bluuebunny/crossref_metadata_2025 huggingface dataset:
Emulgels Containing Propolis and Curcumin: The Effect of Type of Vegetable Oil, Poly(Acrylic Acid) and Bioactive Agent on Physicochemical Stability, Mechanical and Rheological Properties
Authors: Said dos Santos Rafaela , Bassi da Silva Jéssica , Rosseto Hélen Cássia , Vecchi Camila Felix , Campanholi Katieli da Silva Souza , Caetano Wilker , Bruschi Marcos Luciano
Published: August 2021

Emulgels are obtained by the entrapment of an organic phase within a three-dimensional network built by hydrophilic molecules. Polymers based on cross-linked poly(acrylic acid) have been utilized as gel matrices, improving adhesiveness, rheological and mechanical performance. Propolis (PRP) produced by Apis mellifera L. bees displays a wide range of biological activities. Together with curcumin (CUR), they may show synergic anti-inflammatory, antioxidant and antimicrobial action on skin disorders. This work investigated the effect of vegetable oils (sweet almond, andiroba, and passion fruit) with regard to the physicochemical properties of emulgels composed of Carbopol 934P®, Carbopol 974P®, or polycarbophil aiming the CUR and PRP delivery. Physicochemical stability enabled the selection of systems containing passion fruit or andiroba oil. Mechanical and rheological characteristics provided rational comprehension of how vegetable oils and bioactive agents affect the structure of emulsion gels. All formulations exhibited high physiochemical stability and properties dependent on the polymer type, oil, and bioactive agent. Formulations displayed pseudoplastic, thixotropic and viscoelastic properties. Emulgels containing andiroba oil were the most stable systems. Carbopol 934P® or polycarbophil presence resulted in formulations with improved smoothness and mechanical properties. Systems containing andiroba oil and one of these two polymers are promising for further investigations as topical delivery systems of CUR and/or PRP on the skin and mucous membranes.
NAM-NMM Temperature Downscaling Using Personal Weather Stations to Study Urban Heat Hazards
Authors: Calovi Martina , Hu Weiming , Cervone Guido , Delle Monache Luca
Published: August 2021

Rising temperatures worldwide pose an existential threat to people, properties, and the environment. Urban areas are particularly vulnerable to temperature increases due to the heat island effect, which amplifies local heating. Throughout the world, several megacities experience summer temperatures that stress human survival. Generating very high-resolution temperature forecasts is a fundamental problem to mitigate the effects of urban warming. This paper uses the Analog Ensemble technique to downscale existing temperature forecast from a low resolution to a much higher resolution using private weather stations. A new downscaling approach, based on the reuse of the Analog Ensemble (AnEn) indices, resulted by the combination of days and Forecast Lead Time (FLT)s, is proposed. Specifically, temperature forecasts from the NAM-NMM Numerical Weather Prediction model at 12 km are downscaled using 83 Private Weather Stations data over Manhattan, New York City, New York. Forecasts for 84 h are generated, hourly for the first 36 h, and every three hours thereafter. The results are dense forecasts that capture the spatial variability of ambient conditions. The uncertainty associated with using non-vetted data is addressed.
Cosmogenic and Geological Evidence for the Occurrence of a Ma-Long Feedback between Uplift and Denudation, Chur Region, Swiss Alps
Authors: da Silva Guimarães Ewerton , Delunel Romain , Schlunegger Fritz , Akçar Naki , Stutenbecker Laura , Christl Marcus
Published: August 2021

We used concentrations of in situ cosmogenic 10Be from riverine sediment to quantify the basin-averaged denudation rates and sediment fluxes in the Plessur Basin, Eastern Swiss Alps, which is a tributary stream to the Alpine Rhine, one of the largest streams in Europe. We complement the cosmogenic dataset with the results of morphometric analyses, geomorphic mapping, and sediment fingerprinting techniques. The results reveal that the Plessur Basin is still adjusting to the landscape perturbation caused by the glacial carving during the Last Glacial Maximum c. 20,000 years ago. This adjustment has been most efficient in the downstream part where the bedrock comprises high erodibility North Penninic flysch and Bündnerschist, whereas glacial landforms are still prominently preserved in the upstream region, comprising low erodibility South Penninic and Austroalpine bedrock. This geomorphic observation is supported by the 10Be based denudation rate and sediment provenance analysis, which indicate a much faster sediment production in the flysch and schist lithologies. Interestingly, the reach of fast denudation has experienced the highest exhumation and rock uplift rates. This suggests that lithologic and glacial conditioning have substantially contributed to the local uplift and denudation as some of the driving forces of a positive feedback system.
Loss Aversion and Health Behaviors: Results from Two Incentivized Economic Experiments
Authors: Bessey Donata
Published: August 2021

Experimental research in health economics has analyzed the effects of economic preference parameters such as risk attitude and time preference on the probability of adopting risky health behaviors. However, the existing evidence is mixed and previous research often fails to include controls for other determinants of health behaviors such as personality traits. The aim of this research is to analyze the relationships between an incentivized measure of loss aversion and three health behaviors: smoking, binge drinking, and engaging in physical activity. Loss aversion is a preference measure that has been derived from prospect theory as an alternative approach to analyze decision-making under risk, such as the decision to invest in health capital, and has never been used in an analysis of the determinants of health behaviors before. Using two experimental samples of college students in the Republic of Korea and the United States of America, and controlling for Big Five personality traits and a host of individual-level control variables, there are no statistically significant relationships between loss aversion and the three aforementioned health behaviors, but relationships for Big Five conscientiousness, extraversion, agreeableness, and neuroticism. A candidate explanation might be lack of domain independence for loss aversion. Differences between the Korean and the US samples indicate the possibility of intercultural differences.
Contemporary Sound Practices: Church Bells and Bell Ringing in New South Wales, Australia
Authors: Parker Murray , Spennemann Dirk H. R.
Published: August 2021

As a social species, humans have developed soundscapes that surround, and to some extent circumscribe, their daily existence. The concept of aural heritage, its conceptualization and its management represent a rapidly expanding area of research, covering aspects of both natural and human heritage. However, there have been no contemporary regional or supra-regional studies that examine the nature of sound making in Christian religious settings, nor the extent to which it is still used. This paper presents the results of a survey into the presence of bells and bell ringing practices among five major Christian denominations in New South Wales, and examines to what extent bell ringing is still practiced and what factors may determine any differentiation. In doing so, it provides an objective basis from which to investigate future changes in bell ringing practices, and provides a solid foundation with reference to aural heritage of sound in a religious setting.
The Cultural Heritage of Architectural Linear Perspective: The Mural Paintings in Nantang Church
Authors: Castilla Manuel V.
Published: August 2021

This paper presents a contextual use of the innovative drawing techniques that involved architecture and painting in the Qing court during the first half of the eighteenth century. At this point architectural linear perspective in painting (quadratura) and stage design had become common fields of experimentation for the Chinese and Jesuit artists missionaries. In this conceptual context, Western quadratura was developed in China by Giovanni Gherardini. (1655–1729), and especially by Giuseppe Castiglione (1688–1766), who is remembered as an extraordinarily versatile architect–painter. The focus of this paper is on the “illusory mural paintings of architectural perspective in Nantang Church” (Beijing), which has now disappeared, and which spread the influence of the Western Renaissance. The imported Western linear perspective and the fundamentals of architectural drawing facilitated the systematization and dissemination of the quadratura as an unknown technique in China. Based on the text described by the contemporary scholar Yao Yuan Zhi, an original interpretation of the architectural perspective mural paintings in Nantang Church is proposed. These paintings provide an important case study of Sino-European collaboration in the eighteenth century from different points of view: the representation of the light in drawings and the fact that the concept of shadow in some respects was unknown to the Chinese artist.
Knowledge, Attitude, Practices and Viewpoints of Undergraduate University Students towards Self-Medication: An Institution-Based Study in Riyadh
Authors: Mannasaheb Basheerahmed Abdulaziz , Al-Yamani Mohammed Jaber , Alajlan Sarah Abdulrahman , Alqahtani Lamyaa Munahi , Alsuhimi Shrouq Eid , Almuzaini Razan Ibrahim , Albaqawi Abeer Fahad , Alshareef Zahaa Majed
Published: August 2021

Rational and responsible self-medication (SM) is not only the key to better health outcomes, but also key to limiting adverse drug events. This institution-based cross-sectional study utilized seven- and four-item scales to assess the knowledge and attitude towards SM. Similarly, SM practices were measured using eight scale questions consisting of SM practice during the last six months, type of drug consumed, reason and frequency of SM, and so on. Statistical analyses were performed using SPSS. Overall, 371 students completed the questionnaire. The students with a good level of knowledge and positive attitude towards SM were 60.64% and 66.8%, respectively. About 55.5% of students practiced SM during the last six months using antipyretics (37.7%), multivitamins (36.4%), sleeping aids (20.2%), and anti-histamines (18.6%). Headache (79.2%), fever (37.7%), pain (25.9%), and colds and coughs (25.3%) were the illnesses for which they sought SM. The students admitted that drug side effects (75%), drug resistance (33.7%), drug interaction (41.5%), and poor treatment outcome (28.3%) were the consequences of irrational SM practice. Students (87.6%) propose that extending SM awareness through the Ministry of Health (83%) and pharmaceutical companies (48%) as major platforms would improvise the rational practice. Since AlMaarefa University students will be future healthcare professionals, their perception must be considered and accordingly educated to practice rational SM.
Detection of SARS-CoV-2 in Wastewater Northeast of Mexico City: Strategy for Monitoring and Prevalence of COVID-19
Authors: González-Reyes José Roberto , Hernández-Flores María de la Luz , Paredes-Zarco Jesús Eduardo , Téllez-Jurado Alejandro , Fayad-Meneses Omar , Carranza-Ramírez Lamán
Published: August 2021

A month-long wastewater sampling project was conducted along the northeast periphery of Mexico City, specifically in the state of Hidalgo, to assess the presence of SARS-CoV-2. To determine the prevalence of infection and obtain a range of COVID-19 cases in the main metropolitan zones. Viral RNA residues (0–197,655 copies/L) were measured in wastewater from the five central municipalities in the state. By recording the number of RNA viral copies per liter, micro-basins delimitation, demographic and physiological data, an interval of infected people and virus prevalence was estimated using a Monte Carlo model (with 90% confidence) in the micro-basin of five municipalities with metropolitan influence or industrial activity. Our procedure determined that the percentage of the infected population ranges from 1.4% to 41.7%, while the official data reports 0.1–0.3%. This model is proposed as a helpful method of regional epidemiological monitoring through the analysis of viral prevalence.
Analysis of the Consequences of the COVID-19 Pandemic on People with Severe Mental Disorders
Authors: Sánchez-Guarnido Antonio José , Hidalgo Nuria , Arenas de la Cruz Jorge , Esteban Inmaculada , Mondón Silvia , Herruzo Carlos
Published: August 2021

For people with severe mental disorders (SMDs) the COVID-19 pandemic may pose a number of risks. These include the loss of needed care, a higher probability of infection, and the worsening of their mental health. To analyze the pandemic’s impact on care received, relapses, loss of employment, and adherence to preventive guidelines in SMD sufferers, a multicenter retrospective cohort study was carried out comparing 185 patients diagnosed with SMD and 85 with common disorders. The results showed that during lockdown, there was a significant reduction in face-to-face psychotherapeutic, nursing, and occupational therapy interventions. In the same period, telematic interventions were introduced which, although subsequently reduced, now continue to be used to a greater extent than before the pandemic. Employment decreased significantly (13% vs. 9.2%; χ2 = 126.228 p < 0.001). The percentage of people with SMD following preventive guidelines was significantly lower for both hand washing (56.2% vs. 75.3%; χ2 = 9.360, p = 0.002) and social distancing (47% vs. 63.5; χ2 = 6.423 p = 0.011). In conclusion, the COVID-19 pandemic has led to a reduction in the interventions that are needed for the recovery of people with SMDs, together with a significant loss of employment and an increased risk of contagion due to less adherence to preventive guidelines. In the future, appropriate attention to these people’s needs must be guaranteed.
Potential Psychological and Biological Mechanisms Underlying the Effectiveness of Neonatal Music Therapy during Kangaroo Mother Care for Preterm Infants and Their Parents
Authors: Bieleninik Łucja , Ettenberger Mark , Epstein Shulamit , Elefant Cochavit , Arnon Shmuel
Published: August 2021

Neonatal music therapy (MT) has become more accessible worldwide. Previous research suggests multiple benefits of MT for preterm infants and their caregivers; however, far too little attention has been paid to understanding the mechanisms of change in previous Neonatal Intensive Care Unit (NICU)-MT research so far. This perspective article describes potential mechanisms of MT interventions exposed during kangaroo mother care on the preterm infant’s response (behavioral and physiological outcomes) and the mother-infant relationship. The paper focuses on the hypothalamic–pituitary–adrenal axis’ role in stabilization of behavioral state, the autonomic nervous system’s role in stabilization of physiologic state, as well as co-regulation as a potential mechanism for the developing of the parent-infant relationship. Mechanisms play a pivotal role in understanding variables related to the therapy course and well as in generating new knowledge regarding treatment susceptibility and optimizing resources. Understanding of the mechanisms of how interventions may lead to specific outcomes plays an important role in addressing the issue of improvement of currently available approaches of MT used in the NICU.
Bioavailability Assessment of Heavy Metals Using Various Multi-Element Extractants in an Indigenous Zinc Smelting Contaminated Site, Southwestern China
Authors: Wang Jun-Xian , Xu Da-Mao , Fu Rong-Bing , Chen Jia-Peng
Published: August 2021

Despite recent studies have investigated the strong influences of smelting activities on heavy metal contamination in the soil environment, little studies have been conducted on the current information about the potential environmental risks posed by toxic heavy metals in smelting contaminated sites. In the present study, a combination of the bioavailability, speciation, and release kinetics of toxic heavy metals in the indigenous zinc smelting contaminated soil were reliably used as an effective tool to support site risk assessment. The bioavailability results revealed that the bioavailable metal concentrations were intrinsically dependent on the types of chemical extractants. Interestingly, 0.02 mol/L EDTA + 0.5 mol/L CH3COONH4 was found to be the best extractant, which extracted 30.21% of Cu, 31.54% of Mn, 2.39% of Ni and 28.89% of Zn, respectively. The sequential extraction results suggested that Cd, Pb, and Zn were the most mobile elements, which would pose the potential risks to the environment. The correlation of metal bioavailability with their fractionation implied that the exchangeable metal fractions were easily extracted by CaCl2 and Mehlich 1, while the carbonate and organic bound metal fractions could be extracted by EDTA and DTPA with stronger chelating ability. Moreover, the kinetic modeling results suggested that the chemical desorption mechanism might be the major factor controlling heavy metal release. These results could provide some valuable references for the risk assessment and management of heavy metals in the smelting contaminated sites.
School-Based Prevention of Screen-Related Risk Behaviors during the Long-Term Distant Schooling Caused by COVID-19 Outbreak
Authors: Lukavská Kateřina , Burda Václav , Lukavský Jiří , Slussareff Michaela , Gabrhelík Roman
Published: August 2021

The COVID-19 outbreak and related restrictions meant a higher incidence of screen-related risk behaviors in both children and adolescents. Our goal was to assess the perceived importance and extent of school-based preventions related to these risks during the long-term, nation-wide distant schooling period in the Czech Republic. The online survey was responded to by the school-based prevention specialists (N = 1698). For the analysis, within-subject analysis of variance (ANOVA) and binominal logistic regression were used. At-risk internet use and cyber-bullying were perceived as pressing, but other risks, for example, excessive internet use or the use of cyberpornography, received substantially less priority. The differences in all grades were significant and moderate to large (η2G between 0.156 and 0.288). The proportion of schools which conducted prevention interventions of screen-related risks was low (between 0.7% and 27.8%, depending on the grade and the type of the risk). The probability of delivering prevention intervention was in all grades significantly predicted by the presence of screen-related problems in pupils (OR 3.76–4.88) and the perceived importance of the screen-related risks (OR 1.55–1.97). The limited capacity of schools to deliver prevention interventions during distant schooling as well as the low awareness and impaired ability to recognize the importance of some screen-related risks should be addressed.
The Role of Stomach Infrastructures on Children’s Work and Child Labour in Africa: Systematic Review
Authors: Gonsamo Dagim Dawit , Lo Herman Hay Ming , Chan Ko Ling
Published: August 2021

Child labour remains a prevalent global concern, and progress toward eradicating harmful children’s work appears to have stalled in the African continent and henceforth, integrated social policy intervention is still required to address the problem. Among several forms of social policy interventions, stomach infrastructure (i.e., in-kind and/or cash transfers) have been a key policy approach to support vulnerable families to lighten households’ resources burden, which forces them to consider child labour as a coping strategy. There is growing evidence on the impacts of these programs in child labour. However, this evidence is often mixed regarding children’s work outcomes, and the existing studies hardly describe such heterogeneous outcomes from the child-sensitive approach. To this end, a systematic literature search was conducted for studies in African countries. From 743 references retrieved in this study, 27 studies were included for the review, and a narrative approach has been employed to analyse extracted evidence. Results from the current study also demonstrate a mixed effect of in-kind and cash transfers for poor households on child labour decisions. Hence, the finding from the current review also demonstrates a reduced participation of children in paid and unpaid work outside the household due to in-kind and cash transfers to poor households, but children’s time spent in economic and non-economic household labour and farm and non-farm labour, which are detrimental to child health and schooling, has been reported increasing due to the program interventions. The question remains how these programs can effectively consider child-specific and household-related key characteristics. To this end, a child-sensitive social protection perspective has been applied in this study to explain these mixed outcomes to inform policy design.
Psychosocial Health of K-12 Students Engaged in Emergency Remote Education and In-Person Schooling: A Cross-Sectional Study
Authors: Acosta Daniel , Fujii Yui , Joyce-Beaulieu Diana , Jacobs K. D. , Maurelli Anthony T. , Nelson Eric J. , McKune Sarah L.
Published: August 2021

As online classes became the norm in many countries as a response to the COVID-19 pandemic, the concern for child and adolescent mental health became an issue of concern. This study evaluates the differences in the psychosocial status of school children based on engagement in in-person or Emergency Remote Education (ERE) and assessed the prevalence and predictors of symptom-derived risk levels for anxiety, depression, and obsessive-compulsive disorders (OCD). Cross-sectional data were collected from students at a Florida K-12 school and their household members through an online survey conducted in October 2020 (n = 145). No significant difference was found between ERE and in-person learning for risk of anxiety, depression, or OCD. Prevalence of students presenting as at risk for anxiety, depression, and OCD was 42.1%, 44.8%, and 41.4%. Several student factors (e.g., child sex, school level) and parental factors (e.g., parental COVID-19 attitudes) were associated with students presenting as at risk for anxiety, depression, or OCD; child’s participation in sports was protective against all three outcomes. Participation in sports was found to be protective against risk of anxiety (aOR = 0.36, CI = 0.14–0.93), depression (aOR = 0.38, CI = 0.15–0.93), and OCD (aOR = 0.31, CI = 0.11–0.85).
A Comparison of Faculty and Student Acceptance Behavior toward Learning Management Systems
Authors: Kim Jinkyung Jenny , Yoon Yeohyun , Kim Eun-Jung
Published: August 2021

During the COVID-19 pandemic, learning management systems have become the primary channel for lecturing and learning in higher education contexts. The present study investigates the development of user acceptance behavior toward a learning management system through use of the extended technology acceptance model. Moreover, this research identified differences between faculty and student behavior in a university environment. Based on a quantitative approach, the analysis results revealed that the main triggers of user acceptance behavior are self-efficacy, enjoyment, and computer anxiety. This study also documented the different influencing factors between faculty members and student groups, respectively. This work is expected to add to existing knowledge and help guide those working in higher education settings to establish more effective strategies for the optimization of learning management systems.
Development and Validation of a Trigger Tool for Identifying Drug-Related Emergency Department Visits
Authors: Hwang Sung-Hee , Ah Young-Mi , Jun Kwang-Hee , Jung Jae-Woo , Kang Min-Gyu , Park Hye-Kyung , Lee Eui-Kyung , Park Hye-Kyung , Chung Jee-Eun , Kim Sang-Heon , Lee Ju-Yeun
Published: August 2021

There are various trigger tools for detecting adverse drug events (ADEs), however, a drug-related emergency department (ED) visit trigger tool (DrEDTT) has not yet been developed. We aimed to develop and validate a DrEDTT with a multi-center cohort. In this cross-sectional study, we developed the DrEDTT consisting of 28 triggers through a comprehensive literature review and three phase expert group discussion. Next, we evaluated the performance of the DrEDTT by applying it to relevant medical records retrieved from four hospitals from January 2016 to June 2016. Two experts performed an in-depth chart review of a 25% of random sample of trigger flagged and unflagged ED visits and a true ADE was determined through causality assessment. Among 66,564 patients who visited the ED for reasons other than traffic accident and trauma during the study period, at least one trigger was found in 21,268 (32.0%) patients. A total of 959 true ADE cases (5.8%) were identified from a randomly selected 25% of ED visit cases. The overall positive predictive value was 14.0% (range: 8.3–66.7%). Sensitivity and specificity of DrEDTT were 77.7% and 70.4%, respectively. In conclusion, this newly developed trigger tool might be helpful to detect ADE-related ED visits.
Effects of Microenvironmental Changes on the Fluorescence Signal of Alternariol: Magnesium Induces Strong Enhancement in the Fluorescence of the Mycotoxin
Authors: Fliszár-Nyúl Eszter , Lemli Beáta , Kunsági-Máté Sándor , Poór Miklós
Published: August 2021

Alternariol (AOH) is an emerging mycotoxin produced by Alternaria molds. It occurs as a contaminant e.g., in oilseeds, cereals, grapes, and tomatoes. Chronic exposure to AOH may cause genotoxic and endocrine disruptor effects. Our recent studies demonstrated that the fluorescence signal of AOH can be strongly affected by the environmental pH as well as by the presence of serum albumin or cyclodextrins. In the current study, we aimed to characterize the most optimal circumstances regarding the highly sensitive fluorescent detection of AOH. Therefore, the further detailed investigation of the microenvironment on the fluorescence signal of the mycotoxin has been performed, including the effects of different buffers, organic solvents, detergents, and cations. Organic solvents (acetonitrile and methanol) caused only slight increase in the emission signal of AOH, while detergents (sodium dodecyl sulfate and Triton-X100) and Ca2+ induced considerably higher enhancement in the fluorescence of the mycotoxin. In addition, Mg2+ proved to be a superior fluorescence enhancer of the AOH. Spectroscopic and modeling studies suggest the formation of low-affinity AOH-Mg2+ complexes. The effect of Mg2+ was also tested in two HPLC assays: Our results show that Mg2+ can considerably increase the fluorescence signal of AOH even in a chromatographic system.
Bazedoxifene, a GP130 Inhibitor, Modulates EMT Signaling and Exhibits Antitumor Effects in HPV-Positive Cervical Cancer
Authors: Kim Leekyung , Park Sun-Ae , Park Hyemin , Kim Heejung , Heo Tae-Hwe
Published: August 2021

Persistent HPV (Human Papillomavirus) infection is the primary cause of cervical cancer. Despite the development of the HPV vaccine to prevent infections, cervical cancer is still a fatal malignant tumor and metastatic disease, and it is often difficult to treat, so a new treatment strategy is needed. The FDA-approved drug Bazedoxifene is a novel inhibitor of protein–protein interactions between IL-6 and GP130. Multiple ligand simultaneous docking and drug repositioning approaches have demonstrated that an IL-6/GP130 inhibitor can act as a selective estrogen modulator. However, the molecular basis for GP130 activation in cervical cancer remains unclear. In this study, we investigated the anticancer properties of Bazedoxifene in HPV-positive cervical cancer cells. In vitro and in vivo experiments showed that Bazedoxifene inhibited cell invasion, migration, colony formation, and tumor growth in cervical cancer cells. We also confirmed that Bazedoxifene inhibits the GP130/STAT3 pathway and suppresses the EMT (Epithelial-mesenchymal transition) sub-signal. Thus, these data not only suggest a molecular mechanism by which the GP130/STAT3 pathway may promote cancer, but also may provide a basis for cervical cancer replacement therapy.
Pharmacokinetics of Single Domain Antibodies and Conjugated Nanoparticles Using a Hybrid near Infrared Method
Authors: Su Shiran , Esparza Thomas J. , Nguyen Duong , Mastrogiacomo Simone , Kim Joong H. , Brody David L.
Published: August 2021

Iron oxide nanoparticles and single domain antibodies from camelids (VHHs) have been increasingly recognized for their potential uses for medical diagnosis and treatment. However, there have been relatively few detailed characterizations of their pharmacokinetics (PK). The aim of this study was to develop imaging methods and pharmacokinetic models to aid the future development of a novel family of brain MRI molecular contrast agents. An efficient near-infrared (NIR) imaging method was established to monitor VHH and VHH conjugated nanoparticle kinetics in mice using a hybrid approach: kinetics in blood were assessed by direct sampling, and kinetics in kidney, liver, and brain were assessed by serial in vivo NIR imaging. These studies were performed under “basal” circumstances in which the VHH constructs and VHH-conjugated nanoparticles do not substantially interact with targets nor cross the blood brain barrier. Using this approach, we constructed a five-compartment PK model that fits the data well for single VHHs, engineered VHH trimers, and iron oxide nanoparticles conjugated to VHH trimers. The establishment of the feasibility of these methods lays a foundation for future PK studies of candidate brain MRI molecular contrast agents.
PI3-Kinase p110α Deficiency Modulates T Cell Homeostasis and Function and Attenuates Experimental Allergic Encephalitis in Mature Mice
Authors: Rojo José M. , Montes-Casado María , Aragoneses-Fenoll Laura , Ojeda Gloria , Dianzani Umberto , Portolés Pilar
Published: August 2021

Class I phosphoinositide 3-kinases (PI3K) are involved in the development of normal and autoimmune responses, including Experimental Autoimmune Encephalomyelitis (EAE), a mouse model for human multiple sclerosis (MS). Here, the role of the ubiquitously expressed class IA PI3K p110α catalytic subunits in EAE has been analyzed using a model of Cre/flox mediated T cell specific deletion of p110α catalytic chain (p110αΔT). Comparison of two month-old (young) and six month-old (mature) p110αΔT mice and their wild type (WT) counterparts indicated loss of spleen CD4+ T cells that increased with age, indicating a role of p110α in their homeostasis. In contrast, CD4+ T regulatory (Treg) cells were enhanced in mature p110αΔT mice when compared to WT mice. Since Myelin Oligodendrocyte Glycoprotein (MOG) peptide-induced EAE is dependent on, or mediated by CD4+ T cells and CD4+ T cell-derived cytokines and controlled by Treg cells, development of EAE in young and mature WT or p110αΔT mice was analyzed. EAE clinical symptoms and disease scores in six month p110αΔT mice were significantly lower than those of mature WT, or young WT and p110αΔT mice. Furthermore, ex vivo antigen activation of lymph node cells from MOG immunized mature p110αΔT mice induced significantly lower levels of IFN-γ and IL-17A than young p110αΔT or young and mature WT mice. Other cytokines including IL-2, IL-10 or TNF-α showed no significant differences between p110αΔT and WT mature mice. Our data show a lower incidence of MOG-induced EAE in mature p110αΔT mice linked to altered T cell homeostasis and lower secretion of inflammatory cytokines.
RT-qPCR Diagnostics: The “Drosten” SARS-CoV-2 Assay Paradigm
Authors: Bustin Stephen , Kirvell Sara , Huggett Jim F. , Nolan Tania
Published: August 2021

The reverse transcription quantitative polymerase chain reaction (RT-qPCR) is an established tool for the diagnosis of RNA pathogens. Its potential for automation has caused it to be used as a presence/absence diagnostic tool even when RNA quantification is not required. This technology has been pushed to the forefront of public awareness by the COVID-19 pandemic, as its global application has enabled rapid and analytically sensitive mass testing, with the first assays targeting three viral genes published within days of the publication of the SARS-CoV-2 genomic sequence. One of those, targeting the RNA-dependent RNA polymerase gene, has been heavily criticised for supposed scientific flaws at the molecular and methodological level, and this criticism has been extrapolated to doubts about the validity of RT-qPCR for COVID-19 testing in general. We have analysed this assay in detail, and our findings reveal some limitations but also highlight the robustness of the RT-qPCR methodology for SARS-CoV-2 detection. Nevertheless, whilst our data show that some errors can be tolerated, it is always prudent to confirm that the primer and probe sequences complement their intended target, since, when errors do occur, they may result in a reduction in the analytical sensitivity. However, in this case, it is unlikely that a mismatch will result in poor specificity or a significant number of false-positive SARS-CoV-2 diagnoses, especially as this is routinely checked by diagnostic laboratories as part of their quality assurance.
Interest of Homodialkyl Neamine Derivatives against Resistant P. aeruginosa, E. coli, and β-Lactamases-Producing Bacteria—Effect of Alkyl Chain Length on the Interaction with LPS
Authors: Swain Jitendriya , Dezanet Clément , Chalhoub Hussein , Auquière Marie , Kempf Julie , Décout Jean-Luc , Mingeot-Leclercq Marie-Paule
Published: August 2021

Development of novel therapeutics to treat antibiotic-resistant infections, especially those caused by ESKAPE pathogens, is urgent. One of the most critical pathogens is P. aeruginosa, which is able to develop a large number of factors associated with antibiotic resistance, including high level of impermeability. Gram-negative bacteria are protected from the environment by an asymmetric Outer Membrane primarily composed of lipopolysaccharides (LPS) at the outer leaflet and phospholipids in the inner leaflet. Based on a large hemi-synthesis program focusing on amphiphilic aminoglycoside derivatives, we extend the antimicrobial activity of 3′,6-dinonyl neamine and its branched isomer, 3′,6-di(dimethyloctyl) neamine on clinical P. aeruginosa, ESBL, and carbapenemase strains. We also investigated the capacity of 3′,6-homodialkyl neamine derivatives carrying different alkyl chains (C7–C11) to interact with LPS and alter membrane permeability. 3′,6-Dinonyl neamine and its branched isomer, 3′,6-di(dimethyloctyl) neamine showed low MICs on clinical P. aeruginosa, ESBL, and carbapenemase strains with no MIC increase for long-duration incubation. In contrast from what was observed for membrane permeability, length of alkyl chains was critical for the capacity of 3′,6-homodialkyl neamine derivatives to bind to LPS. We demonstrated the high antibacterial potential of the amphiphilic neamine derivatives in the fight against ESKAPE pathogens and pointed out some particular characteristics making the 3′,6-dinonyl- and 3′,6-di(dimethyloctyl)-neamine derivatives the best candidates for further development.
Molecular Dynamics Studies on the Structural Characteristics for the Stability Prediction of SARS-CoV-2
Authors: Choi Kwang-Eun , Kim Jeong-Min , Rhee JeeEun , Park Ae Kyung , Kim Eun-Jin , Kang Nam Sook
Published: August 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affects the COVID-19 pandemic in the world. The spike protein of the various proteins encoded in SARS-CoV-2 binds to human ACE2, fuses, and enters human cells in the respiratory system. Spike protein, however, is highly variable, and many variants were identified continuously. In this study, Korean mutants for spike protein (D614G and D614A-C terminal domain, L455F and F456L-RBD, and Q787H-S2 domain) were investigated in patients. Because RBD in spike protein is related to direct interaction with ACE2, almost all researches were focused on the RBD region or ACE2-free whole domain region. The 3D structure for spike protein complexed with ACE2 was recently released. The stability analysis through RBD distance among each spike protein chain and the binding free energy calculation between spike protein and ACE2 were performed using MD simulation depending on mutant types in 1-, 2-, and 3-open-complex forms. D614G mutant of CT2 domain, showing to be the most prevalent in the global pandemic, showed higher stability in all open-complex forms than the wild type and other mutants. We hope this study will provide an insight into the importance of conformational fluctuation in the whole domain, although RBD is involved in the direct interaction with ACE2.
Co-Ultra PEALut Enhances Endogenous Repair Response Following Moderate Traumatic Brain Injury
Authors: Campolo Michela , Crupi Rosalia , Cordaro Marika , Cardali Salvatore Massimo , Ardizzone Alessio , Casili Giovanna , Scuderi Sarah Adriana , Siracusa Rosalba , Esposito Emanuela , Conti Alfredo , Cuzzocrea Salvatore
Published: August 2021

This study aimed to assess the neuro-regenerative properties of co-ultramicronized PEALut (Glialia®), composed of palmitoylethanolamide (PEA) and the flavonoid luteolin (Lut), in an in vivo model of traumatic brain injury (TBI) and patients affected by moderate TBI. An increase in neurogenesis was seen in the mice at 72 h and 7 d after TBI. The co-ultra PEALut treatment helped the neuronal reconstitution process to restore the basal level of both novel and mature neurons; moreover, it induced a significant upregulation of the neurotrophic factors, which ultimately led to progress in terms of memory recall during behavioral testing. Moreover, our preliminary findings in a clinical trial suggested that Glialia® treatment facilitated neural recovery on working memory. Thus, co-ultra PEALut (Glialia®) could represent a valuable therapeutic agent for intensifying the endogenous repair response in order to better treat TBI.
The Emerging Role of Epigenetics in Therapeutic Targeting of Cardiomyopathies
Authors: Pagiatakis Christina , Di Mauro Vittoria
Published: August 2021

Cardiomyopathies (CMPs) are a heterogeneous group of myocardial diseases accountable for the majority of cases of heart failure (HF) and/or sudden cardiac death (SCD) worldwide. With the recent advances in genomics, the original classification of CMPs on the basis of morphological and functional criteria (dilated (DCM), hypertrophic (HCM), restrictive (RCM), and arrhythmogenic ventricular cardiomyopathy (AVC)) was further refined into genetic (inherited or familial) and acquired (non-inherited or secondary) forms. Despite substantial progress in the identification of novel CMP-associated genetic variations, as well as improved clinical recognition diagnoses, the functional consequences of these mutations and the exact details of the signaling pathways leading to hypertrophy, dilation, and/or contractile impairment remain elusive. To date, global research has mainly focused on the genetic factors underlying CMP pathogenesis. However, growing evidence shows that alterations in molecular mediators associated with the diagnosis of CMPs are not always correlated with genetic mutations, suggesting that additional mechanisms, such as epigenetics, may play a role in the onset or progression of CMPs. This review summarizes published findings of inherited CMPs with a specific focus on the potential role of epigenetic mechanisms in regulating these cardiac disorders.
The Imaginal Characters of Neoephemera projecta Showing Its Plesiomorphic Position and a New Genus Status in the Family (Ephemeroptera: Neoephemeridae)
Authors: Ma Zhenxing , Zhou Changfa
Published: August 2021

The newly collected imaginal materials of the species Neoephemera projecta Zhou and Zheng, 2001 from Southwestern China, which is linking the other genera of the family Neoephemeridae, are described in detail. Nymphs are also photographed for the first time. The morphology of this species shows some characters of the other genera in Neoephemeridae and several autapomorphies. However, most characters can be seen as plesiomorphies of the family. Specifically, the dorsal-oriented fimbriate gills, projected frons and slim labial palpi in nymphs plus large reddishly pigmented wings, many crossveins, 4-segmented forceps with a relatively long basal segment, fused penes and unforked anal vein show that this species is closer to the taxon Fossoriae rather than to the previously considered Potamanthidae. To reflect its primitive position, a new genus, Pulchephemera Zhou gen. n., is established for this species, Pulchephemera projecta comb. n. Its eggs and observed biology are also described.
A Temperature Conditioned Markov Chain Model for Predicting the Dynamics of Mosquito Vectors of Disease
Authors: Damos Petros T. , Dorrestijn Jesse , Thomidis Thomas , Tuells José , Caballero Pablo
Published: August 2021

Understanding and predicting mosquito population dynamics is crucial for gaining insight into the abundance of arthropod disease vectors and for the design of effective vector control strategies. In this work, a climate-conditioned Markov chain (CMC) model was developed and applied for the first time to predict the dynamics of vectors of important medical diseases. Temporal changes in mosquito population profiles were generated to simulate the probabilities of a high population impact. The simulated transition probabilities of the mosquito populations achieved from the trained model are very near to the observed data transitions that have been used to parameterize and validate the model. Thus, the CMC model satisfactorily describes the temporal evolution of the mosquito population process. In general, our numerical results, when temperature is considered as the driver of change, indicate that it is more likely for the population system to move into a state of high population level when the former is a state of a lower population level than the opposite. Field data on frequencies of successive mosquito population levels, which were not used for the data inferred MC modeling, were assembled to obtain an empirical intensity transition matrix and the frequencies observed. Our findings match to a certain degree the empirical results in which the probabilities follow analogous patterns while no significant differences were observed between the transition matrices of the CMC model and the validation data (ChiSq = 14.58013, df = 24, p = 0.9324451). The proposed modeling approach is a valuable eco-epidemiological study. Moreover, compared to traditional Markov chains, the benefit of the current CMC model is that it takes into account the stochastic conditional properties of ecological-related climate variables. The current modeling approach could save costs and time in establishing vector eradication programs and mosquito surveillance programs.
Antibody–Drug Conjugates for the Treatment of Acute Pediatric Leukemia
Authors: Stokke Jamie L. , Bhojwani Deepa
Published: August 2021

The clinical development of antibody–drug conjugates (ADCs) has gained momentum in recent years and these agents are gradually moving into frontline regimens for pediatric acute leukemias. ADCs consist of a monoclonal antibody attached to a cytotoxic payload by a cleavable linker. This structure allows for highly cytotoxic agents to be directly delivered to leukemia cells leading to cell death and avoids excessive off-tumor toxicity. Near universal expression on B-cell acute lymphoblastic leukemia (ALL) blasts and the ability of rapid internalization has rendered CD22 an ideal target for ADC in B-ALL. Inotuzumab ozogamicin, the anti-CD22 antibody linked to calicheamicin led to complete remission rates of 60–80% in patients with relapsed/refractory B-ALL. In acute myeloid leukemia (AML), the CD33 targeting gemtuzumab ozogamicin has demonstrated modest improvements in survival and is the only ADC currently licensed in the United States for pediatric patients with de novo AML. Several other ADCs have been developed and tested clinically for leukemia but have achieved limited success to date. The search for additional leukemia-specific targets and optimization of ADC structure and specificity are ongoing efforts to improve their therapeutic window. This review provides a comprehensive overview of ADCs in acute leukemias, with a focus on pediatric ALL and AML.
Weighted Gene Co-Expression Network Analysis Combined with Machine Learning Validation to Identify Key Modules and Hub Genes Associated with SARS-CoV-2 Infection
Authors: Karami Hassan , Derakhshani Afshin , Ghasemigol Mohammad , Fereidouni Mohammad , Miri-Moghaddam Ebrahim , Baradaran Behzad , Tabrizi Neda , Najafi Souzan , Solimando Antonio , Marsh Leigh , Silvestris Nicola , De Summa Simona , Paradiso Angelo , Racanelli Vito , Safarpour Hossein
Published: August 2021

The coronavirus disease-2019 (COVID-19) pandemic has caused an enormous loss of lives. Various clinical trials of vaccines and drugs are being conducted worldwide; nevertheless, as of today, no effective drug exists for COVID-19. The identification of key genes and pathways in this disease may lead to finding potential drug targets and biomarkers. Here, we applied weighted gene co-expression network analysis and LIME as an explainable artificial intelligence algorithm to comprehensively characterize transcriptional changes in bronchial epithelium cells (primary human lung epithelium (NHBE) and transformed lung alveolar (A549) cells) during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Our study detected a network that significantly correlated to the pathogenicity of COVID-19 infection based on identified hub genes in each cell line separately. The novel hub gene signature that was detected in our study, including PGLYRP4 and HEPHL1, may shed light on the pathogenesis of COVID-19, holding promise for future prognostic and therapeutic approaches. The enrichment analysis of hub genes showed that the most relevant biological process and KEGG pathways were the type I interferon signaling pathway, IL-17 signaling pathway, cytokine-mediated signaling pathway, and defense response to virus categories, all of which play significant roles in restricting viral infection. Moreover, according to the drug–target network, we identified 17 novel FDA-approved candidate drugs, which could potentially be used to treat COVID-19 patients through the regulation of four hub genes of the co-expression network. In conclusion, the aforementioned hub genes might play potential roles in translational medicine and might become promising therapeutic targets. Further in vitro and in vivo experimental studies are needed to evaluate the role of these hub genes in COVID-19.