The 2023 MDPI Annual Report has
been released!
 
15 pages, 1748 KiB  
Article
Comprehensive Analysis of the Genetic Variation in the LPA Gene from Short-Read Sequencing
by Raphael O. Betschart, Georgios Koliopanos, Paras Garg, Linlin Guo, Massimiliano Rossi, Sebastian Schönherr, Stefan Blankenberg, Raphael Twerenbold, Tanja Zeller and Andreas Ziegler
BioMed 2024, 4(2), 156-170; https://doi.org/10.3390/biomed4020013 (registering DOI) - 4 Jun 2024
Abstract
Lipoprotein (a) (Lp(a)) is a risk factor for cardiovascular diseases and mainly regulated by the complex LPA gene. We investigated the types of variation in the LPA gene and their predictive performance on Lp(a) concentration. We determined the Kringle IV-type 2 (KIV-2) copy [...] Read more.
Lipoprotein (a) (Lp(a)) is a risk factor for cardiovascular diseases and mainly regulated by the complex LPA gene. We investigated the types of variation in the LPA gene and their predictive performance on Lp(a) concentration. We determined the Kringle IV-type 2 (KIV-2) copy number (CN) using the DRAGEN LPA Caller (DLC) and a read depth-based CN estimator in 8351 short-read whole genome sequencing samples from the GENESIS-HD study. The pentanucleotide repeat in the promoter region was genotyped with GangSTR and ExpansionHunter. Lp(a) concentration was available in 4861 population-based subjects. Predictive performance on Lp(a) concentration was investigated using random forests. The agreement of the KIV-2 CN between the two specialized callers was high (r = 0.9966; 95% confidence interval [CI] 0.9965–0.9968). Allele-specific KIV-2 CN could be determined in 47.0% of the subjects using the DLC. Lp(a) concentration can be better predicted from allele-specific KIV-2 CN than total KIV-2 CN. Two single nucleotide variants, 4925G>A and rs41272114C>T, further improved prediction. The genetically complex LPA gene can be analyzed with excellent agreement between different callers. The allele-specific KIV-2 CN is more important for predicting Lp(a) concentration than the total KIV-2 CN. Full article
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34 pages, 4303 KiB  
Review
Molecular Mechanisms in Tumorigenesis of Hepatocellular Carcinoma and in Target Treatments—An Overview
by Raluca-Margit Szilveszter, Mara Muntean and Adrian Florea
Biomolecules 2024, 14(6), 656; https://doi.org/10.3390/biom14060656 (registering DOI) - 4 Jun 2024
Abstract
Hepatocellular carcinoma is the most common primary malignancy of the liver, with hepatocellular differentiation. It is ranked sixth among the most common cancers worldwide and is the third leading cause of cancer-related deaths. The most important etiological factors discussed here are viral infection [...] Read more.
Hepatocellular carcinoma is the most common primary malignancy of the liver, with hepatocellular differentiation. It is ranked sixth among the most common cancers worldwide and is the third leading cause of cancer-related deaths. The most important etiological factors discussed here are viral infection (HBV, HCV), exposure to aflatoxin B1, metabolic syndrome, and obesity (as an independent factor). Directly or indirectly, they induce chromosomal aberrations, mutations, and epigenetic changes in specific genes involved in intracellular signaling pathways, responsible for synthesis of growth factors, cell proliferation, differentiation, survival, the metastasis process (including the epithelial–mesenchymal transition and the expression of adhesion molecules), and angiogenesis. All these disrupted molecular mechanisms contribute to hepatocarcinogenesis. Furthermore, equally important is the interaction between tumor cells and the components of the tumor microenvironment: inflammatory cells and macrophages—predominantly with a pro-tumoral role—hepatic stellate cells, tumor-associated fibroblasts, cancer stem cells, extracellular vesicles, and the extracellular matrix. In this paper, we reviewed the molecular biology of hepatocellular carcinoma and the intricate mechanisms involved in hepatocarcinogenesis, and we highlighted how certain signaling pathways can be pharmacologically influenced at various levels with specific molecules. Additionally, we mentioned several examples of recent clinical trials and briefly described the current treatment protocol according to the NCCN guidelines. Full article
(This article belongs to the Special Issue Molecular Mechanisms Underlying Liver Diseases)
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11 pages, 269 KiB  
Review
Safety of Progestogen Hormonal Contraceptive Methods during Lactation: An Overview
by Karolina Chmaj-Wierzchowska, Katarzyna Wszołek, Katarzyna Tomczyk and Maciej Wilczak
Clin. Pract. 2024, 14(3), 1054-1064; https://doi.org/10.3390/clinpract14030083 (registering DOI) - 4 Jun 2024
Abstract
Background: Breastfeeding is a process for not only nourishing infants but also for building a unique emotional bond between mother and child. Therefore, the ideal contraception during lactation should not affect lactation (milk composition, milk volume) and offspring development. Objectives: This study aims [...] Read more.
Background: Breastfeeding is a process for not only nourishing infants but also for building a unique emotional bond between mother and child. Therefore, the ideal contraception during lactation should not affect lactation (milk composition, milk volume) and offspring development. Objectives: This study aims to analyze the literature on the safety of progestogen hormonal contraceptive methods during lactation. Methods: We conducted a thorough search across various databases, including the National Library of Medicine (PubMed), and the Cochrane Database, Drugs and Lactation Database (LactMed). Our search utilized specific phrases such as: “lactation” and “breastfeeding” and “oral contraception” with “drospirenone” or “desogestrel”, with “subcutaneous etonogestrel implant” or “etonogestrel implant”, with “levonorgestrel-releasing intrauterine system”, and “emergency contraception”, with “levonorgestrel” or “ulipristal acetate”. Conclusions: Based on published scientific reports, progestogen hormonal contraceptives can be considered a relatively safe solution for women desiring to continue feeding their infant with their milk while using hormonal contraception. It is important to seek guidance on selecting the best contraception method based on the latest medical knowledge, tailored to the individual needs and clinical circumstances of each woman and place of residence. A woman should always be informed of the potential risks of such a treatment and then allowed to make her own decision based on the knowledge received from a specialist. Full article
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20 pages, 11867 KiB  
Article
Predicting the Remaining Useful Life of Solid Oxide Fuel Cell Systems Using Adaptive Trend Models of Health Indicators
by Luka Žnidarič, Žiga Gradišar and Đani Juričić
Energies 2024, 17(11), 2729; https://doi.org/10.3390/en17112729 (registering DOI) - 4 Jun 2024
Abstract
Degradation is an inevitable companion in the operation of solid oxide fuel cell (SOFC) systems since it directly deteriorates the reliability of the system’s operation and the system’s durability. Both are seen as barriers that limit the extensive commercial use of SOFC systems. [...] Read more.
Degradation is an inevitable companion in the operation of solid oxide fuel cell (SOFC) systems since it directly deteriorates the reliability of the system’s operation and the system’s durability. Both are seen as barriers that limit the extensive commercial use of SOFC systems. Therefore, diagnosis and prognosis are valuable tools that can contribute to raising the reliability of the system operation, efficient health management, increased durability and implementation of predictive maintenance techniques. Remaining useful life (RUL) prediction has been extensively studied in many areas like batteries and proton-exchange membrane fuel cell (PEM) systems, and a range of different approaches has been proposed. On the other hand, results available in the domain of SOFC systems are still relatively limited. Moreover, methods relying on detailed process models and models of degradation turned out to have limited applicability for in-field applications. Therefore, in this paper, we propose an effective, data-driven approach to predicting RUL where the trend of the health index is modeled by an adaptive linear model, which is updated at all times during the system operation. This allows for a closed-form solution of the probability distribution of the RUL, which is the main novelty of this paper. Such a solution requires no computational load and is as such very convenient for the application in ordinary low-cost control systems. The performance of the approach is demonstrated first on the simulated case studies and then on the data obtained from a long-term experiment on a laboratory SOFC system. From the tests conducted so far, it turns out that the quality of the RUL prediction is usually rather low at the beginning of the system operation, but then gradually improves while the system is approaching the end-of-life (EOL), making it a viable tool for prognosis. Full article
(This article belongs to the Special Issue Advanced Research on Fuel Cells and Hydrogen Energy Conversion)
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25 pages, 11409 KiB  
Article
Influence of Polymer Flow on Polypropylene Morphology, Micro-Mechanical, and Tribological Properties of Injected Part
by Martin Ovsik, Klara Fucikova, Lukas Manas and Michal Stanek
Lubricants 2024, 12(6), 202; https://doi.org/10.3390/lubricants12060202 (registering DOI) - 4 Jun 2024
Abstract
This research investigates the micro-mechanical and tribological properties of injection-molded parts made from polypropylene. The tribological properties of polymers are a very interesting area of research. Understanding tribological processes is very crucial. Considering that the mechanical and tribological properties of injected parts are [...] Read more.
This research investigates the micro-mechanical and tribological properties of injection-molded parts made from polypropylene. The tribological properties of polymers are a very interesting area of research. Understanding tribological processes is very crucial. Considering that the mechanical and tribological properties of injected parts are not uniform at various points of the part, this research was conducted to explain the non-homogeneity of properties along the flow path. Non-homogeneity can be influenced by numerous factors, including distance from the gate, mold and melt temperature, injection pressure, crystalline structure, cooling rate, the surface of the mold, and others. The key factor from the micro-mechanical and tribological properties point of view is the polymer morphology (degree of crystallinity and size of the skin and core layers). The morphology is influenced by polymer flow and the injection molding process conditions. Gained results indicate that the indentation method was sufficiently sensitive to capture the changes in polypropylene morphology, which is a key parameter for the resulting micro-mechanical and tribological properties of the part. It was proven that the mechanical and tribological properties are not equal in varying regions of the part. Due to cooling and process parameters, the difference in the indentation modulus in individual measurement points was up to 55%, and the tribological properties, in particular the friction coefficient, showed a difference of up to 20%. The aforementioned results indicate the impact this finding signifies for injection molding technology in technical practice. Tribological properties are a key property of the part surface and, together with micro-mechanical properties, characterize the resistance of the surface to mechanical failure of the plastic part when used in engineering applications. A suitable choice of gate location, finishing method of the cavity surface, and process parameters can ensure the improvement of mechanical and tribological properties in stressed regions of the part. This will increase the stiffness and wear resistance of the surface. Full article
(This article belongs to the Special Issue Mechanical Tribology and Surface Technology)
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18 pages, 289 KiB  
Article
Sustaining the Yield of Maize, Blackgram, Greengram, Groundnut, Cotton, Sugarcane, and Coconut through the Application of Nutrients and Plant Growth Regulator Mixture
by Senthil Alagarswamy, Kalarani M. Karuppasami, Maduraimuthu Djanaguiraman, Prasad B. R. Venugopal, Sritharan Natarajan, Sivakumar Rathinavelu, Vijayalakshmi Dhashnamurthi, Ravichandran Veerasamy and Boominathan Parasuraman
Plants 2024, 13(11), 1549; https://doi.org/10.3390/plants13111549 (registering DOI) - 4 Jun 2024
Abstract
The foliar application of nutrients and plant growth regulators (PGRs) at critical crop growth periods can improve the yield of field crops. Hence, the present study was conducted to quantify the effects of the combined application of nutrients and PGRs (crop-specific formulation) on [...] Read more.
The foliar application of nutrients and plant growth regulators (PGRs) at critical crop growth periods can improve the yield of field crops. Hence, the present study was conducted to quantify the effects of the combined application of nutrients and PGRs (crop-specific formulation) on maize, blackgram, greengram, groundnut, cotton, sugarcane, and coconut yield. In all the crops except coconut, the treatments included (i) a foliar spray of crop-specific nutrients and PGR combinations and (ii) an unsprayed control. In coconut, the treatments included (i) the root feeding of coconut-specific nutrients and PGR combinations and (ii) an untreated control. Crop-specific nutrient and PGR formulations were sprayed, namely, Tamil Nadu Agricultural University (TNAU) maize maxim 1.5% at the tassel initiation and grain-filling stages of maize, TNAU pulse wonder 1.0% at the peak flowering stage of green gram and black gram, TNAU groundnut-rich 1.0% at the flowering and pod-filling stages of groundnut, TNAU cotton plus 1.25% at the flowering and boll development stages of cotton, and TNAU sugarcane booster 0.5% at 45 days after planting (DAP), 0.75% at 60 DAP, and 1.0% at 75 DAP of sugarcane. The results showed that the foliar application of TNAU maize maxim, TNAU pulse wonder, TNAU groundnut-rich, TNAU cotton plus and TNAU sugarcane booster and the root feeding of TNAU coconut tonic increased the yield of maize, pulses, groundnut, cotton, sugarcane, and coconut, resulting in higher economic returns. Full article
(This article belongs to the Topic Plants Nutrients, 2nd Volume)
15 pages, 1337 KiB  
Article
Exploring the Impact of Efavirenz on Aflatoxin B1 Metabolism: Insights from a Physiologically Based Pharmacokinetic Model and a Human Liver Microsome Study
by Orphélie Lootens, Marthe De Boevre, Elke Gasthuys, Sarah De Saeger, Jan Van Bocxlaer and An Vermeulen
Toxins 2024, 16(6), 259; https://doi.org/10.3390/toxins16060259 (registering DOI) - 4 Jun 2024
Abstract
Physiologically based pharmacokinetic (PBPK) models were utilized to investigate potential interactions between aflatoxin B1 (AFB1) and efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor drug and inducer of several CYP enzymes, including CYP3A4. PBPK simulations were conducted in a North European Caucasian and Black [...] Read more.
Physiologically based pharmacokinetic (PBPK) models were utilized to investigate potential interactions between aflatoxin B1 (AFB1) and efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor drug and inducer of several CYP enzymes, including CYP3A4. PBPK simulations were conducted in a North European Caucasian and Black South African population, considering different dosing scenarios. The simulations predicted the impact of EFV on AFB1 metabolism via CYP3A4 and CYP1A2. In vitro experiments using human liver microsomes (HLM) were performed to verify the PBPK predictions for both single- and multiple-dose exposures to EFV. Results showed no significant difference in the formation of AFB1 metabolites when combined with EFV (0.15 µM) compared to AFB1 alone. However, exposure to 5 µM of EFV, mimicking chronic exposure, resulted in increased CYP3A4 activity, affecting metabolite formation. While co-incubation with EFV reduced the formation of certain AFB1 metabolites, other outcomes varied and could not be fully attributed to CYP3A4 induction. Overall, this study provides evidence that EFV, and potentially other CYP1A2/CYP3A4 perpetrators, can impact AFB1 metabolism, leading to altered exposure to toxic metabolites. The results emphasize the importance of considering drug interactions when assessing the risks associated with mycotoxin exposure in individuals undergoing HIV therapy in a European and African context. Full article
(This article belongs to the Special Issue Toxins: 15th Anniversary)
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12 pages, 5196 KiB  
Article
Investigating Kinematics and Electromyography Changes in Manual Handling Tasks with an Active Lumbar Exoskeleton
by Mélissa Moulart, Maxime Acien, Audrey Leonard, Mathilde Loir, Nicolas Olivier and Frédéric Marin
Biomechanics 2024, 4(2), 357-368; https://doi.org/10.3390/biomechanics4020025 (registering DOI) - 4 Jun 2024
Abstract
Companies are becoming increasingly aware of the health of their employees and are now integrating exoskeleton solutions for both prevention and job maintenance. However, the effect of using exoskeletons is still an open question. Therefore, this study aimed to evaluate the impact of [...] Read more.
Companies are becoming increasingly aware of the health of their employees and are now integrating exoskeleton solutions for both prevention and job maintenance. However, the effect of using exoskeletons is still an open question. Therefore, this study aimed to evaluate the impact of an active lumbar exoskeleton and its passive belt on trunk kinematics and muscle activity using instrumented motion analysis. Twenty-three healthy subjects volunteered to perform three handlings of a 5 kg load (free lifting, squat lifting, and load transfer) under three different experimental conditions. The “Control” condition was when the subject did not wear any device, the “Belt” condition was when the subject wore only the passive part of the exoskeleton, and the “Exo” condition was when the subject wore the active exoskeleton. Based on the Rapid Upper Limb Assessment scale, the exoskeleton reduced the time spent in angles that were considered dangerous for the back, according to ergonomic evaluations. Furthermore, for the handling sessions, it was observed that the exoskeleton did not modify muscle activity in the abdominal–lumbar region. Full article
(This article belongs to the Section Tissue and Vascular Biomechanics)
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29 pages, 5111 KiB  
Article
Hypoxia Increases the Efficiencies of Cellular Reprogramming and Oncogenic Transformation in Human Blood Cell Subpopulations In Vitro and In Vivo
by Adrián Moratilla, Diana Martín, Marta Cadenas-Martín, Martha Stokking, Maria Angustias Quesada, Francisco Arnalich and Maria P. De Miguel
Cells 2024, 13(11), 971; https://doi.org/10.3390/cells13110971 (registering DOI) - 4 Jun 2024
Abstract
Patients with chronic hypoxia show a higher tumor incidence; however, no primary common cause has been recognized. Given the similarities between cellular reprogramming and oncogenic transformation, we directly compared these processes in human cells subjected to hypoxia. Mouse embryonic fibroblasts were employed as [...] Read more.
Patients with chronic hypoxia show a higher tumor incidence; however, no primary common cause has been recognized. Given the similarities between cellular reprogramming and oncogenic transformation, we directly compared these processes in human cells subjected to hypoxia. Mouse embryonic fibroblasts were employed as controls to compare transfection and reprogramming efficiency; human adipose-derived mesenchymal stem cells were employed as controls in human cells. Easily obtainable human peripheral blood mononuclear cells (PBMCs) were chosen to establish a standard protocol to compare cell reprogramming (into induced pluripotent stem cells (iPSCs)) and oncogenic focus formation efficiency. Cell reprogramming was achieved for all three cell types, generating actual pluripotent cells capable for differentiating into the three germ layers. The efficiencies of the cell reprogramming and oncogenic transformation were similar. Hypoxia slightly increased the reprogramming efficiency in all the cell types but with no statistical significance for PBMCs. Various PBMC types can respond to hypoxia differently; lymphocytes and monocytes were, therefore, reprogrammed separately, finding a significant difference between normoxia and hypoxia in monocytes in vitro. These differences were then searched for in vivo. The iPSCs and oncogenic foci were generated from healthy volunteers and patients with chronic obstructive pulmonary disease (COPD). Although higher iPSC generation efficiency in the patients with COPD was found for lymphocytes, this increase was not statistically significant for oncogenic foci. Remarkably, a higher statistically significant efficiency in COPD monocytes was demonstrated for both processes, suggesting that physiological hypoxia exerts an effect on cell reprogramming and oncogenic transformation in vivo in at least some cell types. Full article
(This article belongs to the Collection Feature Papers in 'Tissues and Organs')
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22 pages, 1448 KiB  
Systematic Review
A Systematic Review of the Role of Multimodal Resources for Inclusive STEM Engagement in Early-Childhood Education
by Sarika Kewalramani, George Aranda, Jiqing Sun, Gerarda Richards, Linda Hobbs, Lihua Xu, Victoria Millar, Belinda Dealy and Bridgette Van Leuven
Educ. Sci. 2024, 14(6), 604; https://doi.org/10.3390/educsci14060604 (registering DOI) - 4 Jun 2024
Abstract
This paper presents the findings from a systematic review of 29 websites and 13 frameworks that provide STEM (Science, Technology, Engineering, Mathematics) educational resources for parents, educators, and children (birth–8 years of age). Our theoretical approach is rooted within a social semiotic perspective [...] Read more.
This paper presents the findings from a systematic review of 29 websites and 13 frameworks that provide STEM (Science, Technology, Engineering, Mathematics) educational resources for parents, educators, and children (birth–8 years of age). Our theoretical approach is rooted within a social semiotic perspective that has indicated that multimodality enables children to use different types of expression to communicate a message or share an idea. Using the PRISMA methodology and the narrative document analysis approach, the themes that emerged included how the content and resources available on the websites addressed whether multimodality supported STEM engagement in an inclusive manner. The findings revealed that there were scarce multimodal resources that engaged children with fun, interactive, and meaningful opportunities to be autonomous learners (e.g., children had agency) (n = 11 out of 29), moving between the digital and hands-on physical spaces (n = 8 out of 29), employing gamification for deep learning (n = 4 out of 29), and piquing children’s imagination, inquiry, and creativity, and links to everyday STEM scenarios were hardly present (n = 10 out of 29). The implications lie in addressing early STEM engagement by considering children’s learning abilities and agency, bearing in mind parents/educators’ sociocultural backgrounds, confidence in STEM awareness, and multimodal avenues for communicating STEM learning and inquiry. Full article
(This article belongs to the Section STEM Education)
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17 pages, 1500 KiB  
Article
Lipid Characterization of Beach-Cast Seaweeds from Gran Canaria Island: Potential Use in Human and Animal Nutrition
by Ana Galindo, Coraima del Mar García, José Antonio Pérez, Beatriz Abdul-Jalbar, Marianna Venuleo, Nieves Guadalupe Acosta, Manuel Marrero and Covadonga Rodríguez
J. Mar. Sci. Eng. 2024, 12(6), 942; https://doi.org/10.3390/jmse12060942 (registering DOI) - 4 Jun 2024
Abstract
Macroalgal wracks can be considered unpleasant for beach users and, consequently, they are usually collected from most touristic beaches and discarded. However, seaweeds are an important source of bioactive lipid compounds, such as phospholipids, glycolipids, and n-3 polyunsaturated fatty acids (n-3 PUFA), displaying [...] Read more.
Macroalgal wracks can be considered unpleasant for beach users and, consequently, they are usually collected from most touristic beaches and discarded. However, seaweeds are an important source of bioactive lipid compounds, such as phospholipids, glycolipids, and n-3 polyunsaturated fatty acids (n-3 PUFA), displaying multiple health-promoting properties, including antioxidant and antimicrobial activities. The aim of this study is to characterize the lipid composition of twelve marine seaweed species (two green, six red, and four brown species) from macroalgal wracks of Gran Canaria Island, and to evaluate their potential use for several purposes, including human and animal nutrition. Lipid content, lipid classes, and fatty acid profiles of isolated specimens from the macroalgal wracks were determined. Lipid contents ranged between 0.27 and 3.17% of dry weight, with all species showing high phytosterols proportions and balanced omega-6/omega-3 (n-6/n-3) ratios. In addition, Cymopolia barbata, Asparagopsis sp., and Hypnea spinella seem to be an attractive source of both mono- and di-galactosyl-diacylglycerols, while A. stellata, Jania sp., and Lobophora sp. are relatively rich in n-3 LC−PUFA. Finally, both green algae showed the most favorable values for the nutritional indicators of cardiovascular health promotion. Overall, the macroalgal species analyzed could be considered as interesting sources for human and animal nutrition. Full article
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30 pages, 4176 KiB  
Article
Advancing Artificial Intelligence (AI) and Machine Learning (ML) Based Soft Sensors for In-Cylinder Predictions with a Real-Time Simulator and a Crank Angle Resolved Engine Model
by Robert Jane, Samantha Rose and Corey M. James
Energies 2024, 17(11), 2731; https://doi.org/10.3390/en17112731 (registering DOI) - 4 Jun 2024
Abstract
In a previous research effort by this group, pseudo engine dynamometer data in multi-dimensional arrays were combined with dynamic equations to form a crank angle resolved engine model compatible with a real-time simulator. The combination of the real-time simulator and external targets enabled [...] Read more.
In a previous research effort by this group, pseudo engine dynamometer data in multi-dimensional arrays were combined with dynamic equations to form a crank angle resolved engine model compatible with a real-time simulator. The combination of the real-time simulator and external targets enabled the development of a software-in-the-loop (SIL) environment that enabled near-real-time development of AI/ML and real-time deployment of the resulting AI/ML. Military applications, in particular, are unlikely to possess large quantities of non-sparse operational data that span the full operational range of the system, stove-piping the ability to develop and deploy AI/ML which is sufficient for near-real-time or real-time control. AI/ML has been shown to be well suited for predicting highly non-linear mathematical phenomena and thus military systems could potentially benefit from the development and deployment of AI/ML acting as soft sensors. Given the non-sparse nature of the data, it becomes exceedingly important that AI/ML be developed and deployed in near-real-time or real-time in parallel to a real-time system to overcome the inadequacy of applicable data. This research effort used parallel processing to reduce the training duration of the shallow artificial neural networks (SANN) and forest algorithms forming ensemble models. This research is novel in that the SIL environment enables pre-developed AI/ML to be adapted in near-real-time or develop AI/ML in response to changes within the operation of the applied system, different load torques, engine speeds, and atmospheric conditions to name a few. Over time it is expected that the continued adaptation of the algorithms will lead to the development of AI/ML that is suitable for real-time control and energy management. Full article
(This article belongs to the Section K: State-of-the-Art Energy Related Technologies)
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25 pages, 4484 KiB  
Review
Evolving Strategies for Use of Phytochemicals in Prevention and Long-Term Management of Cardiovascular Diseases (CVD)
by Donald David Haines, Fred M. Cowan and Arpad Tosaki
Int. J. Mol. Sci. 2024, 25(11), 6176; https://doi.org/10.3390/ijms25116176 (registering DOI) - 4 Jun 2024
Abstract
This report describes major pathomechanisms of disease in which the dysregulation of host inflammatory processes is a major factor, with cardiovascular disease (CVD) as a primary model, and reviews strategies for countermeasures based on synergistic interaction between various agents, including drugs and generally [...] Read more.
This report describes major pathomechanisms of disease in which the dysregulation of host inflammatory processes is a major factor, with cardiovascular disease (CVD) as a primary model, and reviews strategies for countermeasures based on synergistic interaction between various agents, including drugs and generally regarded as safe (GRAS) natural medical material (NMM), such as Ginkgo biloba, spice phytochemicals, and fruit seed flavonoids. The 15 well-defined CVD classes are explored with particular emphasis on the extent to which oxidative stressors and associated ischemia-reperfusion tissue injury contribute to major symptoms. The four major categories of pharmaceutical agents used for the prevention of and therapy for CVD: statins, beta blockers (β-blockers), blood thinners (anticoagulants), and aspirin, are presented along with their adverse effects. Analyses of major cellular and molecular features of drug- and NMM-mediated cardioprotective processes are provided in the context of their development for human clinical application. Future directions of the evolving research described here will be particularly focused on the characterization and manipulation of calcium- and calcineurin-mediated cascades of signaling from cell surface receptors on cardiovascular and immune cells to the nucleus, with the emergence of both protective and pathological epigenetic features that may be modulated by synergistically-acting combinations of drugs and phytochemicals in which phytochemicals interact with cells to promote signaling that reduces the effective dosage and thus (often) toxicity of drugs. Full article
(This article belongs to the Special Issue Molecular Mechanism Study of Natural Products for Human Health)
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18 pages, 4413 KiB  
Article
Estimation of Pollution Export Coefficients of Tea Farms and Its Application in Watershed Management
by Chia-Chun Ho, Yu-Qian Su, Chi-Feng Chen, Yi-Xuan Lin and Hsiu-Feng Liu
Water 2024, 16(11), 1603; https://doi.org/10.3390/w16111603 (registering DOI) - 4 Jun 2024
Abstract
Tea is an important economic crop worldwide, especially in Asian countries. However, tea cultivation requires substantial fertilizer use and may become a nutrient pollution source and affect water quality. This study presented two objectives: one was to estimate the pollution export coefficients of [...] Read more.
Tea is an important economic crop worldwide, especially in Asian countries. However, tea cultivation requires substantial fertilizer use and may become a nutrient pollution source and affect water quality. This study presented two objectives: one was to estimate the pollution export coefficients of tea farms, and the other was to assess the performance of bioretention cells in terms of tea farm pollution control. This study employed a tea farm pollutant transport model (TPTM) and a watershed pollutant transport model (WPTM) to link watershed management goals and the tea farm control strategy. Field data collected for Jingualiao Creek in the Feitsui Reservoir watershed in Taipei, Taiwan, were analyzed. The resulting export coefficients for total phosphorus (TP), NH3-N, suspended solids (SS), and chemical oxygen demand (COD) were 2.55, 4.22, 768.39, and 145.71 kg/ha-y, respectively. Bioretention cells, which are low-impact development (LID) facilities and structural best management practices (BMPs), were installed and tested for their ability to reduce nonpoint source pollution. The field investigation and modeling results showed that 1 m2 of bioretention cells could reduce TP, NH3-N, SS, and COD by 18.6, 20.9, 5545.5, and 881.4 g/y, respectively. According to the WPTM results, 540 m2 of bioretention cells could achieve an 85% water quality attainment goal, and 715 m2 could reach 90% water quality attainment. Four tea farms covering 1.43 ha require 30.0 m2 of bioretention cells to achieve an 85% goal and 33.5 m2 to 90% goal. The export coefficients of tea nonpoint pollution sources presented in this study can serve as a valuable tool for estimating potential exported nutrients, and the field test results of bioretention cells are helpful information for policymakers in formulating effective watershed management measures. Full article
(This article belongs to the Special Issue Water Quality Assessment and Modelling)
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13 pages, 2527 KiB  
Article
Contribution of Extracellular Particles Isolated from Morus sp. (Mulberry) Fruit to Their Reported Protective Health Benefits: An In Vitro Study
by Neve R. Garrett, Ryan C. Pink and Charlotte Lawson
Int. J. Mol. Sci. 2024, 25(11), 6177; https://doi.org/10.3390/ijms25116177 (registering DOI) - 4 Jun 2024
Abstract
Morus sp. (mulberry) has a long tradition of use as a medicinal treatment, including for cardiovascular disease and type 2 diabetes, being shown to have antioxidant properties and to promote wound healing. Extracellular vesicles (EVs) are sub-micron, membrane-enclosed particles that were first identified [...] Read more.
Morus sp. (mulberry) has a long tradition of use as a medicinal treatment, including for cardiovascular disease and type 2 diabetes, being shown to have antioxidant properties and to promote wound healing. Extracellular vesicles (EVs) are sub-micron, membrane-enclosed particles that were first identified in mammalian bodily fluids. EV-like particles have been described in plants (PDVs) and shown to have similar characteristics to mammalian EVs. We hypothesised that some of the health benefits previously attributed to the fruit of Morus sp. could be due to the release of PDVs. We isolated PDVs from Morus nigra and Morus alba via ultracentrifugation and incubated THP-1 monocytes, differentiated THP-1 macrophages, or HMEC-1 endothelial cells with pro-oxidant compounds DMNQ (THP-1) and glucose oxidase (HMEC-1) or lipopolysaccharide (LPS) in the presence of different fractions of mulberry EVs. Mulberry EVs augmented ROS production with DMNQ in THP-1 and caused the downregulation of ROS in HMEC-1. Mulberry EVs increased LPS-induced IL-1β secretion but reduced CCL2 and TGF-β secretion in THP-1 macrophages. In scratch wound assays, mulberry EVs inhibited HMEC-1 migration but increased proliferation in both low and high serum conditions, suggesting that they have opposing effects in these two important aspects of wound healing. One of the limitations of plant-derived therapeutics has been overcoming the low bioavailability of isolated compounds. We propose that PDVs could provide the link between physiological dose and therapeutic benefit by protecting plant active compounds in the GIT as well as potentially delivering genetic material or proteins that contribute to previously observed health benefits. Full article
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20 pages, 4061 KiB  
Article
Transcriptomic Profiling of Sugarcane White Leaf (SCWL) Canes during Maturation Phase
by Karan Lohmaneeratana, Kantinan Leetanasaksakul and Arinthip Thamchaipenet
Plants 2024, 13(11), 1551; https://doi.org/10.3390/plants13111551 (registering DOI) - 4 Jun 2024
Abstract
Sugarcane white leaf (SCWL) disease, caused by Candidatus Phytoplasma sacchari, results in the most damage to sugarcane plantations. Some SCWL canes can grow unnoticed through the maturation phase, subsequently resulting in an overall low sugar yield, or they can be used accidentally as [...] Read more.
Sugarcane white leaf (SCWL) disease, caused by Candidatus Phytoplasma sacchari, results in the most damage to sugarcane plantations. Some SCWL canes can grow unnoticed through the maturation phase, subsequently resulting in an overall low sugar yield, or they can be used accidentally as seed canes. In this work, 12-month-old SCWL and asymptomatic canes growing in the same field were investigated. An abundance of phytoplasma in SCWL canes affected growth and sugar content as well as alterations of transcriptomic profiles corresponding to several pathways that responded to the infection. Suppression of photosynthesis, porphyrin and chlorophyll metabolism, coupled with an increase in the expression of chlorophyllase, contributed to the reduction in chlorophyll levels and photosynthesis. Blockage of sucrose transport plausibly occurred due to the expression of sugar transporters in leaves but suppression in stalks, resulting in low sugar content in canes. Increased expression of genes associated with MAPK cascades, plant hormone signaling transduction, callose plug formation, the phenylpropanoid pathway, and calcium cascades positively promoted defense mechanisms against phytoplasma colonization by an accumulation of lignin and calcium in response to plant immunity. Significant downregulation of CPK plausibly results in a reduction in antioxidant enzymes and likely facilitates pathogen invasion, while expression of sesquiterpene biosynthesis possibly attracts the insect vectors for transmission, thereby enabling the spread of phytoplasma. Moreover, downregulation of flavonoid biosynthesis potentially intensifies the symptoms of SCWL upon challenge by phytoplasma. These SCWL sugarcane transcriptomic profiles describe the first comprehensive sugarcane–phytoplasma interaction during the harvesting stage. Understanding molecular mechanisms will allow for sustainable management and the prevention of SCWL disease—a crucial benefit to the sugar industry. Full article
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11 pages, 279 KiB  
Article
An Assessment of the Effects of Guanidinoacetic Acid on the Performance and Immune Response of Laying Hens Fed Diets with Three Levels of Metabolizable Energy
by Santiago García-Gómora, Gabriela Gómez-Verduzco, Claudia C. Márquez-Mota, Arturo Cortés-Cuevas, Oscar Vicente Vazquez-Mendoza and Ernesto Ávila-González
Animals 2024, 14(11), 1675; https://doi.org/10.3390/ani14111675 (registering DOI) - 4 Jun 2024
Abstract
Different levels of metabolizable energy (ME) and the inclusion of guanidinoacetic acid (GAA) in the diet of 53-week-old Lohmann LSL-CLASSIC hens were used to evaluate its effect on reproductive parameters, egg quality, intestinal morphology, and the immune response. Six diets were used in [...] Read more.
Different levels of metabolizable energy (ME) and the inclusion of guanidinoacetic acid (GAA) in the diet of 53-week-old Lohmann LSL-CLASSIC hens were used to evaluate its effect on reproductive parameters, egg quality, intestinal morphology, and the immune response. Six diets were used in a 3 × 2 factorial design, with three levels of ME (2850, 2800, and 2750 kcal/kg), and with (0.08%) or without the inclusion of GAA. The addition of GAA to diets with low levels of ME increased (p < 0.05) egg production and egg mass. Moreover, hens fed with 2800 kcal/g without GAA had the highest concentration (p < 0.05) of serum interleukin IL-2, while those fed diets with the same amount of ME but supplemented with 0.08% GAA had the lowest concentration. Finally, the inclusion of 0.08% GAA increased (p < 0.05) the concentration of vascular endothelial growth factor (VEGF), regardless of the ME level in the diet. This study highlights the potential role of GAA in decreasing the energy level of ME (50–100 kcal/g) in the feeding of hens and in the modulation of specific immune responses. Further research is recommended to fully understand the mechanisms of action of GAA on the mechanism target of rapamycin and its relationship with the immune response. Full article
(This article belongs to the Section Poultry)
16 pages, 6339 KiB  
Article
Sex Differences in the Ergogenic Response of Acute Caffeine Intake on Muscular Strength, Power and Endurance Performance in Resistance-Trained Individuals: A Randomized Controlled Trial
by Juan Jesús Montalvo-Alonso, Carmen Ferragut, Marta del Val-Manzano, David Valadés, Justin Roberts and Alberto Pérez-López
Nutrients 2024, 16(11), 1760; https://doi.org/10.3390/nu16111760 (registering DOI) - 4 Jun 2024
Abstract
Background: This study assessed the impact of acute caffeine intake on muscular strength, power, and endurance performance between resistance-trained male and female individuals according to load in upper- and lower-body exercises. Methods: Here, 76 resistance-trained individuals (38 females, 38 males) participated in a [...] Read more.
Background: This study assessed the impact of acute caffeine intake on muscular strength, power, and endurance performance between resistance-trained male and female individuals according to load in upper- and lower-body exercises. Methods: Here, 76 resistance-trained individuals (38 females, 38 males) participated in a study comparing caffeine and a placebo. Each received either 3 mg/kg of caffeine or a placebo 60 min before tests measuring muscular strength and power through bench press and back squat exercises at different intensities (25%, 50%, 75%, 90% 1RM). Muscular endurance at 65% 1RM was also assessed by performing reps until reaching task failure. Results: Compared to placebo, caffeine increased mean, peak and time to reach peak velocity and power output (p < 0.01, ηp2 = 0.242–0.293) in the muscular strength/power test in males and females. This effect was particularly observed in the back squat exercise at 50%, 75% and 90% 1RM (2.5–8.5%, p < 0.05, g = 1.0–2.4). For muscular endurance, caffeine increased the number of repetitions, mean velocity and power output (p < 0.001, ηp2 = 0.177–0.255) in both sexes and exercises (3.0–8.9%, p < 0.05, g = 0.15–0.33). Conclusions: Acute caffeine intake resulted in a similar ergogenic effect on muscular strength, power, and endurance performance in upper- and lower-body exercises for male and female resistance-trained participants. Full article
(This article belongs to the Special Issue Nutrition for Muscular Strength, Power and Endurance)
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20 pages, 2093 KiB  
Article
Can Environmental Stressors Determine the Condition of Ecological Plant Groups?
by Beata Koim-Puchowska, Piotr Kamiński, Piotr Puchowski, Anna Ossowska, Monika Wieloch, Mateusz Labudda, Halina Tkaczenko, Tadeusz Barczak, Alina Woźniak and Natalia Kurhaluk
Plants 2024, 13(11), 1550; https://doi.org/10.3390/plants13111550 (registering DOI) - 4 Jun 2024
Abstract
There is still a need to investigate the relationships between glycophytes and halophytes and the many biotic and abiotic factors in their natural environments. Therefore, we study the effects of the type of environment on the ecophysiological responses and condition of the glycophyte [...] Read more.
There is still a need to investigate the relationships between glycophytes and halophytes and the many biotic and abiotic factors in their natural environments. Therefore, we study the effects of the type of environment on the ecophysiological responses and condition of the glycophyte Elder Sambucus nigra L., the macrophyte Common Reed Phragmites australis (Cav.) Trin. ex Steud., the facultative halophyte Weeping Alkaligrass Puccinellia distans (Jacq.) Parl, and the obligate halophyte Common Glasswort Salicornia europaea L. in a saline-disturbed anthropogenic region of central Poland. We analyzed the effects of salinity, acidity, and soil organic matter on shoot length, lipoperoxidation, and proline in roots and green parts, and evaluated plant responses to environmental disturbance, which allowed for the comparison of adaptation strategies. The studies were carried out in (1) “sodium production” (near sodium factories), (2) “anthropogenic environments” (waste dumps, agroecosystems, calcium deposits, post-production tanks), (3) “wetland environments” (near river channels and riparian areas), and (4) “control” (natural, unpolluted environments). Green parts of plants are better suited to indicate environmental stress than roots. Their higher structural MDA membrane damage is related to the transport of toxic ions to the shoots by a rapid transpiration stream in the xylem. We found high salinity to be the main factor inducing growth and found it to be correlated with the high pH effect on proline increase in glycophytes (Elder, Reed) and Weeping Alkaligrass, in contrast to Common Glasswort. We suggest that proline accumulation allows osmotic adjustment in the green parts of reeds and alkaligrasses, but may have another function (in Elder). Common Glasswort accumulates large amounts of Na+, which is energetically more effective than proline accumulation for osmotic adjustment. Organic matter affects plant growth and proline levels, but soil salinity and pH alter nutrient availability. Plant distribution along the salinity gradient indicates that Elder is the most salt-sensitive species compared to Reed, Alkaligrass, and Glasswort. Salinity and the lack of control of thick reeds, which compete with other plant groups, affect the distribution of halophytes in saline environments. Full article
(This article belongs to the Special Issue Adaptive Strategies of Plants to Stress Factors)
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12 pages, 281 KiB  
Article
Research on Application of Japanese Quince (Chaenomeles L.) and Pork Collagen in Dark Chocolate—Benefits in Prevention of Inflammation In Vitro Model
by Szymon Byczkiewicz, Dominik Szwajgier, Ewa Baranowska-Wójcik, Aleksandra Telichowska, Krystyna Szymandera-Buszka, Janusz Wojtczak and Joanna Kobus-Cisowska
Nutrients 2024, 16(11), 1758; https://doi.org/10.3390/nu16111758 (registering DOI) - 4 Jun 2024
Abstract
In the present study, the effect of the addition of quince and collagen type I and III to dessert chocolate on its functional properties was determined. The study evaluated the antioxidant potential of the tested formulations using the FRAP method and the linoleic [...] Read more.
In the present study, the effect of the addition of quince and collagen type I and III to dessert chocolate on its functional properties was determined. The study evaluated the antioxidant potential of the tested formulations using the FRAP method and the linoleic acid oxidation test and beta-carotene bleaching test. The tested samples were also evaluated for inhibitory activity against enzymes important in preventive health (inflammation and neurodegenerative disorders) namely: AChE, BChE, GR, GPx, COX, and SOD. The addition of quince and collagen to the chocolate samples resulted in higher activity compared to the control sample, as indicated by the FRAP test. The experiment highlighted the impact of including quince fruit on the antioxidant activity of the chocolate samples. Interestingly, merely increasing the quince fruit amount did not consistently enhance antioxidant potential. Specifically, chocolate samples with a lower proportion of quince fruit (2 g/100 g) exhibited greater antioxidant activity when supplemented with collagen I. Conversely, in samples with higher quince percentages (3 g and 4 g), those enriched with collagen III showed higher antioxidant activity. Similar correlations were observed in the linoleic acid oxidation test. Notably, samples containing 3 g and 4 g of quince and type III collagen demonstrated statistically similar highest antioxidant properties. Regardless of the collagen type used, there was no observed increase in activity towards the tested enzymes for samples with the lowest percentage of quince fruit. Both collagen types exhibited the highest activity in the inhibition assay against acetylcholinesterase and butyrylcholinesterase when combined with 3 g and 4 g of quince. Overall, the experimental incorporation of both fruit and collagen enhanced the chocolates’ activity. Similarly to the antioxidant activity findings, chocolates with lower quince fruit quantities showed increased activity when supplemented with collagen III, while those with higher quince content (3 g and 4 g) displayed higher activity with collagen I. Bitter chocolate by itself is an attractive food product, rich in many bioactive compounds. However, enriching it with other attractive raw materials can make its properties and taste even more attractive. Full article
(This article belongs to the Special Issue Plant-Based Diets in the Prevention of Inflammation)
18 pages, 2257 KiB  
Article
Isolation and Identification of Lichen Photobionts Collected from Different Environments in North of Portugal and Evaluation of Bioactivities of Their Extracts
by Luís Loureiro, João Morais, Raquel Silva, Joana T. Martins, Pedro Geada, Vítor Vasconcelos and António A. Vicente
Foods 2024, 13(11), 1759; https://doi.org/10.3390/foods13111759 (registering DOI) - 4 Jun 2024
Abstract
Lichens are organisms constituted by a symbiotic relationship between a fungus (mycobiont) and a photoautotrophic partner (photobiont). Lichens produce several bioactive compounds; however, the biotechnological exploitation of this organism is hampered by its slow growth. To start studying the possibility of exploiting lichens [...] Read more.
Lichens are organisms constituted by a symbiotic relationship between a fungus (mycobiont) and a photoautotrophic partner (photobiont). Lichens produce several bioactive compounds; however, the biotechnological exploitation of this organism is hampered by its slow growth. To start studying the possibility of exploiting lichens as alternative sources of bioactive compounds, eighteen lichens were collected in the north of Portugal in order to isolate and study the bioactivity of their photobionts. It was possible to isolate and cultivate only eight photobionts. Three of them, LFR1, LFA2 and LCF3, belong to the Coelastrella genus, the other two (LFA1 and LCF1) belong to the Chlorella genus and for the remaining three photobionts, LFS1, LCA1 and LCR1, it was impossible to isolate their microalgae. These only grow in consortium with bacteria and/or cyanobacteria. All extracts showed antioxidant activity, mainly at a concentration of 10 mg.mL−1. LFS1, a consortium extract, showed the highest antioxidant power, as well as the highest concentration of phenolic compounds (5.16 ± 0.53 mg of gallic acid equivalents (GAE).g−1). The extracts under study did not show significant antibacterial activity against Escherichia coli, Listeria or Salmonella. The Coelastrella sp. and LFA1 extracts showed the highest hyaluronidase inhibition. The LFR1 extract at a concentration of 5 mg.mL−1 showed the highest anti-inflammatory activity (79.77 ± 7.66%). The extracts of Coelastrella sp. and LFA1 also showed greater antidiabetic activity, demonstrating the high inhibitory power of α-amylase and α-glucosidase. LFR1 at a concentration of 5 mg.mL−1, due to its selective cytotoxicity inhibiting the growth of cancer cells (Caco-2 cells), is a promising anticancer agent. Full article
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11 pages, 2501 KiB  
Article
Effect of Powdery Mildew on the Photosynthetic Parameters and Leaf Microstructure of Melon
by Mei Tian, Rong Yu, Wanbang Yang, Song Guo, Shengfeng Liu, Huiying Du, Jinjin Liang and Xingxu Zhang
Agriculture 2024, 14(6), 886; https://doi.org/10.3390/agriculture14060886 (registering DOI) - 4 Jun 2024
Abstract
Powdery mildew is a fungal disease devastating to crops, causing significant quality and yield loss. As one of the most important fruits in the world, melon also is damaged by powdery mildew. The present study investigated the effect of powdery mildew on the [...] Read more.
Powdery mildew is a fungal disease devastating to crops, causing significant quality and yield loss. As one of the most important fruits in the world, melon also is damaged by powdery mildew. The present study investigated the effect of powdery mildew on the photosynthetic parameters and leaf microstructure of melons, the ultrastructure of the leaf surface, photosynthetic index, chlorophyll content, yield, and quality index of five thick-skinned and differently shaped melon varieties. The net photosynthetic rate, transpiration rate, leaf water use efficiency, and chlorophyll levels were significantly (p < 0.05) higher in Kangbing F3800 plants compared to the other four varieties. In the case of powdery mildew infection, the total number of stomata in the upper and lower epidermis was particularly high in the Zhongtian No. 8 and Zhongtianxueqiong varieties, respectively. The stomatal length and width were highest in the upper epidermis of Zhongtian No. 12 leaves and in the lower epidermis of Zhongtian No. 8 leaves compared to the other varieties. The total yield and meat thickness were significantly (p < 0.05) higher in the Zhongtianxueqiong variety than the others, along with the low edge sugar content. Overall, powdery mildew impacted differently the photosynthetic and leaf surface characteristics of the five melon varieties. Kangbing F3800 emerged as the most resistant variety, making it the preferred choice for introducing and promoting thick-skinned melon varieties in the Ningxia Hui Autonomous Region of China. Full article
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20 pages, 3230 KiB  
Article
SLR Validation and Evaluation of BDS-3 MEO Satellite Precise Orbits
by Ran Li, Chen Wang, Hongyang Ma, Yu Zhou, Chengpan Tang, Ziqian Wu, Guang Yang and Xiaolin Zhang
Remote Sens. 2024, 16(11), 2016; https://doi.org/10.3390/rs16112016 (registering DOI) - 4 Jun 2024
Abstract
Starting from February 2023, the International Laser Ranging Service (ILRS) began releasing satellite laser ranging (SLR) data for all BeiDou global navigation satellite system (BDS-3) medium earth orbit (MEO) satellites. SLR data serve as the best external reference for validating satellite orbits, providing [...] Read more.
Starting from February 2023, the International Laser Ranging Service (ILRS) began releasing satellite laser ranging (SLR) data for all BeiDou global navigation satellite system (BDS-3) medium earth orbit (MEO) satellites. SLR data serve as the best external reference for validating satellite orbits, providing a basis for comprehensive evaluation of the BDS-3 satellite orbit. We utilized the SLR data from February to May 2023 to comprehensively evaluate the orbits of BDS-3 MEO satellites from different analysis centers (ACs). The results show that, whether during the eclipse season or the yaw maneuver season, the accuracy was not significantly decreased in the BDS-3 MEO orbit products released from the Center for Orbit Determination in Europe (CODE), Wuhan University (WHU), and the Deutsches GeoForschungsZentrum (GFZ) ACs, and the STD (Standard Deviation) of SLR residuals of those three ACs are all less than 5 cm. Among these, CODE had the smallest SLR residuals, with 9% and 12% improvement over WHU and GFZ, respectively. Moreover, the WHU precise orbits exhibit the smallest systematic biases, whether during non-eclipse seasons, eclipse seasons, or satellite yaw maneuver seasons. Additionally, we found some BDS-3 satellites (C32, C33, C34, C35, C45, and C46) exhibit orbit errors related to the Sun elongation angle, which indicates that continued effort for the refinement of the non-conservative force model further to improve the orbit accuracy of BDS-3 MEO satellites are in need. Full article
(This article belongs to the Special Issue Space-Geodetic Techniques (Third Edition))
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