bluuebunny/crossref_metadata_2025 huggingface dataset:
Development and Validation of a Sub-National, Satellite-Based Land-Use Regression Model for Annual Nitrogen Dioxide Concentrations in North-Western China
Authors: Popovic Igor , Magalhães Ricardo J. Soares , Yang Shukun , Yang Yurong , Ge Erjia , Yang Boyi , Dong Guanghui , Wei Xiaolin , Marks Guy B. , Knibbs Luke D.
Published: December 2021

Existing national- or continental-scale models of nitrogen dioxide (NO2) exposure have a limited capacity to capture subnational spatial variability in sparsely-populated parts of the world where NO2 sources may vary. To test and validate our approach, we developed a land-use regression (LUR) model for NO2 for Ningxia Hui Autonomous Region (NHAR) and surrounding areas, a small rural province in north-western China. Using hourly NO2 measurements from 105 continuous monitoring sites in 2019, a supervised, forward addition, linear regression approach was adopted to develop the model, assessing 270 potential predictor variables, including tropospheric NO2, optically measured by the Aura satellite. The final model was cross-validated (5-fold cross validation), and its historical performance (back to 2014) assessed using 41 independent monitoring sites not used for model development. The final model captured 63% of annual NO2 in NHAR (RMSE: 6 ppb (21% of the mean of all monitoring sites)) and contiguous parts of Inner Mongolia, Gansu, and Shaanxi Provinces. Cross-validation and independent evaluation against historical data yielded adjusted R2 values that were 1% and 10% lower than the model development values, respectively, with comparable RMSE. The findings suggest that a parsimonious, satellite-based LUR model is robust and can be used to capture spatial contrasts in annual NO2 in the relatively sparsely-populated areas in NHAR and neighbouring provinces.
Research on the Spatial and Temporal Differences of China’s Provincial Carbon Emissions and Ecological Compensation Based on Land Carbon Budget Accounting
Authors: Jing Xiaodong , Tian Guiliang , Li Minrui , Javeed Sohail Ahmad
Published: December 2021

The establishment of a complete carbon ecological compensation mechanism is of great significance for China to achieve “carbon peak and carbon neutrality” as soon as possible. From the perspective of land carbon budget accounting, this paper measures the carbon emissions and the value of carbon ecological compensation in 30 provinces in China from 2010 to 2019, by constructing a carbon ecological compensation model, and analyzes it from both time and space perspectives. The study found that: (1) during the period 2010–2019, China’s carbon absorption remained basically stable, and woodland and grassland were the main carriers of China’s land carbon absorption. The total carbon sequestration of woodland and grassland showed a pattern of being high in the west and low in the east, and the total carbon sequestration of cultivated land showed a pattern of being high in the east and low in the west. (2) Construction land is the main source of carbon emissions in China. Cultivated land carbon emissions mainly come from major agricultural provinces such as Henan and Heilongjiang, while construction land carbon emissions are mainly concentrated in energy-consuming provinces such as Shandong and Shanxi. (3) After revising the carbon compensation benchmark value, it is found that provinces such as Guangdong and Jiangsu should receive carbon ecological compensation, while provinces dominated by heavy industries such as Shanxi and Shandong need to pay corresponding carbon compensation fees. Finally, this article puts forward corresponding policy recommendations, such as that China should give full play to the role of the government and the market, accelerate the optimization and improvement of the ecological resource asset property rights system, and optimize the development and utilization of land.
Analysis of Superspreading Potential from Transmission Clusters of COVID-19 in South Korea
Authors: Lee Hyojung , Han Changyong , Jung Jooyi , Lee Sunmi
Published: December 2021

The COVID-19 pandemic has been spreading worldwide with more than 246 million confirmed cases and 5 million deaths across more than 200 countries as of October 2021. There have been multiple disease clusters, and transmission in South Korea continues. We aim to analyze COVID-19 clusters in Seoul from 4 March to 4 December 2020. A branching process model is employed to investigate the strength and heterogeneity of cluster-induced transmissions. We estimate the cluster-specific effective reproduction number Reff and the dispersion parameter κ using a maximum likelihood method. We also compute Rm as the mean secondary daily cases during the infection period with a cluster size m. As a result, a total of 61 clusters with 3088 cases are elucidated. The clusters are categorized into six groups, including religious groups, convalescent homes, and hospitals. The values of Reff and κ of all clusters are estimated to be 2.26 (95% CI: 2.02–2.53) and 0.20 (95% CI: 0.14–0.28), respectively. This indicates strong evidence for the occurrence of superspreading events in Seoul. The religious groups cluster has the largest value of Reff among all clusters, followed by workplaces, schools, and convalescent home clusters. Our results allow us to infer the presence or absence of superspreading events and to understand the cluster-specific characteristics of COVID-19 outbreaks. Therefore, more effective suppression strategies can be implemented to halt the ongoing or future cluster transmissions caused by small and sporadic clusters as well as large superspreading events.
To Be (Vaccinated) or Not to Be: The Effect of Media Exposure, Institutional Trust, and Incentives on Attitudes toward COVID-19 Vaccination
Authors: Zimand-Sheiner Dorit , Kol Ofrit , Frydman Smadar , Levy Shalom
Published: December 2021

The COVID-19 vaccine has become a strategic vehicle for reducing the spread of the pandemic. However, the uptake of the vaccine by the public is more complicated than simply making it available. Based on social learning theory, this study examines the role of communication sources and institutional trust as barriers and incentives as motivators of people’s attitudes toward vaccination and actual vaccination. Data were collected via an online panel survey among Israelis aged 18–55 and then analyzed using structural equation modeling (SEM). Findings show that social media trust negatively mediates the effect of exposure to information on the vaccine on attitudes toward vaccination. However, mass media trust and institutional trust positively mediate this relationship. Incentives were effective motivators for forming positive attitudes and moderating the effect of institutional trust on attitude toward vaccination. This study facilitates a deeper understanding of health communication theory in pandemics and makes important recommendations for practitioners and policy makers.
Acute Effects of Particulate Matter on All-Cause Mortality in Urban, Rural, and Suburban Areas, Italy
Authors: Renzi Matteo , Marchetti Stefano , de' Donato Francesca , Pappagallo Marilena , Scortichini Matteo , Davoli Marina , Frova Luisa , Michelozzi Paola , Stafoggia Massimo
Published: December 2021

Background: Short-term exposure to particulate matter (PM) has been related to mortality worldwide. Most evidence comes from studies conducted in major cities, while little is known on the effects of low concentrations of PM and in less urbanized areas. We aim to investigate the relationship between PM and all-cause mortality at national level in Italy. Methods: Daily numbers of all-cause mortality were collected for all 8092 municipalities of Italy, from 2006 to 2015. A satellite-based spatiotemporal model was developed to estimate daily PM10 (inhalable particles) and PM2.5 (fine particles) concentrations at 1-km resolution. Multivariate Poisson regression models were fit to estimate the association between daily PM and mortality at province level, and then, results were pooled with a random-effects meta-analysis. Associations were estimated by combination of age and sex and degree of urbanization of the municipalities. Flexible functions were estimated to explore the shape of the associations at low PM concentrations. Results: We analyzed 5,884,900 deaths (40% among subjects older than 85 years, 60% occurring outside the main urban areas). National daily mean (interquartile range) PM10 and PM2.5 concentrations were 23 (14) μg/m3 and 15 (11) μg/m3, respectively. Relative increases of mortality per 10 μg/m3 variation in lag 0–5 (average of last six days since death) PM10 and PM2.5 were 1.47% (95% Confidence Intervals (CI): 1.15%, 1.79%) and 1.96% (1.33%, 2.59%), respectively. Associations were highest among elderly and women for PM10 only, similar between rural and urbanized areas, and were present even at low concentrations, e.g., below WHO guidelines. Conclusions: Air pollution was robustly associated with peaks in daily all-cause mortality in Italy, both in large cities and in less urbanized areas of Italy. Current WHO Air Quality Guidelines (2021) for PM10 and PM2.5 are not sufficient to protect public health.
Assessment of the Mandatory Non-Financial Reporting of Romanian Companies in the Circular Economy Context
Authors: Hategan Camelia-Daniela , Pitorac Ruxandra-Ioana , Milu Nicoleta-Daniela
Published: December 2021

Between the circular economy and corporate social responsibility, there is an ever-closer connection. Non-financial reporting of social responsibility actions is based on the circular economy concept, so reporting contributes to increasing the level of disclosure of circular strategies. In this context, large companies are required to report non-financial information to understand their activities better. The paper’s objective is to assess the mandatory non-financial reporting of Romanian companies active in the non-financial sector for 2017–2019. The empirical analysis consisted of creating and awarding an evaluation score to the reports of the companies. An econometric model was tested using a feasible generalized least squares (FGLS) regression to identify the link of the obtained Score with a series of variables representing the characteristics of the companies: Information on a website (I), Foreign ownership (F), Private ownership (P), Listed company (L), Return on assets (ROA), and Return on equity (ROE). Research results highlight a positive correlation between Score and all variables statistically significant in the model. Our study empirically validated the link between non-financial reporting and financial performance. The practical implications for managers can be to focus on improving the quality of non-financial reporting by better presenting the sustainability actions in a circular economy context.
The Impact of Dental Midline on Asymmetric Faces: Perspective of Laypersons and Dentists
Authors: Martins Joana Meneses , Costa Liliana Gavinha , Carvalho Ana Lidia , Manso Maria Conceição , Gavinha Sandra , Herrero-Climent Mariano , Ríos-Carrasco Blanca , Falcão Carlos , Ribeiro Paulo
Published: December 2021

Background: The objective was to determine if asymmetric facial features, nasal and chin deviations, affect the perception of attractiveness of a dental midline angulation, and if it is consistent among both dentists and laypeople. It was also analyzed if factors, such as the sex, age group of the participants and the dentist’s area of operation are relevant in their assessment. Methods: A cross-sectional study, approved by the Ethics Committee of Fernando Pessoa University. From a symmetrical facial model (SFM) image, a natural-looking asymmetrical face was created. Based on this asymmetric facial model six images were created, with different directions and degrees of inclination of the dental midline. In total, 236 laypersons and 242 dentists completed the online questionnaire where they rated the self-perception of attractiveness of the eight images (VAS scale from 0 to 10). Non-parametric comparisons (IBM© SPSS Statistics vs. 27.0, p < 0.05). Results: The results showed a significant difference in the perception of attractiveness between laypeople and dentists. This finding was consistent regarding every image, except for the SFM. The factors, sex of the people participating and dentist’s area of operation, seemed only to contribute to a significant difference in the perception when it came to the SFM. The perceived attractiveness of the images, for dentists and laypersons, did not differ by age group of the participant, apart from images 6 and 8. Conclusions: Dentists are more rigorous about dental midline inclinations than laypersons. The perception of attractiveness was affected by the age group and sex of the participants and the dentist’s area of operation.
Mental Fatigue-Associated Decrease in Table Tennis Performance: Is There an Electrophysiological Signature?
Authors: Habay Jelle , Proost Matthias , De Wachter Jonas , Díaz-García Jesús , De Pauw Kevin , Meeusen Romain , Van Cutsem Jeroen , Roelands Bart
Published: December 2021

Mental fatigue (MF) is a psychobiological state negatively impacting both cognitive and physical performance. Although recent research implies that some table tennis (TT) performance outcomes are impaired by MF, open skill sports such as TT require a more detailed overview of MF-related performance decrements. Moreover, research into MF and sport-specific psychomotor performance lacks the inclusion of brain-related measurements to identify MF mechanisms. Eleven experienced TT players participated in this randomized counterbalanced crossover trial. Participants were either required to perform an individualized Stroop task (MF condition) or watch a documentary (control condition). The primary outcomes were reaction time on a sport-specific visuomotor task and EEG activity throughout the trial. The subjective feeling of MF was significantly different between both conditions and confirmed that the MF condition induced the mentally fatigue state of participants (p < 0.001), though no behavioral indicators (i.e., decrease in performance on Stroop and flanker task) of MF. MF worsened reaction time on the visuomotor task, while other secondary measurements remained largely ambiguous. Spectral power (i.e., decreases in upper α band and θ band) was influenced by MF, while ERPs measured during the visuomotor task remained unaltered. The present study confirms that MF negatively impacts table tennis performance, specifically inhibitory stimuli during the visuomotor task. These findings also further augment our understanding of the effects of MF on human performance.
Developing a Hybrid Platform for Emergency Remote Education of Nursing Students in the Context of COVID-19
Authors: Kawasaki Hiromi , Yamasaki Satoko , Rahman Md Moshiur
Published: December 2021

Due to the COVID-19 pandemic, many nursing students are being taught remotely. Remote learning has drawbacks, such as decreased motivation for learning and difficulties conveying the instructor’s intentions. Strategies that compensate for the shortcomings of remote learning should be identified. This study aimed to evaluate the understanding of the knowledge use and awareness of negotiation methods through cases and teaching tools in nursing student classes on environmental assessment and daily life support, and to examine whether supplementary assistance can compensate for the drawbacks of remote learning. This study used a mixed-method design, and included 59 second-year nursing students attending an environmental assessment course in 2021. Students’ knowledge use and awareness of negotiation methods were evaluated using self-assessment worksheets before and after the class. The pre- and post-class scores were compared using the Wilcoxon signed-rank test. The mean knowledge score increased significantly during the study period (p < 0.001). Students acquired awareness of how to use the knowledge gained during class and negotiation awareness by observing role play, factors that strengthen motivation when learning alone. This study provides insight into the potential of class supplements to compensate for the deficits of remote learning. Supplementing the shortcomings of remote learning should be a priority and may be a focal point of hybrid learning.
Detection of CpG Methylation in G-Quadruplex Forming Sequences Using G-Quadruplex Ligands
Authors: Hasegawa Hijiri , Sasaki Ikkei , Tsukakoshi Kaori , Ma Yue , Nagasawa Kazuo , Numata Shusuke , Inoue Yuuki , Kim Yeji , Ikebukuro Kazunori
Published: December 2021

Genomic DNA methylation is involved in many diseases and is expected to be a specific biomarker for even the pre-symptomatic diagnosis of many diseases. Thus, a rapid and inexpensive detection method is required for disease diagnosis. We have previously reported that cytosine methylation in G-quadruplex (G4)-forming oligonucleotides develops different G4 topologies. In this study, we developed a method for detecting CpG methylation in G4-forming oligonucleotides based on the structural differences between methylated and unmethylated G4 DNAs. The differences in G4 topologies due to CpG methylation can be discriminated by G4 ligands. We performed a binding assay between methylated or unmethylated G4 DNAs and G4 ligands. The binding abilities of fluorescent G4 ligands to BCL-2, HRAS1, HRAS2, VEGF G4-forming sequences were examined by fluorescence-based microtiter plate assay. The differences in fluorescence intensities between methylated and unmethylated G4 DNAs were statistically significant. In addition to fluorescence detection, the binding of G4 ligand to DNA was detected by chemiluminescence. A significant difference was also detected in chemiluminescence intensity between methylated and unmethylated DNA. This is the first study on the detection of CpG methylation in G4 structures, focusing on structural changes using G4 ligands.
Gut Microbiota Extracellular Vesicles as Signaling Molecules Mediating Host-Microbiota Communications
Authors: Sultan Salma , Mottawea Walid , Yeo JuDong , Hammami Riadh
Published: December 2021

Over the past decade, gut microbiota dysbiosis has been linked to many health disorders; however, the detailed mechanism of this correlation remains unclear. Gut microbiota can communicate with the host through immunological or metabolic signalling. Recently, microbiota-released extracellular vesicles (MEVs) have emerged as significant mediators in the intercellular signalling mechanism that could be an integral part of microbiota-host communications. MEVs are small membrane-bound vesicles that encase a broad spectrum of biologically active compounds (i.e., proteins, mRNA, miRNA, DNA, carbohydrates, and lipids), thus mediating the horizontal transfer of their cargo across intra- and intercellular space. In this study, we provide a comprehensive and in-depth discussion of the biogenesis of microbial-derived EVs, their classification and routes of production, as well as their role in inter-bacterial and inter-kingdom signaling.
Azobenzene/Tetraethyl Ammonium Photochromic Potassium Channel Blockers: Scope and Limitations for Design of Para-Substituted Derivatives with Specific Absorption Band Maxima and Thermal Isomerization Rate
Authors: Strashkov Daniil M. , Mironov Vladimir N. , Nikolaev Dmitrii M. , Panov Maxim S. , Linnik Stanislav A. , Mereshchenko Andrey S. , Kochemirovsky Vladimir A. , Vasin Andrey V. , Ryazantsev Mikhail N.
Published: December 2021

Azobenzene/tetraethyl ammonium photochromic ligands (ATPLs) are photoactive compounds with a large variety of photopharmacological applications such as nociception control or vision restoration. Absorption band maximum and lifetime of the less stable isomer are important characteristics that determine the applicability of ATPLs. Substituents allow to adjust these characteristics in a range limited by the azobenzene/tetraethyl ammonium scaffold. The aim of the current study is to find the scope and limitations for the design of ATPLs with specific spectral and kinetic properties by introducing para substituents with different electronic effects. To perform this task we synthesized ATPLs with various electron acceptor and electron donor functional groups and studied their spectral and kinetic properties using flash photolysis and conventional spectroscopy techniques as well as quantum chemical modeling. As a result, we obtained diagrams that describe correlations between spectral and kinetic properties of ATPLs (absorption maxima of E and Z isomers of ATPLs, the thermal lifetime of their Z form) and both the electronic effect of substituents described by Hammett constants and structural parameters obtained from quantum chemical calculations. The provided results can be used for the design of ATPLs with properties that are optimal for photopharmacological applications.
Soybean miR159-GmMYB33 Regulatory Network Involved in Gibberellin-Modulated Resistance to Heterodera glycines
Authors: Lei Piao , Qi Nawei , Zhou Yuan , Wang Yuanyuan , Zhu Xiaofeng , Xuan Yuanhu , Liu Xiaoyu , Fan Haiyan , Chen Lijie , Duan Yuxi
Published: December 2021

Soybean cyst nematode (SCN, Heterodera glycines) is an obligate sedentary biotroph that poses major threats to soybean production globally. Recently, multiple miRNAome studies revealed that miRNAs participate in complicated soybean-SCN interactions by regulating their target genes. However, the functional roles of miRNA and target genes regulatory network are still poorly understood. In present study, we firstly investigated the expression patterns of miR159 and targeted GmMYB33 genes. The results showed miR159-3p downregulation during SCN infection; conversely, GmMYB33 genes upregulated. Furthermore, miR159 overexpressing and silencing soybean hairy roots exhibited strong resistance and susceptibility to H. glycines, respectively. In particular, miR159-GAMYB genes are reported to be involve in GA signaling and metabolism. Therefore, we then investigated the effects of GA application on the expression of miR159-GAMYB module and the development of H. glycines. We found that GA directly controls the miR159-GAMYB module, and exogenous GA application enhanced endogenous biologically active GA1 and GA3, the abundance of miR159, lowered the expression of GmMYB33 genes and delayed the development of H. glycines. Moreover, SCN infection also results in endogenous GA content decreased in soybean roots. In summary, the soybean miR159-GmMYB33 module was directly involved in the GA-modulated soybean resistance to H. glycines.
Experimental Characterization of the Interaction between the N-Terminal SH3 Domain of Crkl and C3G
Authors: Pagano Livia , Malagrinò Francesca , Nardella Caterina , Gianni Stefano , Toto Angelo
Published: December 2021

Crkl is a protein involved in the onset of several cancer pathologies that exerts its function only through its protein–protein interaction domains, a SH2 domain and two SH3 domains. SH3 domains are small protein interaction modules that mediate the binding and recognition of proline-rich sequences. One of the main physiological interactors of Crkl is C3G (also known as RAPGEF1), an interaction with key implications in regulating cellular growth and differentiation, cell morphogenesis and adhesion processes. Thus, understanding the interaction between Crkl and C3G is fundamental to gaining information about the molecular determinants of the several cancer pathologies in which these proteins are involved. In this paper, through a combination of fast kinetics at different experimental conditions and site-directed mutagenesis, we characterize the binding reaction between the N-SH3 domain of Crkl and a peptide mimicking a specific portion of C3G. Our results show a clear effect of pH on the stability of the complex, due to the protonation of negatively charged residues in the binding pocket of N-SH3. Our results are discussed under the light of previous work on SH3 domains.
DFMO Improves Survival and Increases Immune Cell Infiltration in Association with MYC Downregulation in the Pancreatic Tumor Microenvironment
Authors: Nakkina Sai Preethi , Gitto Sarah B. , Beardsley Jordan M. , Pandey Veethika , Rohr Michael W. , Parikh Jignesh G. , Phanstiel Otto , Altomare Deborah A.
Published: December 2021

Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor five-year survival rate of less than 10%. Immune suppression along with chemoresistance are obstacles for PDAC therapeutic treatment. Innate immune cells, such as tumor-associated macrophages, are recruited to the inflammatory environment of PDAC and adversely suppress cytotoxic T lymphocytes. KRAS and MYC are important oncogenes associated with immune suppression and pose a challenge to successful therapies. Here, we targeted KRAS, through inhibition of downstream c-RAF with GW5074, and MYC expression via difluoromethylornithine (DFMO). DFMO alone and with GW5074 reduced in vitro PDAC cell viability. Both DFMO and GW5074 showed efficacy in reducing in vivo PDAC growth in an immunocompromised model. Results in immunocompetent syngeneic tumor-bearing mice showed that DFMO and combination treatment markedly decreased tumor size, but only DFMO increased survival in mice. To further investigate, immunohistochemical staining showed DFMO diminished MYC expression and increased tumor infiltration of macrophages, CD86+ cells, CD4+ and CD8+ T lymphocytes. GW5074 was not as effective in modulating the tumor infiltration of total CD3+ lymphocytes or tumor progression and maintained MYC expression. Collectively, this study highlights that in contrast to GW5074, the inhibition of MYC through DFMO may be an effective treatment modality to modulate PDAC immunosuppression.
Regulation of Serotonin 1A Receptor SUMOylation by SENP2 and PIASxα
Authors: Gupta Sugandha , Wang Mengya , Azuma Yoshiaki , Muma Nancy A.
Published: December 2021

Serotonin 1A receptors (5-HT1ARs) are implicated in the control of mood, cognition, and memory and in various neuropsychiatric disorders such as depression and anxiety. As such, understanding the regulation of 5-HT1ARs will inform the development of better treatment approaches. We previously demonstrated 5-HT1ARs are SUMOylated by SUMO1 in the rat brain. Agonist stimulation increased SUMOylation and was further enhanced when combined with 17β-estradiol-3-benzoate (EB), which are treatments that cause the transient and prolonged desensitization of 5-HT1AR signaling, respectively. In the current study, we identified the protein inhibitor of activated STAT (PIAS)xα as the enzyme that facilitates SUMOylation, and SENP2 as the protein that catalyzes the deSUMOylation of 5-HT1ARs. We demonstrated that PIASxα significantly increased in the membrane fraction of rats co-treated with EB and an agonist, compared to either the EB-treated or vehicle-treated groups. The acute treatment with an agonist alone shifted the location of SENP2 from the membrane to the cytoplasmic fraction, but it has little effect on PIASxα. Hence, two separate mechanisms regulate SUMOylation and the activity of 5-HT1ARs by an agonist and EB. The effects of EB on 5-HT1AR SUMOylation and signaling may be related to the higher incidence of mood disorders in women during times with large fluctuations in estrogens. Targeting the SUMOylation of 5-HT1ARs could have important clinical relevance for the therapy for several neuropsychiatric disorders in which 5-HT1ARs are implicated.
The Link between Gut Dysbiosis Caused by a High-Fat Diet and Hearing Loss
Authors: Kociszewska Dagmara , Chan Jeffrey , Thorne Peter R. , Vlajkovic Srdjan M.
Published: December 2021

This review aims to provide a conceptual and theoretical overview of the association between gut dysbiosis and hearing loss. Hearing loss is a global health issue; the World Health Organisation (WHO) estimates that 2.5 billion people will be living with some degree of hearing loss by 2050. The aetiology of sensorineural hearing loss (SNHL) is complex and multifactorial, arising from congenital and acquired causes. Recent evidence suggests that impaired gut health may also be a risk factor for SNHL. Inflammatory bowel disease (IBD), type 2 diabetes, diet-induced obesity (DIO), and high-fat diet (HFD) all show links to hearing loss. Previous studies have shown that a HFD can result in microangiopathy, impaired insulin signalling, and oxidative stress in the inner ear. A HFD can also induce pathological shifts in gut microbiota and affect intestinal barrier (IB) integrity, leading to a leaky gut. A leaky gut can result in chronic systemic inflammation, which may affect extraintestinal organs. Here, we postulate that changes in gut microbiota resulting from a chronic HFD and DIO may cause a systemic inflammatory response that can compromise the permeability of the blood–labyrinth barrier (BLB) in the inner ear, thus inducing cochlear inflammation and hearing deficits.
Two Opposing Functions of Angiotensin-Converting Enzyme (ACE) That Links Hypertension, Dementia, and Aging
Authors: Le Duc , Brown Lindsay , Malik Kundan , Murakami Shin
Published: December 2021

A 2018 report from the American Heart Association shows that over 103 million American adults have hypertension. The angiotensin-converting enzyme (ACE) (EC 3.4.15.1) is a dipeptidyl carboxylase that, when inhibited, can reduce blood pressure through the renin–angiotensin system. ACE inhibitors are used as a first-line medication to be prescribed to treat hypertension, chronic kidney disease, and heart failure, among others. It has been suggested that ACE inhibitors can alleviate the symptoms in mouse models. Despite the benefits of ACE inhibitors, previous studies also have suggested that genetic variants of the ACE gene are risk factors for Alzheimer’s disease (AD) and other neurological diseases, while other variants are associated with reduced risk of AD. In mice, ACE overexpression in the brain reduces symptoms of the AD model systems. Thus, we find two opposing effects of ACE on health. To clarify the effects, we dissect the functions of ACE as follows: (1) angiotensin-converting enzyme that hydrolyzes angiotensin I to make angiotensin II in the renin–angiotensin system; (2) amyloid-degrading enzyme that hydrolyzes beta-amyloid, reducing amyloid toxicity. The efficacy of the ACE inhibitors is well established in humans, while the knowledge specific to AD remains to be open for further research. We provide an overview of ACE and inhibitors that link a wide variety of age-related comorbidities from hypertension to AD to aging. ACE also serves as an example of the middle-life crisis theory that assumes deleterious events during midlife, leading to age-related later events.
Molecular Effectors of Photodynamic Therapy-Mediated Resistance to Cancer Cells
Authors: Aniogo Eric Chekwube , George Blassan P. , Abrahamse Heidi
Published: December 2021

Photodynamic therapy (PDT) is currently enjoying considerable attention as the subject of experimental research to treat resistant cancers. The preferential accumulation of a non-toxic photosensitizer (PS) in different cellular organelles that causes oxidative damage by combining light and molecular oxygen leads to selective cell killing. However, one major setback, common among other treatment approaches, is tumor relapse and the development of resistance causing treatment failure. PDT-mediated resistance could result from increased drug efflux and decreased localization of PS, reduced light exposure, increased DNA damage repair, and altered expression of survival genes. This review highlights the essential insights of PDT reports in which PDT resistance was observed and which identified some of the molecular effectors that facilitate the development of PDT resistance. We also discuss different perceptions of PDT and how its current limitations can be overturned to design improved cancer resistant treatments.
Cytokine Signalling at the Microglial Penta-Partite Synapse
Authors: Aramideh Jason Abbas , Vidal-Itriago Andres , Morsch Marco , Graeber Manuel B.
Published: December 2021

Microglial cell processes form part of a subset of synaptic contacts that have been dubbed microglial tetra-partite or quad-partite synapses. Since tetrapartite may also refer to the presence of extracellular matrix components, we propose the more precise term microglial penta-partite synapse for synapses that show a microglial cell process in close physical proximity to neuronal and astrocytic synaptic constituents. Microglial cells are now recognised as key players in central nervous system (CNS) synaptic changes. When synaptic plasticity involving microglial penta-partite synapses occurs, microglia may utilise their cytokine arsenal to facilitate the generation of new synapses, eliminate those that are not needed anymore, or modify the molecular and structural properties of the remaining synaptic contacts. In addition, microglia–synapse contacts may develop de novo under pathological conditions. Microglial penta-partite synapses have received comparatively little attention as unique sites in the CNS where microglial cells, cytokines and other factors they release have a direct influence on the connections between neurons and their function. It concerns our understanding of the penta-partite synapse where the confusion created by the term “neuroinflammation” is most counterproductive. The mere presence of activated microglia or the release of their cytokines may occur independent of inflammation, and penta-partite synapses are not usually active in a neuroimmunological sense. Clarification of these details is the main purpose of this review, specifically highlighting the relationship between microglia, synapses, and the cytokines that can be released by microglial cells in health and disease.
Involvement of Rare Mutations of SCN9A, DPP4, ABCA13, and SYT14 in Schizophrenia and Bipolar Disorder
Authors: Chen Chia-Hsiang , Huang Yu-Shu , Fang Ting-Hsuan
Published: December 2021

Rare mutations associated with schizophrenia (SZ) and bipolar disorder (BD) usually have high clinical penetrance; however, they are highly heterogeneous and personalized. Identifying rare mutations is instrumental in making the molecular diagnosis, understanding the pathogenesis, and providing genetic counseling for the affected individuals and families. We conducted whole-genome sequencing analysis in two multiplex families with the dominant inheritance of SZ and BD. We detected a G327E mutation of SCN9A and an A654V mutation of DPP4 cosegregating with SZ and BD in one three-generation multiplex family. We also identified three mutations cosegregating with SZ and BD in another two-generation multiplex family, including L711S of SCN9A, M4554I of ABCA13, and P159L of SYT14. These five missense mutations were rare and deleterious. Mutations of SCN9A have initially been reported to cause congenital insensitivity to pain and neuropathic pain syndromes. Further studies showed that rare mutations of SCN9A were associated with seizure and autism spectrum disorders. Our findings suggest that SZ and BD might also be part of the clinical phenotype spectra of SCN9A mutations. Our study also indicates the oligogenic involvement in SZ and BD and supports the multiple-hit model of SZ and BD.
The Effect of Conjugation with Octaarginine, a Cell-Penetrating Peptide on Antifungal Activity of Imidazoacridinone Derivative
Authors: Rząd Kamila , Paluszkiewicz Ewa , Neubauer Damian , Olszewski Mateusz , Kozłowska-Tylingo Katarzyna , Kamysz Wojciech , Gabriel Iwona
Published: December 2021

Acridine cell-penetrating peptide conjugates are an extremely important family of compounds in antitumor chemotherapy. These conjugates are not so widely analysed in antimicrobial therapy, although bioactive peptides could be used as nanocarriers to smuggle antimicrobial compounds. An octaarginine conjugate of an imidazoacridinone derivative (Compound 1-R8) synthetized by us exhibited high antifungal activity against reference and fluconazole-resistant clinical strains (MICs ≤ 4 μg mL−1). Our results clearly demonstrate the qualitative difference in accumulation of the mother compound and Compound 1-R8 conjugate into fungal cells. Only the latter was transported and accumulated effectively. Microscopic and flow cytometry analysis provide some evidence that the killing activity of Compound 1-R8 may be associated with a change in the permeability of the fungal cell membrane. The conjugate exhibited low cytotoxicity against human embryonic kidney (HEK-293) and human liver (HEPG2) cancer cell lines. Nevertheless, the selectivity index value of the conjugate for human pathogenic strains remained favourable and no hemolytic activity was observed. The inhibitory effect of the analysed compound on yeast topoisomerase II activity suggested its molecular target. In summary, conjugation with R8 effectively increased imidazoacridinone derivative ability to enter the fungal cell and achieve a concentration inside the cell that resulted in a high antifungal effect.
Elucidating the Molecular Mechanisms by which Seed-Borne Endophytic Fungi, Epichloë gansuensis, Increases the Tolerance of Achnatherum inebrians to NaCl Stress
Authors: Cheng Chen , Wang Jianfeng , Hou Wenpeng , Malik Kamran , Zhao Chengzhou , Niu Xueli , Liu Yinglong , Huang Rong , Li Chunjie , Nan Zhibiao
Published: December 2021

Seed-borne endophyte Epichloë gansuensis enhance NaCl tolerance in Achnatherum inebrians and increase its biomass. However, the molecular mechanism by which E. gansuensis increases the tolerance of host grasses to NaCl stress is unclear. Hence, we firstly explored the full-length transcriptome information of A. inebrians by PacBio RS II. In this work, we obtained 738,588 full-length non-chimeric reads, 36,105 transcript sequences and 27,202 complete CDSs from A. inebrians. We identified 3558 transcription factors (TFs), 15,945 simple sequence repeats and 963 long non-coding RNAs of A. inebrians. The present results show that 2464 and 1817 genes were differentially expressed by E. gansuensis in the leaves of E+ and E− plants at 0 mM and 200 mM NaCl concentrations, respectively. In addition, NaCl stress significantly regulated 4919 DEGs and 502 DEGs in the leaves of E+ and E− plants, respectively. Transcripts associated with photosynthesis, plant hormone signal transduction, amino acids metabolism, flavonoid biosynthetic process and WRKY TFs were differentially expressed by E. gansuensis; importantly, E. gansuensis up-regulated biology processes (brassinosteroid biosynthesis, oxidation–reduction, cellular calcium ion homeostasis, carotene biosynthesis, positive regulation of proteasomal ubiquitin-dependent protein catabolism and proanthocyanidin biosynthesis) of host grass under NaCl stress, which indicated an increase in the ability of host grasses’ adaptation to NaCl stress. In conclusion, our study demonstrates the molecular mechanism for E. gansuensis to increase the tolerance to salt stress in the host, which provides a theoretical basis for the molecular breed to create salt-tolerant forage with endophytes.
Lactate Suppresses Retroviral Transduction in Cervical Epithelial Cells through DNA-PKcs Modulation
Authors: Wagner Waldemar , Sobierajska Katarzyna , Kania Katarzyna Dominika , Paradowska Edyta , Ciszewski Wojciech Michał
Published: December 2021

Recently, we have shown the molecular basis for lactate sensing by cervical epithelial cells resulting in enhanced DNA repair processes through DNA-PKcs regulation. Interestingly, DNA-PKcs is indispensable for proper retroviral DNA integration in the cell host genome. According to recent findings, the mucosal epithelium can be efficiently transduced by retroviruses and play a pivotal role in regulating viral release by cervical epithelial cells. This study examined the effects of lactate on lentiviral transduction in cervical cancer cells (HeLa, CaSki, and C33A) and model glioma cell lines (DNA-PKcs proficient and deficient). Our study showed that L- and D-lactate enhanced DNA-PKcs presence in nuclear compartments by between 38 and 63%, which corresponded with decreased lentiviral transduction rates by between 15 and 36%. Changes in DNA-PKcs expression or its inhibition with NU7441 also greatly affected lentiviral transduction efficacy. The stimulation of cells with either HCA1 agonist 3,5-DHBA or HDAC inhibitor sodium butyrate mimicked, in part, the effects of L-lactate. The inhibition of lactate flux by BAY-8002 enhanced DNA-PKcs nuclear localization which translated into diminished lentiviral transduction efficacy. Our study suggests that L- and D-lactate present in the uterine cervix may play a role in the mitigation of viral integration in cervical epithelium and, thus, restrict the viral oncogenic and/or cytopathic potential.
Role of microRNAs in the Pathophysiology of Ulcerative Colitis
Authors: Toyonaga Takahiko , Saruta Masayuki
Published: December 2021

Ulcerative colitis (UC) is an intractable disorder characterized by a chronic inflammation of the colon. Studies have identified UC as a multifactorial disorder affected by both genetic and environmental factors; however, the precise mechanism remains unclear. Recent advances in the field of microRNA (miRNA) research have identified an association between this small non-coding RNA in the pathophysiology of UC and altered miRNA expression profiles in patients with UC. Nevertheless, the roles of individual miRNAs are uncertain due to heterogeneity in both research samples and clinical backgrounds. In this review, we focus on miRNA expression in colonic mucosa where inflammation occurs in UC and discuss the potential roles of individual miRNAs in disease development, outlining the pathophysiology of UC.
Context-Aware Music Recommender Systems for Groups: A Comparative Study
Authors: Valera Adrián , Lozano Murciego Álvaro , Moreno-García María N.
Published: December 2021

Nowadays, recommender systems are present in multiple application domains, such as e-commerce, digital libraries, music streaming services, etc. In the music domain, these systems are especially useful, since users often like to listen to new songs and discover new bands. At the same time, group music consumption has proliferated in this domain, not just physically, as in the past, but virtually in rooms or messaging groups created for specific purposes, such as studying, training, or meeting friends. Single-user recommender systems are no longer valid in this situation, and group recommender systems are needed to recommend music to groups of users, taking into account their individual preferences and the context of the group (when listening to music). In this paper, a group recommender system in the music domain is proposed, and an extensive comparative study is conducted, involving different collaborative filtering algorithms and aggregation methods.
The Efficiency Analysis of Large Banks Using the Bootstrap and Fuzzy DEA: A Case of an Emerging Market
Authors: Gardijan Kedžo Margareta , Tuškan Sjauš Branka
Published: December 2021

In this study, banks’ business performance efficiency was analysed using data envelopment analysis (DEA), with expense categories as inputs and income categories as outputs. By incorporating a bootstrap method and a fuzzy data approach into a DEA model, additional insights and sensitivity analysis of the results were obtained. This study shows how fuzzy and bootstrap DEA can be used for investigating real market problems with uncertain data in an uncertain sample. The empirical analysis was based on the period of 2009–2018 for a sample of seven of Croatia’s largest private banks. The aim of the study was also to interpret the DEA results with regards to the specific market, legal, and macroeconomic conditions, caused by the changes introduced in the last decade. The results, and the changes in the inputs and outputs over time, revealed that the market processes occurring in the observed period had a significant impact on banks’ business performance, but led to a more efficient banking system. Two banks were found to be dominant over the others regardless of the changes in the sample and data fuzziness. DEA results were additionally compared to the most important financial indicators and accounting ratios, as an alternative or additional measure of banks’ efficiency and profitability.
Real-Time Continuous Acoustic Monitoring of Marine Mammals in the Mediterranean Sea
Authors: Sanguineti Matteo , Guidi Carlo , Kulikovskiy Vladimir , Taiuti Mauro Gino
Published: December 2021

The passive acoustic monitoring of cetaceans is a research method that can provide unique information on the animal’s behaviour since the animals can be studied at great depths and at a long-range without interference. Nevertheless, the real-time data collection, transfer, and analysis using these techniques are difficult to implement and maintain. In this paper, a review of several experiments that have used this approach will be provided. The first class of detectors consists of hydrophone systems housed under buoys on the sea surface with wireless data transmission, while the second type comprises several acoustic detector networks integrated within submarine neutrino telescopes cabled to the shore.
Optimization and Experimental Study of the Subsea Retractable Connector Rubber Packer Based on Mooney-Rivlin Constitutive Model
Authors: Jiao Kefeng , Yun Feihong , Yan Zheping , Wang Gang , Jia Peng , Wang Liquan , Liu Dong , Hao Xiaoquan
Published: December 2021

The sealing performance of the rubber packer is of vital importance for the subsea retractable connector, and the cross-sectional shape of the rubber packer is one of the most important factors affecting it. The compression distance of the rubber packer is increased by 19.54% utilizing the established two-dimensional numerical model. In addition, a new parameter called the anti-shoulder extrusion variable was defined in this paper. Shoulder extrusion will not occur when using this variable as a constraint during simulation. In general, the upper end and the lower end of a rubber packer are subject to different constraints, and the structural parameters of the rubber packer affect each other in terms of sealing performance. Therefore, the importance and originality of this study are exploring the optimization of the thickness and chamfer angles of the upper and lower ends of the rubber packer by use of a combination of the response surface optimization method and the multi-objective genetic algorithm, taking the thickness and chamfer angles of the upper and lower ends as design variables, and the stress on the inner side of the casing wall and the axial force of the compressed rubber packer as optimization objectives. Besides that, the anti-shoulder extrusion variables are also introduced as constraints to prevent shoulder extrusion. Ultimately, the cross-sectional shape of the rubber packer with a smaller-thickness and larger-angle upper end, and a larger-thickness and smaller-angle lower end can be obtained. The result to emerge from the test in this paper is that the pipe pressure that can be sealed by the optimized rubber packer structure is 25.61% higher than that before optimization. The anti-shoulder extrusion variable and the asymmetric cross-sectional shape of the rubber packer proposed in this paper shed new light on the finite element simulation of rubber and the research on similar seals.