bluuebunny/crossref_metadata_2025 huggingface dataset:
COVID-19 and Public Health Spending; Effects on the Economic Sustainability of the Spanish Private Healthcare System
Authors: Valls Martínez María del Carmen , Santos-Jaén José Manuel , Valls-Úbeda Rafael Félix , Soriano Román Rafael
Published: January 2023

This research analyzes the influence of COVID-19 and public health spending policies on the economic sustainability of Spanish private hospitals. Moreover, it explores the relationship between public health spending policies and the spread of COVID-19 in Spain. Private health care is an understudied sector, yet it is fundamental to the health of citizens. Moreover, the economic causes linked to the spread of the pandemic have not yet been clearly established. Therefore, this work covers a gap in the literature. Private hospital profitability was analyzed by applying ordinary least squares and panel data regressions on financial and macroeconomic data for the period 2017–2020. The spread of COVID-19 was examined by means of cluster and component analysis. The results show that the COVID-19 pandemic negatively affected the economic sustainability of Spanish private hospitals, which was also influenced by public health spending. In turn, the spread of the pandemic was mainly related to population density, but was also influenced by public health spending and the gross domestic product of the region. Therefore, policymakers must consider that it is essential to make adequate investments in the healthcare system to cope with pandemics such as COVID-19. In addition, managers can see how corporate social responsibility is a valuable strategy for maintaining hospital profitability.
A Comprehensive Contamination Investigation of Bohai Bay Seawater: Antibiotics Occurrence, Distribution, Ecological Risks and Their Interactive Factors
Authors: Tian Liang , Xu Xiaofu , Zhang Zulin , Ding Yongzhen , Zhang Keqiang , Zhi Suli
Published: January 2023

A comprehensive, large-scale coastal investigation of antibiotics in seawater from Bohai Bay is lacking. Therefore, in this study, we investigated the occurrence and ecological risks of 45 antibiotics belonging to 5 classes in seawater from Bohai Bay, as well as their inter-relation with trace elements and other contaminants. The results show that tetracyclines (TCs) were detected in the highest concentration among the five classes (in the range of 0.6–2.0 μg/L). The total concentrations of the five classes of antibiotics were detected in the following order: tetracyclines (TCs) > quinolones (QAs) > sulfonamides (SAs) > macrolides (MAs) > lactams (LAs). Higher antibiotic concentrations were detected at the sampling sites closest to the coast or the shipping port. Among seven trace elements, four were quantitatively detected, with Zn representing the highest concentration. Antibiotic residuals were found to be positively correlated with total organic carbon (TOC), conductivity (Ec) and suspended solids (SS); pH and NH4+-N usually showed a negative correlation with antibiotics; TN and TP also exhibited relationships with antibiotics. The risk quotient (RQ) was calculated for different antibiotics at different sites. It was found that antibiotics pose higher risks to algae than to invertebrates or fish; sulfamethoxazole, enrofloxacin and ofloxacin were all found to pose high risk to algae at some of the sampling sites. Structural equation model (SEM) results show that trace elements, antibiotic levels and EC50 are the main factors affecting the ecological risks of antibiotics.
Primary and Community Care Transformation in Post-COVID Era: Nationwide General Practitioner Survey
Authors: Solanes-Cabús Mònica , Paredes Eugeni , Limón Esther , Basora Josep , Alarcón Iris , Veganzones Irene , Conangla Laura , Casado Núria , Ortega Yolanda , Mestres Jordi , Acezat Jordi , Deniel Joan , Cabré Joan Josep , Ruiz Daniel Sánchez , Sánchez Marcos , Illa Aroa , Viñas Ignasi , Montero Juan José , Cantero Francesc Xavier , Rodriguez Anna , Martín Francisco , Baré Montserrat , Ripollés Rosa , Castellet Montse , Lozano Joan , Sisó-Almirall Antoni
Published: January 2023

Introduction: The health emergency caused by COVID-19 has led to substantial changes in the usual working system of primary healthcare centers and in relations with users. The Catalan Society of Family and Community Medicine designed a survey that aimed to collect the opinions and facilitate the participation of its partners on what the future work model of general practitioners (GPs) should look like post-COVID-19. Methodology: Online survey of Family and Community Medicine members consisting of filiation data, 22 Likert-type multiple-choice questions grouped in five thematic axes, and a free text question. Results: The number of respondents to the questionnaire was 1051 (22.6% of all members): 83.2% said they spent excessive time on bureaucratic tasks; 91.8% were against call center systems; 66% believed that home care is the responsibility of every family doctor; 77.5% supported continuity of care as a fundamental value of patient-centered care; and >90% defended the contracting of complementary tests and first hospital visits from primary healthcare (PHC). Conclusions: The survey responses describe a strong consensus on the identity and competencies of the GP and on the needs of and the threats to the PHC system. The demand for an increase in health resources, greater professional leadership, elimination of bureaucracy, an increase in the number of health professionals, and greater management autonomy, are the axes towards which a new era in PHC should be directed.
Vitamin D Knowledge and Awareness Is Associated with Physical Activity among Adults: A Cross-Sectional Survey
Authors: Al-Daghri Nasser M. , Alfawaz Hanan A. , Khan Nasiruddin , Saadawy Gamal M. , Sabico Shaun
Published: January 2023

The relation between knowledge and awareness of vitamin D (VD) and physical activity in adults has not been well studied. The present cross-sectional study aims to demonstrate this relation among adults living in Saudi Arabia. A total of 774 adults participated and were stratified based on self-reports of whether they were physically active (PA group, N = 562) or not (non-PA, N = 212). The prevalence of VD awareness and its health effects were significantly higher in the PA group compared with their counterparts (97 vs. 93.4%; p = 0.02 and 92.3 vs. 81.6%; p < 0.001, respectively). Sunlight was the preferred overall source of VD among the PA group (91.1%) followed by food, supplements, and fortified foods. Sardine, salmon, oily fish (63.7%) and eggs (54.6%) were reported as good dietary sources. Other positive attitudes, represented by taking supplement or multivitamins (51.2%), high sun exposure (33.1%), and daily duration of exposure to sunlight (15–30 min; 53.4%) were higher in the PA than the non-PA group (p values < 0.05). The body parts exposed to the sun among the PA group were arms (67.1%), hands (64.1%), face and hands (62.5%), legs (58.5%), and face (53.2%), while sunscreen cream (47.2%) was their preferred sun-protection method. High levels of knowledge and positive attitudes were reported by the PA group compared with the non-PA group in regard to walking outdoors for sun exposure (80.6 vs. 62.7%; p < 0.001). Information about good dietary sources, the role of VD in human health, associated diseases, positive attitudes to sun exposure, and the use of supplements or multivitamins were among the determinants of VD knowledge and awareness. In conclusion, VD knowledge and awareness are positively associated with self-reported physical activity in adults. Further objective classifications of PA may strengthen the results of the present investigation.
Individual (Non) Resilience of University Students to Digital Media Manipulation after COVID-19 (Case Study of Slovak Initiatives)
Authors: Tkácová Hedviga , Pavlíková Martina , Stranovská Eva , Králik Roman
Published: January 2023

The starting point of this theoretical article is the presentation of the issue of media manipulation in the contemporary digital media environment. The theoretical part is followed by a description and analysis of selected factors that create a belief of the individual’s resilience to digital media manipulative elements. Among the seven researched factors of an individual’s (non) resilience to digital media manipulation, we include: media illiteracy/literacy, thought activity/laziness, searching/not searching for “consensus” in the media, not emphasizing/emphasizing emotions, non-reliance/reliance on own intuition, non-credibility/credibility in the opinion of celebrities and automatic distrust/trust of recipients in the information presented in the media and others. We do not see the presence of manipulative elements in digital media as the main danger (manipulation is always in a sense part of the media message), nor the fact that manipulative elements have an effect on individuals (media—manipulative and non-manipulative—effects cannot be doubted). In our opinion, the very significant risk is the fact that the media message is followed by a false belief of the recipient’s own “immunity” against (covert and overt) media manipulation. The result of this false notion is the individual’s belief that manipulation in digital media content does not “affect” him (“I can easily recognize media manipulation”) and does not “touch” him (“It can’t happen to me”). Such a person then resembles a “house on the sand”, as his opinions, arguments or beliefs quickly collapse under the onslaught of five skills: challenges in the context of media literacy, critical thinking, strategies for verifying the credibility of information sources, the rational assessment of issues and reflection of reality. This original research article is a qualitative analysis of the legacy of ten Slovak educational initiatives focused on the issue of education in the context of media manipulation. The analysis focuses on the role of individual risk factors associated with resilience. The conclusion of the analysis is the elaboration of a positive proposal for the researched issue.
Phase Angle as a Potential Screening Tool in Adults with Metabolic Diseases in Clinical Practice: A Systematic Review
Authors: Praget-Bracamontes Samantha , González-Arellanes Rogelio , Aguilar-Salinas Carlos A. , Martagón Alexandro J.
Published: January 2023

Background: Phase angle (PhA) has been used as mortality prognostic, but there are no studies about its possible use as a screening tool. Therefore, an assessment of the possible utility of PhA in clinical practice is required. The aim of this systematic review was to explore all recent available evidence of PhA, and its possible utility as a screening tool in clinical practice in subjects with chronic metabolic diseases. Materials and Methods: This systematic review was performed and written as stated in the PRISMA 2020 guidelines. The search was conducted in PubMed, ScienceDirect and SciElo. In order to be considered eligible, within the entire search, only articles involving PhA and their utility in metabolic diseases were included. Results: PhA was associated with hyperuricemia and vitamin D deficiency in obese subjects, and decreased cardiovascular risk and malnutrition in hospitalized patients. Conclusion: PhA may be a potential screening tool in clinical practice to evaluate different biomarkers, cardiovascular risk, and nutritional diagnosis in metabolic diseases in adults.
Need for Distinctiveness Leads to Pathological Internet Use? The Perspective of Cognitive Behavioral Model
Authors: Zeng Wei , Wei Hua , Liu Meiting
Published: January 2023

Based on the cognitive behavioral model of pathological Internet use and the gender role theory, this present study investigated the association between the need for distinctiveness and pathological Internet use. Additionally, we explored a mediating role of maladaptive cognition in the association between the need for distinctiveness and pathological Internet use and tested whether the mediation model was moderated by gender. A sample of 745 Chinese university students (Mage = 19.92, SDage = 1.42) was studied and participants completed anonymous questionnaires regarding the need for distinctiveness, maladaptive cognition, and pathological Internet use. Results revealed that the need for distinctiveness was positively associated with pathological Internet use, and the association between the need for distinctiveness and pathological Internet use was mediated by maladaptive cognition. In addition, gender moderated the association between maladaptive cognition and pathological Internet use; the effect was stronger for female participants than male participants. The findings expanded our understanding of the dark side of seeking distinctiveness. Practically, the results suggest that policymakers and psychological practitioners consider gender in preventing and intervening in pathological Internet use.
Effect of Noninvasive Static Human Data on Maximum Data in Exercise
Authors: Wu Yichen , Sun Yining
Published: January 2023

Maximum data in exercise (Max-Ex), including maximum heart rate (HRmax), peak oxygen uptake (VO2pk), maximum power (MaxP), etc., are frequently used, whether it is for the determination of exercise intensity, the measurement of an athlete’s performance, assessment of recovery from disease, and so on. However, very often this choice does not take into account the targeted individual. We recruited 32 males and 29 females to undergo an incremental graded exercise test (GXT). Therefore, our study seeks to determine variations in Max-Ex, according to the noninvasive static human data (Non-In data). Data showed a significant relationship (p < 0.001) between body composition and Max-Ex. Of the 41 types of Non-In data we collected in communities, the body composition generally showed high correlation (maximum r = 0.839). 57.5% of the data, of which r > 0.6 were about body composition. The muscle-related body composition data had a greater effect on power, and the fat-related ones had a greater effect on HRmax and VO2pk. For some types of Max-Ex, the older and younger ones showed specific differences. Therefore, these results can be employed to adequately prescribe personalized health promotion programs according to diversity and availability, and have some reference value for other studies using Max-Ex.
Examining the Nonlinear and Synergistic Effects of Multidimensional Elements on Commuting Carbon Emissions: A Case Study in Wuhan, China
Authors: Guo Liang , Yang Shuo , Zhang Qinghao , Zhou Leyu , He Hui
Published: January 2023

Understanding the specific effects of multidimensional elements of a built environment, transportation management policies, and the socio-demographics of travelers associated with commuting carbon emissions is significant for planners in promoting low-carbon and healthy urban development through transportation and land use and urban management policies. Most of the existing studies focus on the complex mechanisms affecting commuting behavior, but the relevant elements and specific mechanisms affecting commuting carbon emissions have not received sufficient attention. This study uses a random forest approach to analyze residential travel data from Wuhan, China. The results show that built environment and transportation demand management policies are critical to commuting carbon emissions, and that there is a non-linear association between multidimensional factors and commuting carbon emissions in Chinese cities. In addition, the study examines the synergistic effects of built environment and transportation management policies on commuting carbon emissions among different built environment elements. The results of the study provide valuable insights for planners in formulating low-carbon city and transportation development policies.
Development and Assessment of a Novel Core Biopsy-Based Prediction Model for Pathological Complete Response to Neoadjuvant Chemotherapy in Women with Breast Cancer
Authors: Lan Ailin , Chen Junru , Li Chao , Jin Yudi , Wu Yinan , Dai Yuran , Jiang Linshan , Li Han , Peng Yang , Liu Shengchun
Published: January 2023

Purpose: Pathological complete response (pCR), the goal of NAC, is considered a surrogate for favorable outcomes in breast cancer (BC) patients administrated neoadjuvant chemotherapy (NAC). This study aimed to develop and assess a novel nomogram model for predicting the probability of pCR based on the core biopsy. Methods: This was a retrospective study involving 920 BC patients administered NAC between January 2012 and December 2018. The patients were divided into a primary cohort (769 patients from January 2012 to December 2017) and a validation cohort (151 patients from January 2017 to December 2018). After converting continuous variables to categorical variables, variables entering the model were sequentially identified via univariate analysis, a multicollinearity test, and binary logistic regression analysis, and then, a nomogram model was developed. The performance of the model was assessed concerning its discrimination, accuracy, and clinical utility. Results: The optimal predictive threshold for estrogen receptor (ER), Ki67, and p53 were 22.5%, 32.5%, and 37.5%, respectively (all p < 0.001). Five variables were selected to develop the model: clinical T staging (cT), clinical nodal (cN) status, ER status, Ki67 status, and p53 status (all p ≤ 0.001). The nomogram showed good discrimination with the area under the curve (AUC) of 0.804 and 0.774 for the primary and validation cohorts, respectively, and good calibration. Decision curve analysis (DCA) showed that the model had practical clinical value. Conclusions: This study constructed a novel nomogram model based on cT, cN, ER status, Ki67 status, and p53 status, which could be applied to personalize the prediction of pCR in BC patients treated with NAC.
A Following Wave Pattern of Suicide-Related Pediatric Emergency Room Admissions during the COVID-19 Pandemic
Authors: Mevorach Tomer , Zur Gil , Benaroya-Milshtein Noa , Apter Alan , Fennig Silvana , Barzilay Shira
Published: January 2023

The COVID-19 pandemic and response, which included physical distancing and stay-at-home orders, disrupted the daily lives of children and adolescents, isolating them from their peers, school, and other meaningful contacts. The present study aims to add to the accumulating evidence on the pandemic’s impact on child and adolescent suicidal behavior. Data were extracted from Schneider Children’s Medical Center of Israel’s pediatric emergency room (ER) admissions for psychiatric consultation for suicidal-risk assessment between 1 January 2020, and 16 April 2022. We applied time-lagged cross-correlation analysis and a Granger causality test to assess the temporal relationships between COVID-19 infection waves and patterns of suicide-related ER admissions. The results revealed a significant lagged correlation between national COVID-19 infection rates and ER admission rates. The highest correlation was above 0.4 and was found with a lag of 80 to 100 days from infection rate to ER admission rate. The findings show that the effects of public crises change over time and may be lagged. This may have important implications for mental health services’ readiness to serve growing numbers of children and adolescents at risk for suicide.
Association between Intensity Levels of Physical Activity and Glucose Variability among Children and Adolescents with Type 1 Diabetes
Authors: Jaggers Jason R. , King Kristi M. , McKay Timothy , Dyess Ryan J. , Thrasher Bradly J. , Wintergerst Kupper A.
Published: January 2023

Studies would indicate a reduction in hemoglobin A1c levels following moderate and/or vigorous physical activity (PA) for people managing diabetes. However, prior investigations rarely looked at glucose variability in an adolescent population. Purpose: The purpose of this investigation was to test the relationship between physical activity intensity levels and glucose variability in a sample of adolescents with type 1 diabetes mellitus, and if the amount of time accumulated for each intensity level is predictive of changes in glucose variability. Methods: Glucose variability was determined using continuous glucose monitor data and physical activity intensity time was retrieved through Fitabase®. Both glucose and physical activity data were collected over a two-week timeframe. Data analysis was completed using Pearson’s correlation and a simple linear regression with a p-value of 0.05 to determine significance. Results: A significant inverse relationship was observed (p = 0.04) between glucose variability and average minutes of daily moderate-intensity activity (r = −0.59), as well as moderate and vigorous physical activity (MVPA) combined (r = −0.86; p = 0.03). A simple linear regression indicated that only MVPA was a significant predictor of glucose variability (β = −0.12; 95% CI: −0.23–−0.01, p = 0.03). Conclusion: These data demonstrated that the total amount of daily physical activity is important when properly managing type 1 diabetes mellitus, but time spent in MVPA over two weeks may have an inverse relationship with glucose variability in children and adolescents over a span of two weeks.
Nonprofits and C Corporations: Performance Comparison
Authors: Hull Robert Martin
Published: January 2023

We extend the performance comparison study of nonprofits (NPs) and pass-throughs by examining large NPs and large C corporations (CCs). Unlike that study, we also examine performance outcomes under two different tax shield policies. We use the Capital Structure Model as our main methodology. Our purpose is to compare large NPs with large CCs in terms of debt choice, valuation, leverage gain, and growth-related outcomes. All tests considered, NPs (compared to CCs) have a 34.90% valuation advantage; achieve a 78.12% greater increase in value when going from nongrowth to growth (using a 12.34% lower plowback ratio and 10.97% less in retained earnings); attain a 2.56% greater optimal leverage ratio; and, realize 10.97% less in dollars added from debt. We show that switching from an interest tax shield to a retained earnings tax shield increases CC value between 1.35% and 3.28%. The NP value limit is only 0.42% since NPs pay little taxes. Our findings are value-additive for the comparative ownership form research.
What Makes Farmers Record Farm Financial Transactions? Empirical Evidence from Potato Farmers in Indonesia
Authors: Wulandari Eliana , Karyani Tuti , Ernah  , Alamsyah Raden Trizaldi Prima
Published: January 2023

Financial recording is still difficult due to the limited knowledge of farmers, whereas financial recordings are crucial for producing important reports for business development. This study aims to analyze the factors related to farmers’ activity in recording farm finances and the impact on farmers’ production and income. The study was carried out in West Java and included 200 potato farmers in the Garut and Bandung Districts. Factors related to the farmers’ experiences recording farm finances were investigated using logistic regression analysis. The results of this study showed that the significant factors related to farmers’ activity recording farm finances are the farmers’ education, their participation in the training of financial records, and their experience in obtaining finance from farmers’ associations, traders and agricultural input kiosks. Furthermore, this study also showed that recording financial transactions in agricultural business can increase farmers’ production and income. This study provides insights to policymakers and financial providers, showing the need to provide farmers with assistance in financial recording.
Multi-Scale Massive Points Fast Clustering Based on Hierarchical Density Spanning Tree
Authors: Chen Song , Zhang Fuhao , Zhang Zhiran , Yu Siyi , Qiu Agen , Liu Shangqin , Zhao Xizhi
Published: January 2023

Spatial clustering is dependent on spatial scales. With the widespread use of web maps, a fast clustering method for multi-scale spatial elements has become a new requirement. Therefore, to cluster and display elements rapidly at different spatial scales, we propose a method called Multi-Scale Massive Points Fast Clustering based on Hierarchical Density Spanning Tree. This study refers to the basic principle of Clustering by Fast Search and Find of Density Peaks aggregation algorithm and introduces the concept of a hierarchical density-based spanning tree, combining the spatial scale with the tree links of elements to propose the corresponding pruning strategy, and finally realizes the fast multi-scale clustering of elements. The first experiment proved the time efficiency of the method in obtaining clustering results by the distance-scale adjustment of parameters. Accurate clustering results were also achieved. The second experiment demonstrated the feasibility of the method at the aggregation point element and showed its visual effect. This provides a further explanation for the application of tree-link structures.
Skin Cancer Metabolic Profile Assessed by Different Analytical Platforms
Authors: Hagyousif Yousra A. , Sharaf Basma M. , Zenati Ruba A. , El-Huneidi Waseem , Bustanji Yasser , Abu-Gharbieh Eman , Alqudah Mohammad A. Y. , Giddey Alexander D. , Abuhelwa Ahmad Y. , Alzoubi Karem H. , Soares Nelson C. , Semreen Mohammad H.
Published: January 2023

Skin cancer, including malignant melanoma (MM) and keratinocyte carcinoma (KC), historically named non-melanoma skin cancers (NMSC), represents the most common type of cancer among the white skin population. Despite decades of clinical research, the incidence rate of melanoma is increasing globally. Therefore, a better understanding of disease pathogenesis and resistance mechanisms is considered vital to accomplish early diagnosis and satisfactory control. The “Omics” field has recently gained attention, as it can help in identifying and exploring metabolites and metabolic pathways that assist cancer cells in proliferation, which can be further utilized to improve the diagnosis and treatment of skin cancer. Although skin tissues contain diverse metabolic enzymes, it remains challenging to fully characterize these metabolites. Metabolomics is a powerful omics technique that allows us to measure and compare a vast array of metabolites in a biological sample. This technology enables us to study the dermal metabolic effects and get a clear explanation of the pathogenesis of skin diseases. The purpose of this literature review is to illustrate how metabolomics technology can be used to evaluate the metabolic profile of human skin cancer, using a variety of analytical platforms including gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS), and nuclear magnetic resonance (NMR). Data collection has not been based on any analytical method.
Design, Synthesis and Actual Applications of the Polymers Containing Acidic P–OH Fragments: Part 2—Sidechain Phosphorus-Containing Polyacids
Authors: Nifant’ev Ilya E. , Ivchenko Pavel V.
Published: January 2023

Macromolecules containing acidic fragments in side-groups—polyacids—occupy a special place among synthetic polymers. Properties and applications of polyacids are directly related to the chemical structure of macromolecules: the nature of the acidic groups, polymer backbone, and spacers between the main chain and acidic groups. The chemical nature of the phosphorus results in the diversity of acidic >P(O)OH fragments in sidechain phosphorus-containing polyacids (PCPAs) that can be derivatives of phosphoric or phosphinic acids. Sidechain PCPAs have many similarities with other polyacids. However, due to the relatively high acidity of –P(O)(OH)2 fragment, bone and mineral affinity, and biocompatibility, sidechain PCPAs have immense potential for diverse applications. Synthetic approaches to sidechain PCPAs also have their own specifics. All these issues are discussed in the present review.
Pseudomonas aeruginosa H3-T6SS Combats H2O2 Stress by Diminishing the Amount of Intracellular Unincorporated Iron in a Dps-Dependent Manner and Inhibiting the Synthesis of PQS
Authors: Lin Jinshui , Yang Jianshe , Cheng Juanli , Zhang Weipeng , Yang Xu , Ding Wei , Zhang Heng , Wang Yao , Shen Xihui
Published: January 2023

The type VI secretion system (T6SS), a protein translocation nanomachine, is widely distributed in Gram-negative bacteria and delivers effectors directly into target cells or the extracellular environment to help the bacteria gain a competitive fitness advantage and promote bacterial survival in harmful environments. In this study, we demonstrated that the synthesis of the Pseudomonas quinolone signal (PQS) in Pseudomonas aeruginosa PAO1 was inhibited by the H3-T6SS gene cluster under iron-rich conditions, and that this inhibition was relieved under iron starvation conditions. Conversely, PQS differentially regulated the expression of the H3-T6SS structural genes and the effector protein gene tseF. The expression of tseF was inhibited by PQS, while the expressions of the H3-T6SS structural genes were positively regulated by PQS. Further studies showed that the H3-T6SS was involved in the resistance of P. aeruginosa to oxidative stress caused by hydrogen peroxide (H2O2). Interestingly, H3-T6SS expression was neither induced by H2O2 stress nor regulated by OxyR (a global anti-oxidative transcriptional regulator) but was positively regulated by RpoS (a major transcription regulator of the stress response). In addition, we found that the clpV3 (a structural gene of H3-T6SS) mutation resulted in upregulation of two proteins related to PQS synthesis and many proteins related to oxidative stress resistance, while the expression of some iron storage proteins, especially Dps, were significantly downregulated. Furthermore, the clpV3 mutation led to an increase in the intracellular free Fe2+ content of P. aeruginosa. Further studies showed that both the PQS deficient mutation and overexpression of dps effectively restored the H2O2 sensitive phenotype of the H3-T6SS mutant. Finally, we proposed the following model of H3-T6SS-mediated resistance to H2O2 stress in P. aeruginosa. H3-T6SS not only reduces the intracellular free Fe2+ level by upregulating the expression of ferritin Dps, but also inhibits the synthesis of PQS to mediate the resistance of P. aeruginosa to H2O2 stress. This study highlights the important role of H3-T6SS in the ability of P. aeruginosa to combat H2O2 stress and provides a perspective for understanding the stress response mechanism of bacteria.
Camptothecin Effectively Regulates Germline Differentiation through Bam–Cyclin A Axis in Drosophila melanogaster
Authors: Zhang Jing , Zhang Shijie , Sun Zhipeng , Cai Yu , Zhong Guohua , Yi Xin
Published: January 2023

Camptothecin (CPT), first isolated from Chinese tree Camptotheca acuminate, produces rapid and prolonged inhibition of DNA synthesis and induction of DNA damage by targeting topoisomerase I (top1), which is highly activated in cancer cells. CPT thus exhibits remarkable anticancer activities in various cancer types, and is a promising therapeutic agent for the treatment of cancers. However, it remains to be uncovered underlying its cytotoxicity toward germ cells. In this study we found that CPT, a cell cycle-specific anticancer agent, reduced fecundity and exhibited significant cytotoxicity toward GSCs and two-cell cysts. We showed that CPT induced GSC loss and retarded two-cell cysts differentiation in a niche- or apoptosis-independent manner. Instead, CPT induced ectopic expression of a differentiation factor, bag of marbles (Bam), and regulated the expression of cyclin A, which contributed to GSC loss. In addition, CPT compromised two-cell cysts differentiation by decreasing the expression of Bam and inducing cell arrest at G1/S phase via cyclin A, eventually resulting in two-cell accumulation. Collectively, this study demonstrates, for the first time in vivo, that the Bam–cyclin A axis is involved in CPT-mediated germline stem cell loss and two-cell cysts differentiation defects via inducing cell cycle arrest, which could provide information underlying toxicological effects of CPT in the productive system, and feature its potential to develop as a pharmacology-based germline stem cell regulation agent.
Red Blood Cell Substitutes: Liposome Encapsulated Hemoglobin and Magnetite Nanoparticle Conjugates as Oxygen Carriers
Authors: Hafeez Saleha , Zaidi Najam Us Sahar Sadaf
Published: January 2023

The established blood donation and transfusion system has contributed a lot to human health and welfare, but for this system to function properly, it requires a sufficient number of healthy donors, which is not always possible. Pakistan was a country hit hardest by COVID-19 which additionally reduced the blood donation rates. In order to address such challenges, the present study focused on the development of RBC substitutes that can be transfused to all blood types. This paper reports the development and characterization of RBC substitutes by combining the strategies of conjugated and encapsulated hemoglobin where magnetite nanoparticles would act as the carrier of hemoglobin, and liposomes would separate internal and external environments. The interactions of hemoglobin variants with bare magnetite nanoparticles were studied through molecular docking studies. Moreover, nanoparticles were synthesized, and hemoglobin was purified from blood. These components were then used to make conjugates, and it was observed that only the hemoglobin HbA1 variant was making protein corona. These conjugates were then encapsulated in liposomes to make negatively charged RBC substitutes with a size range of 1–2 μm. Results suggest that these RBC substitutes work potentially in a similar way as natural RBCs work and can be used in the time of emergency.
The Influence of Lactoferrin in Plasma and Peritoneal Fluid on Iron Metabolism in Women with Endometriosis
Authors: Skarżyńska Ewa , Wróbel Monika , Zborowska Hanna , Kołek Mateusz Franciszek , Mańka Grzegorz , Kiecka Mariusz , Lipa Michał , Warzecha Damian , Spaczyński Robert , Piekarski Piotr , Banaszewska Beata , Jakimiuk Artur , Issat Tadeusz , Rokita Wojciech , Młodawski Jakub , Szubert Maria , Sieroszewski Piotr , Raba Grzegorz , Szczupak Kamil , Kluz Tomasz , Kluza Marek , Wielgoś Mirosław , Lisowska-Myjak Barbara , Laudański Piotr
Published: January 2023

The aim of this study was to investigate the relationship between lactoferrin and iron and its binding proteins in women with endometriosis by simultaneously measuring these parameters in plasma and peritoneal fluid. Ninety women were evaluated, of whom 57 were confirmed as having endometriosis. Lactoferrin was measured by ELISA, transferrin, ferritin and iron on a Cobas 8000 analyser. Lactoferrin and transferrin in peritoneal fluid were lower compared to plasma, in contrast to ferritin and iron. In plasma, lactoferrin showeds associations with iron and transferrin in endometriosis and with ferritin in the group without endometriosis. Lactoferrin in peritoneal fluid correlated with lactoferrin, iron and transferrin of plasma in patients without endometriosis. The ratio of lactoferrin concentration in peritoneal fluid to plasma differentiated stage I versus IV of endometriosis and was negatively correlated with the iron ratio in patients without endometriosis. The ferritin ratio differentiated women with and without endometriosis. The very high ferritin ratios, especially in advanced stages of endometriosis, suggest the protective involvement of this protein in peritoneal fluid and the loss of this role by lactoferrin. The results demonstrate the validity of assessing iron metabolism in women with endometriosis, which may be useful as a marker of the disease and its progression.
Cirsium Setidens Water Extracts Containing Linarin Block Estrogen Deprivation-Induced Bone Loss in Mice
Authors: Oh Moon-Sik , Kim Soo-Il , Sim Young Eun , Park Sin-Hye , Kang Min-Kyung , Kang Il-Jun , Lim Soon Sung , Kang Young-Hee
Published: January 2023

Osteoporosis is evident in postmenopausal women and is an osteolytic disease characterized by bone loss that further increases the susceptibility to bone fractures and frailty. The use of complementary therapies to alleviate postmenopausal osteoporosis is fairly widespread among women. Edible Cirsium setidens contains various polyphenols of linarin, pectolinarin, and apigenin with antioxidant and hepatoprotective effects. This study aimed to determine whether Cirsium setidens water extracts (CSEs), the component linarin, and its aglycone acacetin blocked ovariectomy (OVX)-induced bone loss. This study employed OVX C57BL/6 female mice as a model for postmenopausal osteoporosis. CSEs, acacetin, or linarin was orally administrated to OVX mice at a dose of 20 mg/kg for 8 weeks. Surgical estrogen loss in mice for 8 weeks reduced bone mineral density (BMD) of mouse femur and serum 17β-estradiol level and enhanced the serum receptor activator of NF-κB ligand/osteoprotegerin ratio with uterine atrophy. CSEs and linarin reversed such adverse effects and enhanced femoral BMD in OVX mice. Oral administration of CSEs and linarin attenuated tartrate-resistant acid phosphate activity and the induction of αvβ3 integrins and proton suppliers in resorption lacunae in femoral bone tissue of OVX mice. In addition, CSEs and linarin curtailed the bone levels of cathepsin K and matrix metalloproteinase-9 responsible for osteoclastic bone resorption. On the other hand, CSEs and linarin enhanced the formation of trabecular bones in estrogen-deficient femur with increased induction of osteocalcin and osteopontin. Further, treatment with CSEs and linarin enhanced the collagen formation-responsive propeptide levels in the circulation along with the increase in the tissue non-specific alkaline phosphatase level in bone exposed to OVX. Supplementing CSEs, acacetin, or linarin to OVX mice elevated the formation of collagen fibers in OVX trabecular bone, evidenced using Picrosirius red staining. Accordingly, CSEs and linarin were effective in retarding osteoclastic bone resorption and promoting osteoblastic bone matrix mineralization under OVX conditions. Therefore, linarin, which is abundant in CSEs, may be a natural compound for targeting postmenopausal osteoporosis and pathological osteoresorptive disorders.
Synthesis and Antimicrobial Activity of the Pathogenic E. coli Strains of p-Quinols: Additive Effects of Copper-Catalyzed Addition of Aryl Boronic Acid to Benzoquinones
Authors: Koszelewski Dominik , Kowalczyk Paweł , Samsonowicz-Górski Jan , Hrunyk Anastasiia , Brodzka Anna , Łęcka Justyna , Kramkowski Karol , Ostaszewski Ryszard
Published: January 2023

A mild and efficient protocol for the synthesis of p-quinols under aqueous conditions was developed. The pivotal role of additives in the copper-catalyzed addition of aryl boronic and heteroaryl boronic acids to benzoquinones was observed. It was found that polyvinylpyrrolidone (PVP) was the most efficient additive used for the studied reaction. The noteworthy advantages of this procedure include its broad substrate scope, high yields up to 91%, atom economy, and usage of readily available starting materials. Another benefit of this method is the reusability of the catalytic system up to four times. Further, the obtained p-quinols were characterized on the basis of their antimicrobial activities against E. coli. Antimicrobial activity was further compared with the corresponding 4-benzoquinones and 4-hydroquinones. Among tested compounds, seven derivatives showed an antimicrobial activity profile similar to that observed for commonly used antibiotics such as ciprofloxacin, bleomycin, and cloxacillin. In addition, the obtained p-quinols constitute a suitable platform for further modifications, allowing for a convenient change in their biological activity profile.
Epstein–Barr Virus Infection Is Associated with Elevated Hepcidin Levels
Authors: Duque Ximena , Mendoza Eugenia , Morán Segundo , Suárez-Arriaga Mayra C. , Morales-Sánchez Abigail , Fontes-Lemus José I. , Domínguez-Martínez Diana A. , Fuentes-Pananá Ezequiel M.
Published: January 2023

EBV and Helicobacter pylori (H. pylori) cause highly prevalent persistent infections as early as in childhood. Both pathogens are associated with gastric carcinogenesis. H. pylori interferes with iron metabolism, enhancing the synthesis of acute-phase proteins hepcidin, C-reactive protein (CRP), and α-1 glycoprotein (AGP), but we do not know whether EBV does the same. In this study, we correlated the EBV antibody levels and the serum levels of hepcidin, CRP, and AGP in 145 children from boarding schools in Mexico City. We found that children IgG positive to EBV antigens (VCA, EBNA1, and EA) presented hepcidin, AGP, and CRP levels higher than uninfected children. Hepcidin and AGP remained high in children solely infected with EBV, while CRP was only significantly high in coinfected children. We observed positive correlations between hepcidin and EBV IgG antibodies (p < 0.5). Using the TCGA gastric cancer database, we also observed an association between EBV and hepcidin upregulation. The TCGA database also allowed us to analyze the two important pathways controlling hepcidin expression, BMP–SMAD and IL-1β/IL-6. We observed only the IL-1β/IL-6-dependent inflammatory pathway being significantly associated with EBV infection. We showed here for the first time an association between EBV and enhanced levels of hepcidin. Further studies should consider EBV when evaluating iron metabolism and anemia, and whether in the long run this is an important mechanism of undernourishment and EBV gastric carcinogenesis.
The Old and the New: Cardiovascular and Respiratory Alterations Induced by Acute JWH-018 Administration Compared to Δ9-THC—A Preclinical Study in Mice
Authors: Marchetti Beatrice , Bilel Sabrine , Tirri Micaela , Arfè Raffaella , Corli Giorgia , Roda Elisa , Locatelli Carlo Alessandro , Cavarretta Elena , De Giorgio Fabio , Marti Matteo
Published: January 2023

Several new psychoactive substances (NPS) are responsible for intoxication involving the cardiovascular and respiratory systems. Among NPS, synthetic cannabinoids (SCs) provoked side effects in humans characterized by tachycardia, arrhythmias, hypertension, breathing difficulty, apnoea, myocardial infarction, and cardiac arrest. Therefore, the present study investigated the cardio-respiratory (MouseOx Plus; EMKA electrocardiogram (ECG) and plethysmography TUNNEL systems) and vascular (BP-2000 systems) effects induced by 1-naphthalenyl (1-pentyl-1H-indol-3-yl)-methanone (JWH-018; 0.3–3–6 mg/kg) and Δ9-tetrahydrocannabinol (Δ9-THC; 0.3–3–6 mg/kg), administered in awake CD-1 male mice. The results showed that higher doses of JWH-018 (3–6 mg/kg) induced deep and long-lasting bradycardia, alternated with bradyarrhythmia, spaced out by sudden episodes of tachyarrhythmias (6 mg/kg), and characterized by ECG electrical parameters changes, sustained bradypnea, and systolic and transient diastolic hypertension. Otherwise, Δ9-THC provoked delayed bradycardia (minor intensity tachyarrhythmias episodes) and bradypnea, also causing a transient and mild hypertensive effect at the tested dose range. These effects were prevented by both treatment with selective CB1 (AM 251, 6 mg/kg) and CB2 (AM 630, 6 mg/kg) receptor antagonists and with the mixture of the antagonists AM 251 and AM 630, even if in a different manner. Cardio-respiratory and vascular symptoms could be induced by peripheral and central CB1 and CB2 receptors stimulation, which could lead to both sympathetic and parasympathetic systems activation. These findings may represent a starting point for necessary future studies aimed at exploring the proper antidotal therapy to be used in SCs-intoxicated patient management.
Endometriosis and Opioid Receptors: Are Opioids a Possible/Promising Treatment for Endometriosis?
Authors: Guan Qihui , Velho Renata Voltolini , Sehouli Jalid , Mechsner Sylvia
Published: January 2023

Endometriosis (EM), defined as the presence of endometrial-like tissue with surrounding smooth muscle cells outside the uterus, is a disregarded gynecological disease reported to affect 6–10% of women of reproductive age, with 30–50% of them suffering from chronic pelvic pain and infertility. Since the exact pathogenic mechanisms of EM are still unclear, no curative therapy is available. As pain is an important factor in EM, optimal analgesia should be sought, which to date has been treated primarily with non-steroidal anti-inflammatory drugs (NSAIDs), metamizole or, in extreme cases, opioids. Here, we review the pain therapy options, the mechanisms of pain development in EM, the endogenous opioid system and pain, as well as the opioid receptors and EM-associated pain. We also explore the drug abuse and addiction to opioids and the possible use of NOP receptors in terms of analgesia and improved tolerability as a target for EM-associated pain treatment. Emerging evidence has shown a promising functional profile of bifunctional NOP/MOP partial agonists as safe and nonaddictive analgesics. However, until now, the role of NOP receptors in EM has not been investigated. This review offers a thought which still needs further investigation but may provide potential options for relieving EM-associated pain.
A 2.8 Å Structure of Zoliflodacin in a DNA Cleavage Complex with Staphylococcus aureus DNA Gyrase
Authors: Morgan Harry , Lipka-Lloyd Magdalena , Warren Anna J. , Hughes Naomi , Holmes John , Burton Nicolas P. , Mahenthiralingam Eshwar , Bax Ben D.
Published: January 2023

Since 2000, some thirteen quinolones and fluoroquinolones have been developed and have come to market. The quinolones, one of the most successful classes of antibacterial drugs, stabilize DNA cleavage complexes with DNA gyrase and topoisomerase IV (topo IV), the two bacterial type IIA topoisomerases. The dual targeting of gyrase and topo IV helps decrease the likelihood of resistance developing. Here, we report on a 2.8 Å X-ray crystal structure, which shows that zoliflodacin, a spiropyrimidinetrione antibiotic, binds in the same DNA cleavage site(s) as quinolones, sterically blocking DNA religation. The structure shows that zoliflodacin interacts with highly conserved residues on GyrB (and does not use the quinolone water–metal ion bridge to GyrA), suggesting it may be more difficult for bacteria to develop target mediated resistance. We show that zoliflodacin has an MIC of 4 µg/mL against Acinetobacter baumannii (A. baumannii), an improvement of four-fold over its progenitor QPT-1. The current phase III clinical trial of zoliflodacin for gonorrhea is due to be read out in 2023. Zoliflodacin, together with the unrelated novel bacterial topoisomerase inhibitor gepotidacin, is likely to become the first entirely novel chemical entities approved against Gram-negative bacteria in the 21st century. Zoliflodacin may also become the progenitor of a new safer class of antibacterial drugs against other problematic Gram-negative bacteria.