such as cold water immersion and compression garments were rarely used (15.0% and 7.8%, respectively). Overall, recovery methods were used more often when the tiers of the track and field athletes were higher. Massage and sauna bathing were the most used methods of post-exercise recovery among Russian endurance track and field athletes. In most cases, they were used in conjunction with short daytime nap and long night sleep. Higher tier athletes were more likely to use sauna bathing, massage, long night sleep, and daytime nap but not cold water immersion and compression garments as recovery methods; however, all these methods except for cold water immersion were widely used among elite-tier athletes.
A Descriptive Analysis on the Impact of COVID-19 Lockdowns on Road Traffic Incidents in Sydney, Australia
Authors: Chand Sai , Yee Ernest , Alsultan Abdulmajeed , Dixit Vinayak V.
Published: November 2021

COVID-19 has had tremendous effects worldwide, resulting in large-scale death and upheaval. An abundance of studies have shown that traffic patterns have changed worldwide as working from home has become dominant, with many facilities, restaurants and retail services being closed due to the lockdown orders. With regards to road safety, there have been several studies on the reduction in fatalities and crash frequencies and increase in crash severity during the lockdown period. However, no scientific evidence has been reported on the impact of COVID-19 lockdowns on traffic incident duration, a key metric for crash management. It is also unclear from the existing literature whether the impacts on traffic incidents are consistent across multiple lockdowns. This paper analyses the impact of two different COVID-19 lockdowns in Sydney, Australia, on traffic incident duration and frequency. During the first (31 March–28 April 2020) and second (26 June–31 August 2021) lockdowns, the number of incidents fell by 50% and 60%, respectively, in comparison to the same periods in 2018 and 2019. The proportion of incidents involving towing increased significantly during both lockdowns. The mean duration of crashes increased by 16% during the first lockdown, but the change was less significant during the subsequent lockdown. Crashes involving diversions, emergency services and towing saw an increase in the mean duration by 67%, 16%, and 47%, respectively, during the first lockdown. However, this was not reflected in the 2021 data, with only major crashes seeing a significant increase, i.e., by 58%. There was also a noticeable shift in the location of incidents, with more incidents recorded in suburban areas, away from the central business area. Our findings suggest drastic changes in incident characteristics, and these changes should be considered by policymakers in promoting a safer and more sustainable transportation network in the future.
Epidemiological, Mitigation and Economic Impact of Zoonoses
Authors: Conrady Beate
Published: November 2021

There is increasing evidence on the negative impacts of animal diseases on global productivity [...]
Family and School Relationship during COVID-19 Pandemic: A Systematic Review
Authors: Carrión-Martínez José Juan , Pinel-Martínez Cristina , Pérez-Esteban María Dolores , Román-Sánchez Isabel María
Published: November 2021

Education systems worldwide have been affected by a sudden interruption in classroom learning because the coronavirus pandemic forced both the closure of all schools in March 2020 and the beginning of distance learning from home, thus compelling families, schools, and students to work together in a more coordinated fashion. The present systematic review was carried out following PRISMA guidelines. The main objective was to present critical information on the relationship between the family and the school in the face of the imposed distance learning scenario caused by COVID-19. A total of 25 articles dealing with the relationships established during the pandemic of any of the three agents involved (family, students, and school) were analysed. The results showed that the relationships between the three groups involved must be improved to some extent to meet the needs that have arisen as a result of distance learning. In conclusion, the educational scenario during the pandemic has been one of the most significant challenges experienced in the recent history of education.
Sexual and Gender Minorities and Risk Behaviours among University Students in Italy
Authors: Fonzo Marco , Cocchio Silvia , Centomo Matteo , Baldovin Tatjana , Buja Alessandra , Majori Silvia , Baldo Vincenzo , Bertoncello Chiara
Published: November 2021

Sexual and gender minorities (SGM) may experience stigma, discrimination and show higher prevalence of behavioural risk factors than heterosexual counterparts. In Italy, the information on SGM is scarce and outdated. The present cross-sectional study aims to provide a more up-to-date estimate of the SGM proportion in young adults and to assess differences in the adoption of risk behaviours compared to their heterosexual counterparts. The study involved university students aged 18–25. Information on socio-demographic and behavioural characteristics were collected. The effect of sexual orientation on risk behaviours was assessed with a multinomial single-step logistic regression analysis. A total of 9988 participants were included. Overall, 518 students (5.2%) self-identified as SGM. While lesbians showed significantly higher odds of only non-regular use of protective barriers (AOR: 11.16), bisexuals showed higher odds for frequent drinking (AOR: 2.67), smoking (AOR: 1.85), multiple sexual partnerships (AOR: 1.78) and non-regular use of protective barriers (AOR: 1.90) compared with heterosexual women. Gay men showed higher odds of multiple sexual partnerships compared with heterosexual males (AOR: 5.52). SGM accounted for 5.2% of the sample, slightly more than the proportion found in the general population, but substantially in line with similarly aged populations abroad. Our findings confirm that unhealthy risk behaviours are more frequent among LGBTQ+, in particular among bisexual women. Rather than targeting specific subpopulations, our study aims to show the need for health promotion interventions that aim at the empowerment of all students regardless of sexual orientation, being aware that SGMs can benefit to a relatively greater extent.
Electrification Planning for Healthcare Facilities in Low-Income Countries, Application of a Portfolio-Level, Multi Criteria Decision-Making Approach
Authors: Pakravan Mohammad H. , Johnson Andrea C.
Published: November 2021

This study presents a multi-platform analysis for accelerating the deployment of distributed renewable energy (DRE) systems for the electrification of healthcare facilities (HCFs) in low-income regions. While existing tools capture national and regional scale planning for DRE deployment in HCFs, there are limited tools for facility level energy needs and no existing data-driven approach for systematic decision-making and resource allocation across a portfolio of HCFs. We address this gap by utilizing decentralized data collection, and multi-criteria decision-making to evaluate each HCF against a set of weighted decision criteria. We applied the approach presented in this research in a case study across 56 HCF in Uganda. Results present current and future energy needs for each individual clinic and the prioritization of HCFs for allocation of resources for DRE deployment. Additionally, results provide insight for best practices for reliability of services that are specific to each HCF. For example, failures in the existing solar photovoltaic (PV) systems are approximately up to 60% due to a lack of proper operation and management (O&M) strategy, and 40% is attributable to improper system design and installation. Thus, this study enables decision-makers to better understand the electrification needs of different HCFs, prioritize DRE deployment, financial investments, cost-effective procurement, and long-term O&M.
Pleiotropic Roles of NOTCH1 Signaling in the Loss of Maturational Arrest of Human Osteoarthritic Chondrocytes
Authors: Minguzzi Manuela , Panichi Veronica , D’Adamo Stefania , Cetrullo Silvia , Cattini Luca , Flamigni Flavio , Mariani Erminia , Borzì Rosa Maria
Published: November 2021

Notch signaling has been identified as a critical regulator of cartilage development and homeostasis. Its pivotal role was established by both several joint specific Notch signaling loss of function mouse models and transient or sustained overexpression. NOTCH1 is the most abundantly expressed NOTCH receptors in normal cartilage and its expression increases in osteoarthritis (OA), when chondrocytes exit from their healthy “maturation arrested state” and resume their natural route of proliferation, hypertrophy, and terminal differentiation. The latter are hallmarks of OA that are easily evaluated in vitro in 2-D or 3-D culture models. The aim of our study was to investigate the effect of NOTCH1 knockdown on proliferation (cell count and Picogreen mediated DNA quantification), cell cycle (flow cytometry), hypertrophy (gene and protein expression of key markers such as RUNX2 and MMP-13), and terminal differentiation (viability measured in 3-D cultures by luminescence assay) of human OA chondrocytes. NOTCH1 silencing of OA chondrocytes yielded a healthier phenotype in both 2-D (reduced proliferation) and 3-D with evidence of decreased hypertrophy (reduced expression of RUNX2 and MMP-13) and terminal differentiation (increased viability). This demonstrates that NOTCH1 is a convenient therapeutic target to attenuate OA progression.
Reconstituting Immune Surveillance in Breast Cancer: Molecular Pathophysiology and Current Immunotherapy Strategies
Authors: Cilibrasi Chiara , Papanastasopoulos Panagiotis , Samuels Mark , Giamas Georgios
Published: November 2021

Over the past 50 years, breast cancer immunotherapy has emerged as an active field of research, generating novel, targeted treatments for the disease. Immunotherapies carry enormous potential to improve survival in breast cancer, particularly for the subtypes carrying the poorest prognoses. Here, we review the mechanisms by which cancer evades immune destruction as well as the history of breast cancer immunotherapies and recent developments, including clinical trials that have shaped the treatment of the disease with a focus on cell therapies, vaccines, checkpoint inhibitors, and oncolytic viruses.
Cationic Peptides and Their Cu(II) and Ni(II) Complexes: Coordination and Biological Characteristics
Authors: Kotynia Aleksandra , Wiatrak Benita , Kamysz Wojciech , Neubauer Damian , Jawień Paulina , Marciniak Aleksandra
Published: November 2021

Antimicrobial peptides are a promising group of compounds used for the treatment of infections. In some cases, metal ions are essential to activate these molecules. Examples of metalloantibiotics are, for instance, bleomycin and dermcidin. This study is focused on three new pseudopeptides with potential biological activity. The coordination behavior of all ligands with Cu(II) and Ni(II) ions has been examined. Various analytical methods such as potentiometric titration, UV-Vis and CD spectroscopies, and mass spectrometry were used. All compounds are convenient chelators for metal ion-binding. Two of the ligands tested have histidine residues. Surprisingly, imidazole nitrogen is not involved in the coordination of the metal ion. The N-terminal amino group, Dab side chains, and amide nitrogen atoms of the peptide bonds coordinated Cu(II) and Ni(II) in all the complexes formed. The cytotoxicity of three pseudopeptides and their complexes was evaluated. Moreover, their other model allowed for assessing the attenuation of LPS-induced cytotoxicity and anti-inflammatory activities were also evaluated, the results of which revealed to be very promising.
Effects of Arachidonic Acid Metabolites on Cardiovascular Health and Disease
Authors: Zhou Yan , Khan Haroon , Xiao Jianbo , Cheang Wai San
Published: November 2021

Arachidonic acid (AA) is an essential fatty acid that is released by phospholipids in cell membranes and metabolized by cyclooxygenase (COX), cytochrome P450 (CYP) enzymes, and lipid oxygenase (LOX) pathways to regulate complex cardiovascular function under physiological and pathological conditions. Various AA metabolites include prostaglandins, prostacyclin, thromboxanes, hydroxyeicosatetraenoic acids, leukotrienes, lipoxins, and epoxyeicosatrienoic acids. The AA metabolites play important and differential roles in the modulation of vascular tone, and cardiovascular complications including atherosclerosis, hypertension, and myocardial infarction upon actions to different receptors and vascular beds. This article reviews the roles of AA metabolism in cardiovascular health and disease as well as their potential therapeutic implication.
Leaf Apoplast of Field-Grown Potato Analyzed by Quantitative Proteomics and Activity-Based Protein Profiling
Authors: Abreha Kibrom B. , Alexandersson Erik , Resjö Svante , Lankinen Åsa , Sueldo Daniela , Kaschani Farnusch , Kaiser Markus , van der Hoorn Renier A. L. , Levander Fredrik , Andreasson Erik
Published: November 2021

Multiple biotic and abiotic stresses challenge plants growing in agricultural fields. Most molecular studies have aimed to understand plant responses to challenges under controlled conditions. However, studies on field-grown plants are scarce, limiting application of the findings in agricultural conditions. In this study, we investigated the composition of apoplastic proteomes of potato cultivar Bintje grown under field conditions, i.e., two field sites in June–August across two years and fungicide treated and untreated, using quantitative proteomics, as well as its activity using activity-based protein profiling (ABPP). Samples were clustered and some proteins showed significant intensity and activity differences, based on their field site and sampling time (June–August), indicating differential regulation of certain proteins in response to environmental or developmental factors. Peroxidases, class II chitinases, pectinesterases, and osmotins were among the proteins more abundant later in the growing season (July–August) as compared to early in the season (June). We did not detect significant differences between fungicide Shirlan treated and untreated field samples in two growing seasons. Using ABPP, we showed differential activity of serine hydrolases and β-glycosidases under greenhouse and field conditions and across a growing season. Furthermore, the activity of serine hydrolases and β-glycosidases, including proteins related to biotic stress tolerance, decreased as the season progressed. The generated proteomics data would facilitate further studies aiming at understanding mechanisms of molecular plant physiology in agricultural fields and help applying effective strategies to mitigate biotic and abiotic stresses.
Angiogenesis in Chronic Inflammatory Skin Disorders
Authors: Lee Hyun Ji , Hong Yong Jun , Kim Miri
Published: November 2021

Angiogenesis, the growth of new blood vessels from preexisting vessels, is associated with inflammation in various pathological conditions. Well-known angiogenetic factors include vascular endothelial growth factor (VEGF), angiopoietins, platelet-derived growth factor, transforming growth factor-β, and basic fibroblast growth factor. Yes-associated protein 1 (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) have recently been added to an important angiogenic factor. Accumulating evidence indicates associations between angiogenesis and chronic inflammatory skin diseases. Angiogenesis is deeply involved in the pathogenesis of psoriasis. VEGF, angiopoietins, tumor necrosis factor-a, interleukin-8, and interleukin-17 are unregulated in psoriasis and induce angiogenesis. Angiogenesis may be involved in the pathogenesis of atopic dermatitis, and in particular, mast cells are a major source of VEGF expression. Angiogenesis is an essential process in rosacea, which is induced by LL-37 from a signal cascade by microorganisms, VEGF, and MMP-3 from mast cells. In addition, angiogenesis by increased VEGF has been reported in chronic urticaria and hidradenitis suppurativa. The finding that VEGF is expressed in inflammatory skin lesions indicates that inhibition of angiogenesis is a useful strategy for treatment of chronic, inflammatory skin disorders.
A Small Step, a Giant Leap: Somatic Hypermutation of a Single Amino Acid Leads to Anti-La Autoreactivity
Authors: Bartsch Tabea , Arndt Claudia , Loureiro Liliana R. , Kegler Alexandra , Puentes-Cala Edinson , Soto Javier Andrés , Kurien Biji T. , Feldmann Anja , Berndt Nicole , Bachmann Michael P.
Published: November 2021

The anti-La mab 312B, which was established by hybridoma technology from human-La transgenic mice after adoptive transfer of anti-human La T cells, immunoprecipitates both native eukaryotic human and murine La protein. Therefore, it represents a true anti-La autoantibody. During maturation, the anti-La mab 312B acquired somatic hypermutations (SHMs) which resulted in the replacement of four aa in the complementarity determining regions (CDR) and seven aa in the framework regions. The recombinant derivative of the anti-La mab 312B in which all the SHMs were corrected to the germline sequence failed to recognize the La antigen. We therefore wanted to learn which SHM(s) is (are) responsible for anti-La autoreactivity. Humanization of the 312B ab by grafting its CDR regions to a human Ig backbone confirms that the CDR sequences are mainly responsible for anti-La autoreactivity. Finally, we identified that a single amino acid replacement (D > Y) in the germline sequence of the CDR3 region of the heavy chain of the anti-La mab 312B is sufficient for anti-La autoreactivity.
Multi-Omics Study of Keystone Species in a Cystic Fibrosis Microbiome
Authors: Silveira Cynthia B. , Cobián-Güemes Ana G. , Uranga Carla , Baker Jonathon L. , Edlund Anna , Rohwer Forest , Conrad Douglas
Published: November 2021

Ecological networking and in vitro studies predict that anaerobic, mucus-degrading bacteria are keystone species in cystic fibrosis (CF) microbiomes. The metabolic byproducts from these bacteria facilitate the colonization and growth of CF pathogens like Pseudomonas aeruginosa. Here, a multi-omics study informed the control of putative anaerobic keystone species during a transition in antibiotic therapy of a CF patient. A quantitative metagenomics approach combining sequence data with epifluorescence microscopy showed that during periods of rapid lung function loss, the patient’s lung microbiome was dominated by the anaerobic, mucus-degrading bacteria belonging to Streptococcus, Veillonella, and Prevotella genera. Untargeted metabolomics and community cultures identified high rates of fermentation in these sputa, with the accumulation of lactic acid, citric acid, and acetic acid. P. aeruginosa utilized these fermentation products for growth, as indicated by quantitative transcriptomics data. Transcription levels of P. aeruginosa genes for the utilization of fermentation products were proportional to the abundance of anaerobic bacteria. Clindamycin therapy targeting Gram-positive anaerobes rapidly suppressed anaerobic bacteria and the accumulation of fermentation products. Clindamycin also lowered the abundance and transcription of P. aeruginosa, even though this patient’s strain was resistant to this antibiotic. The treatment stabilized the patient’s lung function and improved respiratory health for two months, lengthening by a factor of four the between-hospitalization time for this patient. Killing anaerobes indirectly limited the growth of P. aeruginosa by disrupting the cross-feeding of fermentation products. This case study supports the hypothesis that facultative anaerobes operated as keystone species in this CF microbiome. Personalized multi-omics may become a viable approach for routine clinical diagnostics in the future, providing critical information to inform treatment decisions.
Inhibition of Sphingosine-1-Phosphate Receptor 2 by JTE013 Promoted Osteogenesis by Increasing Vesicle Trafficking, Wnt/Ca2+, and BMP/Smad Signaling
Authors: Lin Simon , Pandruvada Subramanya , Yu Hong
Published: November 2021

Sphingosine-1-phosphate receptor 2 (S1PR2) is a G protein-coupled receptor that regulates various immune responses. Herein, we determine the effects of a S1PR2 antagonist (JTE013) or a S1PR2 shRNA on osteogenesis by culturing murine bone marrow stromal cells (BMSCs) in osteogenic media with JTE013, dimethylsulfoxide (DMSO), a S1PR2 shRNA, or a control shRNA. Treatment with JTE013 or the S1PR2 shRNA increased alkaline phosphatase and alizarin red s staining, and enhanced alkaline phosphatase, RUNX2, osteocalcin, and osterix mRNA levels in BMSCs compared with the controls. Protein analysis revealed that a high dose of JTE013 (4 or 8 μM) increased vesicle trafficking-associated proteins (F-actin, clathrin, Early Endosome Antigen 1 (EEA1), and syntaxin 6) and Wnt/Ca2+ signaling. On the other hand, a low dose of JTE013 (1 to 2 μM) increased BMP/Smad signaling. In contrast, the S1PR2 shRNA reduced vesicle trafficking-associated proteins and attenuated Wnts and BMP/Smad signaling, but enhanced p-CaMKII compared with the control, suggesting that the S1PR2 shRNA influenced osteogenesis via different signaling pathways. Moreover, inhibiting protein trafficking by brefeldin A in BMSCs suppressed Wnts and BMPRs expressions. These data supported that enhanced osteogenesis in JTE013-treated BMSCs is associated with increased vesicle trafficking, which promotes the synthesis and transport of osteogenic protein and matrix vesicles and enhances matrix mineralization.
Rhizosphere Microbiomes of Potato Cultivated under Bacillus subtilis Treatment Influence the Quality of Potato Tubers
Authors: Song Jian , Kong Zhi-Qiang , Zhang Dan-Dan , Chen Jie-Yin , Dai Xiao-Feng , Li Ran
Published: November 2021

Plants serve as a niche for the growth and proliferation of a diversity of microorganisms. Soil microorganisms, which closely interact with plants, are increasingly being recognized as factors important to plant health. In this study, we explored the use of high-throughput DNA sequencing of the fungal ITS and bacterial 16S for characterization of the fungal and bacterial microbiomes following biocontrol treatment (DT) with Bacillus subtilis strain Bv17 relative to treatments without biocontrol (DC) during the potato growth cycle at three time points. A total of 5631 operational taxonomic units (OTUs) were identified from the 16S data, and 2236 OTUs were identified from the ITS data. The number of bacterial and fungal OTU in DT was higher than in DC and gradually increased during potato growth. In addition, indices such as Ace, Chao, Shannon, and Simpson were higher in DT than in DC, indicating greater richness and community diversity in soil following the biocontrol treatment. Additionally, the potato tuber yields improved without a measurable change in the bacterial communities following the B. subtilis strain Bv17 treatment. These results suggest that soil microbial communities in the rhizosphere are differentially affected by the biocontrol treatment while improving potato yield, providing a strong basis for biocontrol utilization in crop production.
Cubic Octa-Carbon: Quantum-Chemical Design of Molecular Structure and Potential Way of Its Synthesis from Cubane
Authors: Chachkov Denis V. , Mikhailov Oleg V.
Published: November 2021

Quantum-chemical calculation of most important parameters of molecular and electronic structures of octa-carbon C8 having cubic form (bond lengths, bond and torsion angles) using CCSD(T)/QZVP and DFT B3PW91/QZVP methods, has been carried out. NBO analysis data and HOMO/LUMO images for this compound are presented, too. Good agreement was found between the structural data obtained using the above two quantum-chemical methods and, also, with corresponding experimental data. Also, the standard thermodynamic parameters of formation of cubic C8 considered here, and namely standard enthalpy ΔfH0(298K), entropy Sf0(298K) and Gibbs’ energy ΔfG0(298K) of formation for this compound were calculated. By using this data, a theoretically possible variant of the synthesis of this compound by dehydrogenation of cubane C8H8 is considered, and the thermodynamic characteristics of each of the four stages of this process have been calculated. It is noted that each of the four stages of this process is characterized by a very high (about 500 kJ/mol) enthalpy of activation, as a result of that, for their realization within a sufficiently short time, the use of appropriate catalysts is necessary.
The Significance of mRNA in the Biology of Multiple Myeloma and Its Clinical Implications
Authors: Puła Anna , Robak Paweł , Mikulski Damian , Robak Tadeusz
Published: November 2021

Multiple myeloma (MM) is a genetically complex disease that results from a multistep transformation of normal to malignant plasma cells in the bone marrow. However, the molecular mechanisms responsible for the initiation and heterogeneous evolution of MM remain largely unknown. A fundamental step needed to understand the oncogenesis of MM and its response to therapy is the identification of driver mutations. The introduction of gene expression profiling (GEP) in MM is an important step in elucidating the molecular heterogeneity of MM and its clinical relevance. Since some mutations in myeloma occur in non-coding regions, studies based on the analysis of mRNA provide more comprehensive information on the oncogenic pathways and mechanisms relevant to MM biology. In this review, we discuss the role of gene expression profiling in understanding the biology of multiple myeloma together with the clinical manifestation of the disease, as well as its impact on treatment decisions and future directions.
Photopharmacology of Ion Channels through the Light of the Computational Microscope
Authors: Nin-Hill Alba , Mueller Nicolas Pierre Friedrich , Molteni Carla , Rovira Carme , Alfonso-Prieto Mercedes
Published: November 2021

The optical control and investigation of neuronal activity can be achieved and carried out with photoswitchable ligands. Such compounds are designed in a modular fashion, combining a known ligand of the target protein and a photochromic group, as well as an additional electrophilic group for tethered ligands. Such a design strategy can be optimized by including structural data. In addition to experimental structures, computational methods (such as homology modeling, molecular docking, molecular dynamics and enhanced sampling techniques) can provide structural insights to guide photoswitch design and to understand the observed light-regulated effects. This review discusses the application of such structure-based computational methods to photoswitchable ligands targeting voltage- and ligand-gated ion channels. Structural mapping may help identify residues near the ligand binding pocket amenable for mutagenesis and covalent attachment. Modeling of the target protein in a complex with the photoswitchable ligand can shed light on the different activities of the two photoswitch isomers and the effect of site-directed mutations on photoswitch binding, as well as ion channel subtype selectivity. The examples presented here show how the integration of computational modeling with experimental data can greatly facilitate photoswitchable ligand design and optimization. Recent advances in structural biology, both experimental and computational, are expected to further strengthen this rational photopharmacology approach.
Multifunctional Nanomaterials: Synthesis, Properties and Applications
Authors: Yadav Raghvendra Singh
Published: November 2021

In this Special Issue “Multifunctional Nanomaterials: Synthesis, Properties and Applications”, we published three review papers and nine original research articles [...]
Tubular Assembly Formation Induced by Leucine Alignment along the Hydrophobic Helix of Amphiphilic Polypeptides
Authors: Abosheasha Mohammed A. , Itagaki Toru , Ito Yoshihiro , Ueda Motoki
Published: November 2021

The introduction of α-helical structure with a specific helix–helix interaction into an amphipathic molecule enables the determination of the molecular packing in the assembly and the morphological control of peptide assemblies. We previously reported that the amphiphilic polypeptide SL12 with a polysarcosine (PSar) hydrophilic chain and hydrophobic α-helix (l-Leu-Aib)6 involving the LxxxLxxxL sequence, which induces homo-dimerization due to the concave–convex interaction, formed a nanotube with a uniform 80 nm diameter. In this study, we investigated the importance of the LxxxLxxxL sequence for tube formation by comparing amphiphilic polypeptide SL4A4L4 with hydrophobic α-helix (l-Leu-Aib)2-(l-Ala-Aib)2-(l-Leu-Aib)2 and SL12. SL4A4L4 formed spherical vesicles and micelles. The effect of the LxxxLxxxL sequence elongation on tube formation was demonstrated by studying assemblies of PSar-b-(l-Ala-Aib)-(l-Leu-Aib)6-(l-Ala-Aib) (SA2L12A2) and PSar-b-(l-Leu-Aib)8 (SL16). SA2L12A2 formed nanotubes with a uniform 123 nm diameter, while SL16 assembled into vesicles. These results showed that LxxxLxxxL is a necessary and sufficient sequence for the self-assembly of nanotubes. Furthermore, we fabricated a double-layer nanotube by combining two kinds of nanotubes with 80 and 120 nm diameters—SL12 and SA2L12A2. When SA2L12A2 self-assembled in SL12 nanotube dispersion, SA2L12A2 initially formed a rolled sheet, the sheet then wrapped the SL12 nanotube, and a double-layer nanotube was obtained.
Senolytics: A Novel Strategy for Neuroprotection in ALS?
Authors: Maximova Alexandra , Werry Eryn L. , Kassiou Michael
Published: November 2021

Amyotrophic lateral sclerosis (ALS) is a progressive motor neurodegenerative disease that currently has no cure and has few effective treatments. On a cellular level, ALS manifests through significant changes in the proper function of astrocytes, microglia, motor neurons, and other central nervous system (CNS) cells, leading to excess neuroinflammation and neurodegeneration. Damage to the upper and lower motor neurons results in neural and muscular dysfunction, leading to death most often due to respiratory paralysis. A new therapeutic strategy is targeting glial cells affected by senescence, which contribute to motor neuron degeneration. Whilst this new therapeutic approach holds much promise, it is yet to be trialled in ALS-relevant preclinical models and needs to be designed carefully to ensure selectivity. This review summarizes the pathways involved in ALS-related senescence, as well as known senolytic agents and their mechanisms of action, all of which may inform strategies for ALS-focused drug discovery efforts.
AMBRA1 Negatively Regulates the Function of ALDH1B1, a Cancer Stem Cell Marker, by Controlling Its Ubiquitination
Authors: Baek Seung-Heon , Jang Yeun-Kyu
Published: November 2021

Activating molecule in Beclin-1-regulated autophagy (AMBRA1), a negative regulator of tumorigenesis, is a substrate receptor of the ubiquitin conjugation system. ALDH1B1, an aldehyde dehydrogenase, is a cancer stem cell (CSC) marker that is required for carcinogenesis via upregulation of the β-catenin pathway. Although accumulating evidence suggests a role for ubiquitination in the regulation of CSC markers, the ubiquitination-mediated regulation of ALDH1B1 has not been unraveled. While proteome analysis has suggested that AMBRA1 and ALDH1B1 can interact, their interaction has not been validated. Here, we show that AMBRA1 is a negative regulator of ALDH1B1. The expression of ALDH1B1-regulated genes, including PTEN, CTNNB1 (β-catenin), and CSC-related β-catenin target genes, is inversely regulated by AMBRA1, suggesting a negative regulatory role of AMBRA1 in the expression of ALDH1B1-regulated genes. We found that the K27- and K33-linked ubiquitination of ALDH1B1 is mediated via the cooperation of AMBRA1 with other E3 ligases, such as TRAF6. Importantly, ubiquitination site mapping revealed that K506, K511, and K515 are important for the K27-linked ubiquitination of ALDH1B1, while K33-linked ubiquitination occurs at K506. A ubiquitination-defective mutant of ALDH1B1 increased the self-association ability of ALDH1B1, suggesting a negative correlation between the ubiquitination and self-association of ALDH1B1. Together, our findings indicate that ALDH1B1 is negatively regulated by AMBRA1-mediated noncanonical ubiquitination.
Memory Disorders Related to Hippocampal Function: The Interest of 5-HT4Rs Targeting
Authors: Roux Candice M. , Leger Marianne , Freret Thomas
Published: November 2021

The hippocampus has long been considered as a key structure for memory processes. Multilevel alterations of hippocampal function have been identified as a common denominator of memory impairments in a number of psychiatric and neurodegenerative diseases. For many years, the glutamatergic and cholinergic systems have been the main targets of therapeutic treatments against these symptoms. However, the high rate of drug development failures has left memory impairments on the sideline of current therapeutic strategies. This underscores the urgent need to focus on new therapeutic targets for memory disorders, such as type 4 serotonin receptors (5-HT4Rs). Ever since the discovery of their expression in the hippocampus, 5-HT4Rs have gained growing interest for potential use in the treatment of learning and memory impairments. To date, much of the researched information gathered by scientists from both animal models and humans converge on pro-mnesic and anti-amnesic properties of 5-HT4Rs activation, although the mechanisms at work require more work to be fully understood. This review addresses a fundamental, yet poorly understood set of evidence of the potential of 5-HT4Rs to re-establish or limit hippocampal alterations related to neurological diseases. Most importantly, the potential of 5-HT4Rs is translated by refining hypotheses regarding the benefits of their activation in memory disorders at the hippocampal level.
Epstein–Barr Virus Prevalence at Diagnosis and Seroconversion during Follow-Up in Pediatric Inflammatory Bowel Disease
Authors: Bachmann Jennifer , Le Thi Giang , Brückner Annecarin , Kalteis Anna-Lena , Schwerd Tobias , Koletzko Sibylle , Lurz Eberhard
Published: November 2021

Primary Epstein–Barr virus infection in pediatric patients with inflammatory bowel disease during immunomodulation with thiopurines has been associated with increased risk for malignancies or hemophagocytic lymphohistiocytosis. We determined Epstein–Barr virus (EBV) seroprevalence at inflammatory bowel disease (IBD) diagnosis and seroconversion during follow-up in a large single center cohort of children with IBD. EBV serology results and patient characteristics were retrospectively retrieved from the hospital documentation system. EBV seronegative patients at IBD diagnosis were prospectively retested. We report on IBD patients with symptomatic active EBV infection and a complicated disease course, and those diagnosed with malignancy with respect to EBV status and drug exposure. Of 402 patients, 194 (48%) had available EBV serology results at time of IBD diagnosis at a median of 12 years (IQR 9–14 years). Thereof, 102 (53%) were EBV-positive. Of 92 EBV-negative patients, 66 were retested and 17% showed a seroconversion at a mean follow-up time of 4.3 years (SD 3 years). Three children treated with azathioprine experienced acute clinically relevant EBV infection 2, 2.5, and 4 years after IBD diagnosis, two developed signs of hemophagocytic lymphohistiocytosis. Three cases of malignancy occurred in the cohort, though none seemed to be triggered by EBV. In conclusion, almost 50% of pediatric IBD patients were EBV-naïve following diagnosis and may be at increased risk to develop severe EBV infection during immunosuppressive therapy, potentially associated with complications such as hemophagocytic lymphohistiocytosis or malignancy.