bluuebunny/crossref_metadata_2025 huggingface dataset:
Untargeted Metabolomics Analysis of Liquid Endosperm of Cocos nucifera L. at Three Stages of Maturation Evidenced Differences in Metabolic Regulation
Authors: Gómez-Tah Rufino , Islas-Flores Ignacio , Félix Jean Wildort , Granados-Alegría María Inés , Tzec-Simá Miguel , Guerrero-Analco José Antonio , Monribot-Villanueva Juan Luis , Canto-Canché Blondy
Published: July 2023

Cocos nucifera L. is one of the most cultivated palm trees in the world since it is used to obtain both raw materials and food. From a human point of view, the coconut fruit is a very valuable product, producing an aromatic and tasty liquid endosperm (coconut water) containing high levels of sugars, amino acids and other molecules of nutritional and nutraceutical value. Most of the chemical composition studies conducted on coconut to date have focused on the determination of fatty acid content in coconut oil and the extension of the shelf life of coconut water. Despite the economic importance of this species, the maturation of the coconut fruit is a complex biological process scarcely studied from the metabolic approach and biochemical changes occurring during fruit maturation are not well-known. The objective of this study is to investigate and elucidate the metabolic changes that occur during the maturation process of coconut (Cocos nucifera L.) fruits, specifically focusing on the liquid endosperm of the Yucatan green dwarf variety. In this study, the liquid endosperm of coconut fruits at the immature, intermediate and mature stages have been analyzed through an untargeted metabolomics approach by ultra performance liquid chromatography coupled to high resolution mass spectrometry (UPLC-HRMS). A total of 591 spectrometric features were detected and the corresponding identified compounds were classified into 24 chemical classes. The principal component analysis (PCA) showed segregation among the samples, according to their stage of maturation. Most of the metabolites detected were related to the metabolism of flavonoids, carbohydrates and organooxygen compounds. Pathway analysis showed that sphingolipid, starch and sucrose metabolisms were among the most over-accumulated during ripening, followed by the metabolism of glyoxylates and dicarboxylates and the metabolism of amino acids such as alanine, aspartate and glutamate, and others. This is the first study that focuses on elucidating the metabolic profiles of the liquid endosperm of coconut Yucatan green dwarf variety during three stages of maturation with an untargeted metabolomics approach through UPLC-MS.
Transcription Regulation of Anthocyanins and Proanthocyanidins Accumulation by Bagging in ‘Ruby’ Red Mango: An RNA-seq Study
Authors: Zhu Wencan , Wu Hongxia , Yang Chengkun , Wang Xiaowen , Shi Bin , Zheng Bin , Ma Xiaowei , Qian Minjie , Gao Aiping , Zhou Kaibing
Published: July 2023

The biosynthesis of anthocyanins and proanthocyanidins (PAs), components of two main flavonoids in plants, is regulated by environmental factors such as light. We previously found that bagging significantly repressed the biosynthesis of anthocyanins in red ‘Ruby’ mango fruit peel, but induced the accumulation of PAs. However, the molecular mechanism remains unclear. In the current study, transcriptome sequencing was used for screening the essential genes responsible for the opposite accumulation pattern of anthocyanins and PAs by bagging treatment. According to weighted gene co-expression network analysis (WGCNA), structural genes and transcription factors highly positively correlated to anthocyanins and PAs were identified. One flavanone 3-hydroxylase (F3H) and seven structural genes, including one chalcone synthase (CHS), one flavonoid 3’-hydroxylase (F3’H), one anthocyanidin synthesis (ANS), three leucoanthocyanidin reductase (LARs), and one UDP glucose: flavonoid 3-O-glucosyltransferase (UFGT), are crucial for anthocyanin and PA biosynthesis, respectively. In addition to MYB and bHLH, ERF, C2H2, HD-ZIP, and NAC are important transcription factors that participate in the regulation of anthocyanin and PA biosynthesis in ‘Ruby’ mango fruit peel by bagging treatment. Our results are helpful for revealing the transcription regulation mechanism of light-regulated mango anthocyanin and PA biosynthesis, developing new technologies for inducing flavonoid biosynthesis in mangos, and breeding mango cultivars containing high concentrations of flavonoids.
Modeled Forest Conversion Influences Humid Tropical Watershed Hydrology More than Projected Climate Change
Authors: Joyal Taylor , Fremier Alexander K. , Boll Jan
Published: July 2023

In the humid tropics, forest conversion and climate change threaten the hydrological function and stationarity of watersheds, particularly in steep terrain. As climate change intensifies, shifting precipitation patterns and expanding agricultural and pastoral land use may effectively reduce the resilience of headwater catchments. Compounding this problem is the limited long-term monitoring in developing countries for planning in an uncertain future. In this study, we asked which change, climate or land use, more greatly affects stream discharge in humid tropical mountain watersheds? To answer this question, we used the process-based, spatially distributed Soil Moisture Routing model. After first evaluating model performance (Ns = 0.73), we conducted a global sensitivity analysis to identify the model parameters that most strongly influence simulated watershed discharge. In particular, peak flows are most influenced by input model parameters that represent shallow subsurface soil pathways and saturation-excess runoff while low flows are most sensitive to macropore hydraulic conductivity, soil depth and porosity parameters. We then simulated a range of land use and climate scenarios in three mountain watersheds of central Costa Rica. Our results show that deforestation influences streamflow more than altered precipitation and temperature patterns through changes in first-order hydrologic hillslope processes. However, forest conversion coupled with intensifying precipitation events amplifies hydrological extremes, reducing the hydrological resilience to predicted climate shifts in mountain watersheds of the humid tropics. This finding suggests that reforestation can help mitigate the effects of climate change on streamflow dynamics in the tropics including impacts to water availability, flood pulses, channel geomorphology and aquatic habitat associated with altered flow regimes.
Trend of Correlations between Psychological Symptoms and Socioeconomic Inequalities among Italian Adolescents: Cross-Sectional Study from 2006 to 2018 in Tuscany Region
Authors: Lipari Dario , Bocci Bianca Maria , Rivieri Cesare , Frongillo Elena , Miserendino Antonella , Pammolli Andrea , Trombetta Claudia Maria , Manini Ilaria , Simi Rita , Lazzeri Giacomo
Published: July 2023

Adolescence is a critical moment in life; people become individuals, create new relationships, develop social skills and learn behaviours that they will use for the rest of their lives. During this phase, adolescents establish patterns of behaviour that can protect their health. This study aims to 1. assess the presence of psychological disorders in adolescents of both genders, 2. determine their relation to socio-economic differences based on the Family Affluence Scale (FAS), and 3. assess trends from 2006 to 2018. Data were collected from the Italian Health Behaviour in School-aged Children survey given to a representative sample of Tuscan adolescents aged 11–15 years. Participants (n. 12,550) filled out questionnaires to assess whether psychological symptoms such as feeling low, irritability, nervousness, or sleeping difficulties manifested weekly or more often over the past six months. For the study we utilized a cross-sectional survey method and linear regression to examine the association between psychological symptoms (dependent variable measured on an interval scale (0–16)), gender and FAS. We conducted similar analyses using logistic regressions for each of the four symptoms. An increase in psychological symptoms in both genders was revealed between 2006 and 2018, with a statistically significant presence in females: 0.29 (95% Confidence Interval [CI], 0.17 to 0.41), 1.43 (95% CI, 1.37 to 1.48) and 1.43 (95% CI, 1.34 to 1.52) in low-, medium- and high-affluence families, respectively; whereas males presented 0.14 (95% CI, 0.01 to 0.27), 0.71 (95% CI, 0.65 to 0.77) and 0.31 (95% CI, 0.22 to 0.39), respectively. The probability of a predictive episode of psychological symptoms (feeling low, irritability, nervousness, sleeping difficulties) occurring weekly, or more, often was greatly increased in females of all socioeconomic classes. These findings suggest that the increase in psychological disorders in adolescents should be considered a public health problem and further investigated through longitudinal studies and continuous monitoring of health trends.
A Social Cognitive Assessment of Workplace Sedentary Behavior among a Sample of University Employees
Authors: Wilkerson Amanda H. , Abutalib Nuha , McFadden Ny’Nika T. , Bhochhibhoya Shristi , Dragicevic Adriana , Salous Bushra R. , Nahar Vinayak K.
Published: July 2023

Sedentary behavior (SB) is an important public health concern. Adults working in desk-based occupations spend a considerable proportion of the workday sitting. More information is needed regarding the factors that contribute to occupational SB. The aim of this study was to assess the utility of social cognitive theory (SCT) to explain work-related SB using a quantitative, cross-sectional design by administering an online questionnaire. Participants included 381 full-time employees at a large, public university in the south-central United States. Hierarchical multiple linear regression was used to determine the relationship between SCT constructs and SB. Mean work-related SB was 5.95 (SD = 1.30) h/8 h workday. In model 1, 9.6% of the total variance in SB was accounted for by standing desk ownership and physical activity level (p = 0.001; R2 = 0.096). In model 2, SCT constructs led to a statistically significant R2 increase of 4.9% (p < 0.001), where standing desk ownership, physical activity, and self-efficacy explained 13.3% of the variance in work-related SB. Findings from this study suggest that self-efficacy may be an important factor in explaining variation in occupational SB. Public health researchers and practitioners should consider strategies to address self-efficacy when developing workplace interventions to target occupational SB.
Retrospective Analyses of COVID-19 and Population Ageing Effects on Italian Mortality during the Pandemic
Authors: Brunori Damiano , Frajese Giovanni Vanni , Sarno Emma
Published: July 2023

The spread of COVID-19 led to an extremely high number of deaths in Italy in 2020 with respect to previous years. Because the total number of deaths may depend on both the population structure and the mortality rate by age groups, a detailed overview of the Italian pandemic situation is here provided by following two main lines of inquiry: (i) checking for similarities and differences among mortality rates per age groups before and during the COVID-19 spread; (ii) analyzing the responsiveness of the Italian population structure to different mortality rates. Real-based evidence led us to conduct analyses for two groups associated with different population stages of life, referred to as younghood and adulthood periods. We focus on the Italian pandemic from February 2020 to March 2021. Our study helps to understand why elders dramatically impacted the total number of deaths. In addition, it reveals how badly the 2020 Italian population structure would have reacted to mortality rates already faced in the past. Finally, politicians, scientists, and journalists’ statements and other ways of communicating information about COVID-19 are questioned in the light of scientific data available at that time.
Impact of COVID-19 Pandemic on Well-Being, Social Relationships and Academic Performance in a Sample of University Freshmen: A Propensity Score Match Evaluation Pre- and Post-Pandemic
Authors: Buizza Chiara , Ferrari Clarissa , Sbravati Giulio , Dagani Jessica , Cela Herald , Rainieri Giuseppe , Ghilardi Alberto
Published: July 2023

The COVID-19 pandemic has impacted freshmen, compromising their mental health, lifestyles, and academic performance. There are few studies that have investigated changes in the health status and lifestyles of freshmen before and after the pandemic. The aims of this study were: (1) to carry out a pre–post-COVID-19 pandemic comparison between two freshmen samples, in order to detect differences in their socio-demographic characteristics and in some clinical variables; (2) to assess the effect of the COVID-19 pandemic on the social and academic lives of the second sample of freshmen. The samples recruited in 2019 and 2022, matched by propensity score procedure (N = 553), were mostly female (57.3% vs. 55.3%); the mean age was 22.9 and 20.9 years, respectively. The freshmen recruited after the pandemic had less psychological distress and substance use than freshmen recruited before the pandemic. Seventy-eight percent of the freshmen stated that the pandemic had an impact on their social relationships. This effect was greater for females and Italian students. Forty-seven percent reported that the pandemic has worsened their academic performance, while 60% stated that pandemic has improved their grades. The results of this study can provide valuable insights into the impact of the pandemic on freshmen, in order to implement interventions to mitigate the consequences of the pandemic in some subgroups of this target population.
Considerations for Purchasing Drug Checking Technologies: Perspectives from Toronto’s Drug Checking Service
Authors: Thompson Hayley , McDonald Karen
Published: July 2023

With the unregulated drug supply—particularly the unregulated opioid supply—becoming increasingly more toxic, more contaminated, and less predictable, drug checking has emerged as an essential public health service: informing individuals who use drugs, as well as those who care and advocate for them, in real-time. For those looking to offer drug checking services in community settings, choosing a technology can be an arduous task. With very little regulatory oversight of drug checking technologies, it can be difficult for organizations that specialize in harm reduction to ascertain what questions to ask drug checking technology vendors to ensure they invest in a technology that best suits the needs of their community. Looking to help those that lack drug checking and technical expertise, Toronto’s Drug Checking Service has compiled a list of questions to equip organizations to make informed decisions when it comes to purchasing drug checking technologies. Having developed and operated a drug checking service since 2018, Toronto’s Drug Checking Service is uniquely positioned to share its expertise and insights.
Opening a New Era with Machine Learning in Financial Services? Forecasting Corporate Credit Ratings Based on Annual Financial Statements
Authors: Pamuk Mustafa , Schumann Matthias
Published: July 2023

Corporate credit ratings provide multiple strategic, financial, and managerial benefits for decision-makers. Therefore, it is essential to have accurate and up-to-date ratings to continuously monitor companies’ financial situations when making financial credit decisions. Machine learning (ML)-based internal models can be used for the assessment of companies’ financial situations using annual statements. Particularly, it is necessary to check whether these ML models achieve better results compared to statistical methods. Due to the multi-class classification problem when forecasting corporate credit ratings, the development, monitoring, and maintenance of ML-based systems are more challenging compared to simple classifications. This problem becomes even more complex due to the required coordination with financial regulators (e.g., OECD, EBA, BaFin, etc.). Furthermore, the ML models must be updated regularly due to the periodic nature of annual statements as a dataset. To address the problem of the limited dataset, multiple sampling strategies and machine learning algorithms can be combined for accurate and up-to-date forecasting of credit ratings. This paper provides various implications for ML-based forecasting of credit ratings and presents an approach for combining sampling strategies and ML techniques. It also provides design recommendations for ML-based services in the finance industry on how to fulfill the existing regulations.
Explanation and Analysis of Spatio-Temporal Correlations—Towards a Conceptual Approach of a Semantic Comparison Visualization in a Use Case of Carparks in Mainz, Germany
Authors: Rolwes Alexander , Böhm Klaus
Published: July 2023

Geospatial factors, because of their spatio-temporal correlations with demand-driven limited service, offer to improve urban planning decisions and expand the knowledge base in cities. Spatio-temporal analyses require an efficient and comprehensible visualization and explanation in order to analyze and understand geospatial relationships in urban areas. The aim of our research is to support domain experts in these analyses with user-oriented geovisualization. In this article, we propose concepts towards a semantic comparison visualization, which combines a visual analysis view and a visual explanation view. The visual analysis view is a knowledge-oriented view that focuses on analyzing resulting spatio-temporal correlations. The visual explanation view is an understanding-oriented view that focuses on explaining the underlying complex analysis process of geospatial factors and spatio-temporal correlations. We define general requirements for this aim and validate and evaluate our concepts related to these requirements. The results show the benefit of our concepts, but, at the same time, they also point to limitations and potential for optimization in further work.
Convolutional Neural Network-Based Approximation of Coverage Path Planning Results for Parking Lots
Authors: Kriščiūnas Andrius , Čalnerytė Dalia , Fyleris Tautvydas , Jurgutis Tadas , Makackas Dalius , Barauskas Rimantas
Published: July 2023

Parking lots have wide variety of shapes because of surrounding environment and the objects inside the parking lot, such as trees, manholes, etc. In the case of paving the parking lot, as much area as possible should be covered by the construction vehicle to reduce the need for manual workforce. Thus, the coverage path planning (CPP) problem is formulated. The CPP of the parking lots is a complex problem with constraints regarding various issues, such as dimensions of the construction vehicle and data processing time and resources. A strategy based on convolutional neural networks (CNNs) for the fast estimation of the CPP’s average track length, standard deviation of track lengths, and number of tracks was suggested in this article. Two datasets of different complexity were generated to analyze the suggested approach. The first case represented a simple case with a working polygon constructed out of several rectangles with applied shear and rotation transformations. The second case represented a complex geometry generated out of rectangles and ellipses, narrow construction area, and obstacles. The results were compared with the linear regression models, with the area of the working polygon as an input. For both generated datasets, the strategy to use an approximator to estimate outcomes led to more accurate results compared to the respective linear regression models. The suggested approach enables us to have rough estimates of a large number of geometries in a short period of time and organize the working process, for example, planning construction time and price, choosing the best decomposition of the working polygon, etc.
Telocytes/CD34+ Stromal Cells in the Normal, Hyperplastic, and Adenomatous Human Parathyroid Glands
Authors: Díaz-Flores Lucio , Gutiérrez Ricardo , González-Gómez Miriam , García Maria del Pino , Carrasco Jose Luis , Madrid Juan Francisco , Díaz-Flores Lucio
Published: July 2023

Telocytes/CD34+ stromal cells (TCs/CD34+ SCs) have been studied in numerous organs and tissues, but their presence and characteristics in the parathyroid glands have not been explored. Using immunological and ultrastructural procedures, we assess the location, arrangement, and behavior of TCs/CD34+ SCs in normal human parathyroids, during their development and in their most frequent pathologic conditions. In normal parathyroids, TCs/CD34+ SCs show a small somatic body and long thin processes with a moniliform aspect, form labyrinthine systems, connect other neighboring TCs/CD34+ SCs, vessels, adipocytes, and parenchymal cells directly or by extracellular vesicles, and associate with collagen I. TCs/CD34+ SCs and collagen I are absent around vessels and adipocytes within parenchymal clusters. In developing parathyroids, TCs/CD34+ SC surround small parenchymal nests and adipocytes. In hyperplastic parathyroids, TCs/CD34+ SCs are prominent in some thickened internodular septa and surround small extraglandular parenchymal cell nests. TCs/CD34+ SCs are present in delimiting regions with compressed parathyroids and their capsule in adenomas but absent in most adenomatous tissue. In conclusion, TCs/CD34+ SCs are an important cellular component in the human parathyroid stroma, except around vessels within parenchymal nests. They show typical characteristics, including those of connecting cells, are present in developing parathyroids, and participate in the most frequent parathyroid pathology, including hyperplastic and adenomatous parathyroids.
ZSCAN4 Regulates Zygotic Genome Activation and Telomere Elongation in Porcine Parthenogenetic Embryos
Authors: Li Xiao-Han , Sun Ming-Hong , Jiang Wen-Jie , Zhou Dongjie , Lee Song-Hee , Heo Geun , Chen Zhi , Cui Xiang-Shun
Published: July 2023

Zinc finger and SCAN domain-containing 4 (ZSCAN4), a DNA-binding protein, maintains telomere length and plays a key role in critical aspects of mouse embryonic stem cells, including maintaining genomic stability and defying cellular senescence. However, the effect of ZSCAN4 in porcine parthenogenetic embryos remains unclear. To investigate the function of ZSCAN4 and the underlying mechanism in porcine embryo development, ZSCAN4 was knocked down via dsRNA injection in the one-cell stage. ZSCAN4 was highly expressed in the four- and five- to eight-cell stages in porcine embryos. The percentage of four-cell stage embryos, five- to eight-cell stage embryos, and blastocysts was lower in the ZSCAN4 knockdown group than in the control group. Notably, depletion of ZSCAN4 induced the protein expression of DNMT1 and 5-Methylcytosine (5mC, a methylated form of the DNA base cytosine) in the four-cell stage. The H3K27ac level and ZGA genes expression decreased following ZSCAN4 knockdown. Furthermore, ZSCAN4 knockdown led to DNA damage and shortened telomere compared with the control. Additionally, DNMT1-dsRNA was injected to reduce DNA hypermethylation in ZSCAN4 knockdown embryos. DNMT1 knockdown rescued telomere shortening and developmental defects caused by ZSCAN4 knockdown. In conclusion, ZSCAN4 is involved in the regulation of transcriptional activity and is essential for maintaining telomere length by regulating DNMT1 expression in porcine ZGA.
The Role of Mast Cells and Their Inflammatory Mediators in Immunity
Authors: Theoharides Theoharis C.
Published: July 2023

Mast cells have existed for almost 500 million years [...]
Treprostinil Reconstitutes Mitochondrial Organisation and Structure in Idiopathic Pulmonary Fibrosis Cells
Authors: Fang Lei , Chen Wei-Chih , Jaksch Peter , Molino Antonio , Saglia Alessandro , Roth Michael , Lambers Christopher
Published: July 2023

Idiopathic pulmonary fibrosis (IPF) presents as an incurable change in the lung tissue and mitochondrial dysfunction of unknown origin. Treprostinil, a prostacyclin analogue, has been suggested for IPF therapy. This study assessed the effect of treprostinil on the cAMP signalling and mitochondrial activity in healthy lung fibroblasts and fibroblast-like cells from IPF patients. Six control fibroblast strains and six fibroblast-like IPF cell strains were isolated and expanded from freshly resected lung tissue. The cells were grown to confluence before being treated with either transforming growth factor (TGF)-β1, treprostinil, their combination, or a vehicle for up to 2 days. Mitochondria-regulating proteins were analysed using Western blotting and immunofluorescence, and the mitochondria were analysed using cytochrome C, mitochondrial cytochrome C oxidase II (MTCO2), and MTCO4. The IPF cells showed an increased rate of damaged mitochondria, which were significantly reduced when the cells were treated with treprostinil over 24 h. In the control cells, treprostinil prevented TGF-β-induced mitochondrial damage. Treatment with treprostinil modified the expression of several mitochondria-regulating proteins. In both cell types, treprostinil upregulated the expression of PTEN, p21(Waf1/Cip1), beclin1, LC3 II, parkin, PINK1, MTCO2, and MTCO4. In contrast, treprostinil downregulated the phosphorylation of mTOR and the expression of p62, mitofusin1, and mtiofusin2 in IPF cells. This might explain the reduced mitochondrial damage observed in treprostinil-treated IPF cells and suggest an improvement in the mitochondrial function in IPF. In this study, treprostinil improved mitochondrial impairment in vitro, which might, in part, explain the beneficial clinical effects documented in patients.
Superimposed Mosaicism in the Form of Extremely Extended Segmental Plexiform Neurofibroma Caused by a Novel Pathogenic Variant in the NF1 Gene
Authors: Veres Klára , Bene Judit , Hadzsiev Kinga , Garami Miklós , Pálla Sára , Happle Rudolf , Medvecz Márta , Szalai Zsuzsanna Zsófia
Published: July 2023

Plexiform neurofibromas occurring in approximately 20–50% of all neurofibromatosis type-1 (NF1) cases are histologically benign tumors, but they can be fatal due to compression of vital structures or transformation to malignant sarcomas or malignant peripheral nerve sheath tumors. All sizeable plexiform neurofibromas are thought to result from an early second mutation giving rise to a loss of heterozygosity of the NF1 gene. In this unusual case, a 12-year-old girl presented with a rapidly growing, extremely extensive plexiform neurofibroma with segmental distribution over the entire right arm, extending to the right chest wall and mediastinum, superimposed on classic cutaneous lesions of NF1. After several surgical interventions, the patient was efficiently treated with an oral selective MEK inhibitor, selumetinib, which resulted in a rapid reduction of the tumor volume. Molecular analysis of the NF1 gene revealed a c.2326-2 A>G splice-site mutation in the clinically unaffected skin, peripheral blood sample, and plexiform neurofibroma, which explains the general clinical symptoms. Furthermore, a novel likely pathogenic variant, c.4933dupC (p.Leu1645Profs*7), has been identified exclusively in the girl’s plexiform neurofibromas. This second-hit mutation can explain the extremely extensive segmental involvement.
The Role of FAS Receptor Methylation in Osteosarcoma Metastasis
Authors: Sun Jiayi M. , Chow Wing-Yuk , Xu Gufeng , Hicks M. John , Nakka Manjula , Shen Jianhe , Ng Patrick Kwok Shing , Taylor Aaron M. , Yu Alexander , Farrar Jason E. , Barkauskas Donald A. , Gorlick Richard , Guidry Auvil Jaime M. , Gerhard Daniela , Meltzer Paul , Guerra Rudy , Man Tsz-Kwong , Lau Ching C. ,   on behalf of the TARGET Osteosarcoma Consortium
Published: July 2023

Osteosarcoma is the most frequent primary malignant bone tumor with an annual incidence of about 400 cases in the United States. Osteosarcoma primarily metastasizes to the lungs, where FAS ligand (FASL) is constitutively expressed. The interaction of FASL and its cell surface receptor, FAS, triggers apoptosis in normal cells; however, this function is altered in cancer cells. DNA methylation has previously been explored as a mechanism for altering FAS expression, but no variability was identified in the CpG island (CGI) overlapping the promoter. Analysis of an expanded region, including CGI shores and shelves, revealed high variability in the methylation of certain CpG sites that correlated significantly with FAS mRNA expression in a negative manner. Bisulfite sequencing revealed additional CpG sites, which were highly methylated in the metastatic LM7 cell line but unmethylated in its parental non-metastatic SaOS-2 cell line. Treatment with the demethylating agent, 5-azacytidine, resulted in a loss of methylation in CpG sites located within the FAS promoter and restored FAS protein expression in LM7 cells, resulting in reduced migration. Orthotopic implantation of 5-azacytidine treated LM7 cells into severe combined immunodeficient mice led to decreased lung metastases. These results suggest that DNA methylation of CGI shore sites may regulate FAS expression and constitute a potential target for osteosarcoma therapy, utilizing demethylating agents currently approved for the treatment of other cancers.
Whole Transcriptome Analysis of Substantia Nigra in Mice with MPTP-Induced Parkinsonism Bearing Defective Glucocerebrosidase Activity
Authors: Usenko Tatiana , Bezrukova Anastasia , Rudenok Margarita M. , Basharova Katerina , Shadrina Maria I. , Slominsky Petr A. , Zakharova Ekaterina , Pchelina Sofya
Published: July 2023

Mutations in the GBA1 gene represent the major genetic risk factor for Parkinson’s disease (PD). The lysosomal enzyme beta-glucocerebrosidase (GCase) encoded by the GBA1 gene participates in both the endolysosomal pathway and the immune response. Disruption of these mechanisms is involved in PD pathogenesis. However, molecular mechanisms of PD associated with GBA1 mutations (GBA-PD) are unknown today in particular due to the partial penetrance of GBA1 variants in PD. The modifiers of GBA1 penetrance have not been elucidated. We characterized the transcriptomic profiles of cells from the substantia nigra (SN) of mice with co-injection with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and selective inhibitor of GCase activity (conduritol-β-epoxide, (CBE)) to mimic PD bearing GCase dysfunction (MPTP+CBE), mice treated with MPTP, mice treated with CBE and control mice treated with injection of sodium chloride (NaCl) (vehicle). Differential expression analysis, pathway enrichment analysis, and outlier detection were performed. Functional clustering of differentially represented transcripts revealed more processes associated with the functioning of neurogenesis, inflammation, apoptosis and autophagy in MPTP+CBE and MPTP mice than in vehicle mice, with a more pronounced alteration of autophagy processes in MPTP+CBE mice than in MPTP mice. The PI3K-Akt-mTOR signaling pathway may be considered a potential target for therapy in PD with GCase dysfunction.
ω-3 Polyunsaturated Fatty Acids Improve the Blood–Brain-Barrier Integrity in Contrast-Induced Blood–Brain-Barrier Injury in Uremic Mice
Authors: Shin Jin Ah , Park Hyerim , Choi Hyunsu , Chang Yoon-Kyung , Kim Jwa-Jin , Ham Young Rok , Na Ki Ryang , Lee Kang Wook , Choi Dae Eun
Published: July 2023

In patients with chronic kidney disease, the need for examinations using contrast media (CM) increases because of underlying diseases. Although contrast agents can affect brain cells, the blood–brain barrier (BBB) protects against brain-cell damage in vivo. However, uremia can disrupt the BBB, increasing the possibility of contrast-agent-induced brain-cell damage in patients with chronic kidney disease (CKD). ω-3 polyunsaturated fatty acids (PUFAs) have shown protective effects on various neurological disorders, including uremic brain injury. This study examined whether ω-3 PUFAs attenuate damage to the BBB caused by uremia and contrast agents in a uremic mouse model and evaluated its associated mechanisms. C57BL/6 mice (eight weeks old, male) and fat-1 mice (b6 background/eight weeks old, male) were divided into groups according to uremic induction, CM, and ω-3 PUFA administration. Uremia was induced via 24 h ischemia–reperfusion (IR) renal injury. One day after CM treatment, the brain tissue, kidney tissue, and blood were collected. The expression levels of glial fibrillary acidic protein (GFAP), claudin 5, CD31, laminin α4, and laminin α5 increased in ω-3 PUFA + CM-treated uremic mice and the brain of fat-1 + CM-treated uremic mice compared with those in the brains of CM-treated uremic mice. The pro-apoptotic protein expression decreased, whereas the anti-apoptotic proteins increased in ω-3 PUFA + CM-treated uremic mice and fat-1 + CM-treated uremic mice compared with CM-treated uremic mice. In addition, the brain-expression levels of p-JNK, p-P53, and p-P38 decreased in the ω-3 PUFA + CM-treated uremic mice and fat-1 + CM-treated uremic mice compared with those in wild-type uremic mice. Our results confirm that uremic toxin and CM damage the BBB and cause brain-cell death. ω-3 PUFAs play a role in BBB protection caused by CM in uremic mice.
Molecular Motifs in Vascular Morphogenesis: Vascular Endothelial Growth Factor A (VEGFA) as the Leading Promoter of Angiogenesis
Authors: Lungu Claudiu , Mehedinti Mihaela
Published: July 2023

Tissular hypoxia stimulates vascular morphogenesis. Vascular morphogenesis shapes the cell and, consecutively, tissue growth. The development of new blood vessels is intermediated substantially through the tyrosine kinase pathway. There are several types of receptors inferred to be located in the blood vessel structures. Vascular endothelial growth factor A (VEGF-A) is the leading protagonist of angiogenesis. VEGF-A’s interactions with its receptors VEGFR1, VEGFR2, and VEGFR3, together with disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1), connective tissue growth factor (CTGF), and neuropilin-1 (NRP1), independently, are studied computationally. Peripheral artery disease (PAD), which results in tissue ischemia, is more prevalent in the senior population. Presently, medical curatives used to treat cases of PAD—antiplatelet and antithrombotic agents, statins, antihypertensive remedies with ACE (angiotensin-converting enzyme) impediments, angiotensin receptor blockers (ARB) or β- blockers, blood glucose control, and smoking cessation—are not effective. These curatives were largely established from the treatment of complaint cases of coronary disease. However, these medical curatives do not ameliorate lower limb perfusion in cases of PAD. Likewise, surgical or endovascular procedures may be ineffective in relieving symptoms. Eventually, after successful large vessel revascularization, the residual microvascular circulation may well limit the effectiveness of curatives in cases of PAD. It would thus feel rational to attempt to ameliorate perfusion in PAD by enhancing vascular rejuvenescence and function. Likewise, stimulating specific angiogenesis in these cases (PAD) can ameliorate the patient’s symptomatology. Also, the quality of life of PAD patients can be improved by developing new vasodilative and angiogenetic molecules that stimulate the tyrosine kinase pathway. In this respect, the VEGFA angiogenetic pathway was explored computationally. Docking methodologies, molecular dynamics, and computational molecular design methodologies were used. VEGFA’s interaction with its target was primarily studied. Common motifs in the vascular morphogenesis pathway are suggested using conformational energy and Riemann spaces. The results show that interaction with VEGFR2 and ADAMTS1 is pivotal in the angiogenetic process. Also, the informational content of two VEGFA complexes, VEGFR2 and ADAMTS1, is crucial in the angiogenesis process.
Knockdown of PTK7 Reduces the Oncogenic Potential of Breast Cancer Cells by Impeding Receptor Tyrosine Kinase Signaling
Authors: Shin Won-Sik , Oh Si Won , Park Han Na , Kim Jae Hoon , Lee Seung-Taek
Published: July 2023

Protein tyrosine kinase 7 (PTK7), a catalytically defective receptor tyrosine kinase (RTK), is often upregulated in various cancers. This study aimed to validate PTK7 as a target for breast cancer (BC) and investigate its oncogenic signaling mechanism. BC tissue analysis showed significantly elevated PTK7 mRNA levels, especially in refractory triple-negative breast cancer (TNBC) tissues, compared with normal controls. Similarly, BC cell lines exhibited increased PTK7 expression. Knockdown of PTK7 inhibited the proliferation of T-47D and MCF-7 hormone-receptor-positive BC cell-lines and of HCC1187, MDA-MB-231, MDA-MB-436, and MDA-MB-453 TNBC cells. PTK7 knockdown also inhibited the adhesion, migration, and invasion of MDA-MB-231, MDA-MB-436, and MDA-MB-453 cells, and reduced the phosphorylation levels of crucial oncogenic regulators including extracellular signal-regulated kinase (ERK), Akt, and focal adhesion kinase (FAK). Furthermore, PTK7 interacts with fibroblast growth factor receptor 1 (FGFR1) and epidermal growth factor receptor (EGFR) expressed in MDA-MB-231 cells. Knockdown of PTK7 decreased the growth-factor-induced phosphorylation of FGFR1 and EGFR in MDA-MB-231 cells, indicating its association with RTK activation. In conclusion, PTK7 plays a significant role in oncogenic signal transduction by enhancing FGFR1 and EGFR activation, influencing BC tumorigenesis and metastasis. Hence, PTK7 represents a potential candidate for targeted BC therapy, including TNBC.
SARS-CoV-2 and Its Bacterial Co- or Super-Infections Synergize to Trigger COVID-19 Autoimmune Cardiopathies
Authors: Root-Bernstein Robert , Huber Jack , Ziehl Alison , Pietrowicz Maja
Published: July 2023

Autoimmune cardiopathies (AC) following COVID-19 and vaccination against SARS-CoV-2 occur at significant rates but are of unknown etiology. This study investigated the possible roles of viral and bacterial mimicry, as well as viral-bacterial co-infections, as possible inducers of COVID-19 AC using proteomic methods and enzyme-linked immunoadsorption assays. BLAST and LALIGN results of this study demonstrate that SARS-CoV-2 shares a significantly greater number of high quality similarities to some cardiac protein compared with other viruses; that bacteria such as Streptococci, Staphylococci and Enterococci also display very significant similarities to cardiac proteins but to a different set than SARS-CoV-2; that the importance of these similarities is largely validated by ELISA experiments demonstrating that polyclonal antibodies against SARS-CoV-2 and COVID-19-associated bacteria recognize cardiac proteins with high affinity; that to account for the range of cardiac proteins targeted by autoantibodies in COVID-19-associated autoimmune myocarditis, both viral and bacterial triggers are probably required; that the targets of the viral and bacterial antibodies are often molecularly complementary antigens such as actin and myosin, laminin and collagen, or creatine kinase and pyruvate kinase, that are known to bind to each other; and that the corresponding viral and bacterial antibodies recognizing these complementary antigens also bind to each other with high affinity as if they have an idiotype-anti-idiotype relationship. These results suggest that AC results from SARS-CoV-2 infections or vaccination complicated by bacterial infections. Vaccination against some of these bacterial infections, such as Streptococci and Haemophilus, may therefore decrease AC risk, as may the appropriate and timely use of antibiotics among COVID-19 patients and careful screening of vaccinees for signs of infection such as fever, diarrhea, infected wounds, gum disease, etc.
The Key Role of Mitochondria in Somatic Stem Cell Differentiation: From Mitochondrial Asymmetric Apportioning to Cell Fate
Authors: Amato Ilario , Meurant Sébastien , Renard Patricia
Published: July 2023

The study of the mechanisms underlying stem cell differentiation is under intensive research and includes the contribution of a metabolic switch from glycolytic to oxidative metabolism. While mitochondrial biogenesis has been previously demonstrated in number of differentiation models, it is only recently that the role of mitochondrial dynamics has started to be explored. The discovery of asymmetric distribution of mitochondria in stem cell progeny has strengthened the interest in the field. This review attempts to summarize the regulation of mitochondrial asymmetric apportioning by the mitochondrial fusion, fission, and mitophagy processes as well as emphasize how asymmetric mitochondrial apportioning in stem cells affects their metabolism, and thus epigenetics, and determines cell fate.
Neurologic and Psychiatric Manifestations of Bradykinin-Mediated Angioedema: Old and New Challenges
Authors: Mormile Ilaria , Palestra Francesco , Petraroli Angelica , Loffredo Stefania , Rossi Francesca Wanda , Spadaro Giuseppe , de Paulis Amato , Bova Maria
Published: July 2023

Neurologic manifestations have been occasionally described in patients with bradykinin-mediated angioedema. The existing literature is currently limited to case series and case reports mainly described in the hereditary forms (HAE) concerning central nervous system (CNS) involvement. On the contrary, very little is known about peripheral and autonomic nervous system manifestations. CNS involvement in HAE may present with symptoms including severe headaches, visual disturbance, seizures, and various focal and generalized deficits. In addition, a stroke-like clinical picture may present in HAE patients. In turn, some drugs used in patients with cardiovascular and neurologic disorders, such as recombinant tissue plasminogen activator (r-tPA) and angiotensin-converting enzyme inhibitors (ACEI), may produce medication-induced angioedema, resulting in a diagnostic challenge. Finally, most patients with HAE have higher levels of psychological distress, anxiety, and depression. With this review, we aimed to provide an organized and detailed analysis of the existing literature on neurologic and psychiatric manifestations of HAE to shed light on these potentially invalidating symptoms and lay the foundation for further personalized diagnostic pathways for patients affected by this protean disease.
Effects of Paclitaxel on Plasma Membrane Microviscosity and Lipid Composition in Cancer Cells
Authors: Shimolina Liubov , Gulin Alexander , Khlynova Alexandra , Ignatova Nadezhda , Druzhkova Irina , Gubina Margarita , Zagaynova Elena , Kuimova Marina K. , Shirmanova Marina
Published: July 2023

The cell membrane is an important regulator for the cytotoxicity of chemotherapeutic agents. However, the biochemical and biophysical effects that occur in the membrane under the action of chemotherapy drugs are not fully described. In the present study, changes in the microviscosity of membranes of living HeLa–Kyoto tumor cells were studied during chemotherapy with paclitaxel, a widely used antimicrotubule agent. To visualize the microviscosity of the membranes, fluorescence lifetime imaging microscopy (FLIM) with a BODIPY 2 fluorescent molecular rotor was used. The lipid profile of the membranes was assessed using time-of-flight secondary ion mass spectrometry ToF-SIMS. A significant, steady-state decrease in the microviscosity of membranes, both in cell monolayers and in tumor spheroids, was revealed after the treatment. Mass spectrometry showed an increase in the unsaturated fatty acid content in treated cell membranes, which may explain, at least partially, their low microviscosity. These results indicate the involvement of membrane microviscosity in the response of tumor cells to paclitaxel treatment.
The Integrase: An Overview of a Key Player Enzyme in the Antiviral Scenario
Authors: Renzi Gioele , Carta Fabrizio , Supuran Claudiu T.
Published: July 2023

Integration of a desossiribonucleic acid (DNA) copy of the viral ribonucleic acid (RNA) into host genomes is a fundamental step in the replication cycle of all retroviruses. The highly conserved virus-encoded Integrase enzyme (IN; EC 2.7.7.49) catalyzes such a process by means of two consecutive reactions named 3′-processing (3-P) and strand transfer (ST). The Authors report and discuss the major discoveries and advances which mainly contributed to the development of Human Immunodeficiency Virus (HIV) -IN targeted inhibitors for therapeutic applications. All the knowledge accumulated over the years continues to serve as a valuable resource for the design and development of effective antiretroviral drugs.
Epigenetic Factors and ncRNAs in Testicular Cancer
Authors: Nuñez-Corona David , Contreras-Sanzón Estefania , Puente-Rivera Jonathan , Arreola Rodrigo , Camacho-Nuez Minerva , Cruz Santiago José , Estrella-Parra Edgar Antonio , Torres-Romero Julio César , López-Camarillo César , Alvarez-Sánchez María Elizbeth
Published: July 2023

Testicular cancer is the most prevalent tumor among males aged 15 to 35, resulting in a significant number of newly diagnosed cases and fatalities annually. Non-coding RNAs (ncRNAs) have emerged as key regulators in various cellular processes and pathologies, including testicular cancer. Their involvement in gene regulation, coding, decoding, and overall gene expression control suggests their potential as targets for alternative treatment approaches for this type of cancer. Furthermore, epigenetic modifications, such as histone modifications, DNA methylation, and the regulation by microRNA (miRNA), have been implicated in testicular tumor progression and treatment response. Epigenetics may also offer critical insights for prognostic evaluation and targeted therapies in patients with testicular germ cell tumors (TGCT). This comprehensive review aims to present the latest discoveries regarding the involvement of some proteins and ncRNAs, mainly miRNAs and lncRNA, in the epigenetic aspect of testicular cancer, emphasizing their relevance in pathogenesis and their potential, given the fact that their specific expression holds promise for prognostic evaluation and targeted therapies.
Calcitonin Gene-Related Peptide-Mediated Trigeminal Ganglionitis: The Biomolecular Link between Temporomandibular Disorders and Chronic Headaches
Authors: Sangalli Linda , Eli Bradley , Mehrotra Sachi , Sabagh Suzan , Fricton James
Published: July 2023

A bidirectional causal relationship has been established between temporomandibular disorders (TMDs) and chronic headaches. Recent advances in the neurobiology of chronic pain offer a framework for understanding the comorbidity between these two conditions that might reside in the shared biomolecular mechanisms of peripheral and central sensitization. The initiation of these processes is inflammatory in nature and is most likely mediated by key molecules, including calcitonin gene-related peptide (CGRP). This scoping review proposes that CGRP-mediated neuroinflammation in the trigeminal ganglion may partly explain the biomolecular bidirectional link between TMDs and chronic headaches. Finally, clinical implications of this neuropathologic process are briefly discussed.