The 2023 MDPI Annual Report has
been released!
 
20 pages, 2791 KiB  
Article
Towards Modelling Mechanical Shaking Using Potential Energy Surfaces: A Toy Model Analysis
by Sergei D. Odintsov and Vasilis K. Oikonomou
Symmetry 2024, 16(5), 572; https://doi.org/10.3390/sym16050572 (registering DOI) - 07 May 2024
Abstract
In this work, we formalize the effect of mechanical shaking by using various forms of an externally exerted force, which may be constant or may be position-dependent, and we examine the changes in the potential energy surfaces that quantify the chemical reaction. We [...] Read more.
In this work, we formalize the effect of mechanical shaking by using various forms of an externally exerted force, which may be constant or may be position-dependent, and we examine the changes in the potential energy surfaces that quantify the chemical reaction. We use a simple toy model to model the potential energy surfaces of a chemical reaction, and we study the effect of a constant or position-dependent externally exerted force for various forms of the force. As we demonstrate, the effect of the force can be quite dramatic on the potential energy surfaces, which acquire new stationary points and new Newton trajectories that are distinct from the original ones that were obtained in the absence of mechanochemical effects. We also introduce a new approach to mechanochemical interactions, using a dynamical systems approach for the Newton trajectories. As we show, the dynamical system attractor properties of the trajectories in the phase space are identical to the stationary points of the potential energy surfaces, but the phase space contains much more information regarding the possible evolution of the chemical reaction—information that is quantified by the existence of unstable or saddle fixed points in the phase space. We also discuss how an experimental method for a suitable symmetric liquid solution substance might formalize the effect of shaking via various forms of external force, even in the form of an extended coordinate-dependent force matrix. This approach may experimentally quantify the Epstein effect of shaking in chemical solutions via mechanochemistry methods. Full article
(This article belongs to the Special Issue Symmetry: Recent Developments in Engineering Science and Applications)
21 pages, 1685 KiB  
Article
Screening of Small-Molecule Libraries Using SARS-CoV-2-Derived Sequences Identifies Novel Furin Inhibitors
by Alireza Jorkesh, Sylvia Rothenberger, Laura Baldassar, Birute Grybaite, Povilas Kavaliauskas, Vytautas Mickevicius, Monica Dettin, Filippo Vascon, Laura Cendron and Antonella Pasquato
Int. J. Mol. Sci. 2024, 25(10), 5079; https://doi.org/10.3390/ijms25105079 (registering DOI) - 07 May 2024
Abstract
SARS-CoV-2 is the pathogen responsible for the most recent global pandemic, which has claimed hundreds of thousands of victims worldwide. Despite remarkable efforts to develop an effective vaccine, concerns have been raised about the actual protection against novel variants. Thus, researchers are eager [...] Read more.
SARS-CoV-2 is the pathogen responsible for the most recent global pandemic, which has claimed hundreds of thousands of victims worldwide. Despite remarkable efforts to develop an effective vaccine, concerns have been raised about the actual protection against novel variants. Thus, researchers are eager to identify alternative strategies to fight against this pathogen. Like other opportunistic entities, a key step in the SARS-CoV-2 lifecycle is the maturation of the envelope glycoprotein at the RARR685↓ motif by the cellular enzyme Furin. Inhibition of this cleavage greatly affects viral propagation, thus representing an ideal drug target to contain infection. Importantly, no Furin-escape variants have ever been detected, suggesting that the pathogen cannot replace this protease by any means. Here, we designed a novel fluorogenic SARS-CoV-2-derived substrate to screen commercially available and custom-made libraries of small molecules for the identification of new Furin inhibitors. We found that a peptide substrate mimicking the cleavage site of the envelope glycoprotein of the Omicron variant (QTQTKSHRRAR-AMC) is a superior tool for screening Furin activity when compared to the commercially available Pyr-RTKR-AMC substrate. Using this setting, we identified promising novel compounds able to modulate Furin activity in vitro and suitable for interfering with SARS-CoV-2 maturation. In particular, we showed that 3-((5-((5-bromothiophen-2-yl)methylene)-4-oxo-4,5 dihydrothiazol-2-yl)(3-chloro-4-methylphenyl)amino)propanoic acid (P3, IC50 = 35 μM) may represent an attractive chemical scaffold for the development of more effective antiviral drugs via a mechanism of action that possibly implies the targeting of Furin secondary sites (exosites) rather than its canonical catalytic pocket. Overall, a SARS-CoV-2-derived peptide was investigated as a new substrate for in vitro high-throughput screening (HTS) of Furin inhibitors and allowed the identification of compound P3 as a promising hit with an innovative chemical scaffold. Given the key role of Furin in infection and the lack of any Food and Drug Administration (FDA)-approved Furin inhibitor, P3 represents an interesting antiviral candidate Full article
31 pages, 5266 KiB  
Article
A Comprehensive Study to Determine the Residual Elimination Pattern of Major Metabolites of Amoxicillin–Sulbactam Hybrid Molecules in Rats by UPLC‒MS/MS
by Feike Zhao, Xueyan Sun, Jian Li, Junyuan Du, Zhiyi Wu, Shujuan Liu, Liangzhu Chen and Binghu Fang
Molecules 2024, 29(10), 2169; https://doi.org/10.3390/molecules29102169 (registering DOI) - 07 May 2024
Abstract
Amoxicillin and sulbactam are widely used in animal food compounding. Amoxicillin–sulbactam hybrid molecules are bicester compounds made by linking amoxicillin and sulbactam with methylene groups and have good application prospects. However, the residual elimination pattern of these hybrid molecules in animals needs to [...] Read more.
Amoxicillin and sulbactam are widely used in animal food compounding. Amoxicillin–sulbactam hybrid molecules are bicester compounds made by linking amoxicillin and sulbactam with methylene groups and have good application prospects. However, the residual elimination pattern of these hybrid molecules in animals needs to be explored. In the present study, the amoxicillin–sulbactam hybrid molecule (AS group) and a mixture of amoxicillin and sulbactam (mixture group) were administered to rats by gavage, and the levels of the major metabolites of amoxicillin, amoxicilloic acid, amoxicillin diketopiperazine, and sulbactam were determined by UPLC‒MS/MS. The residue elimination patterns of the major metabolites in the liver, kidney, urine, and feces of rats in the AS group and the mixture group were compared. The results showed that the total amount of amoxicillin, amoxicilloic acid, amoxicillin diketopiperazine, and the highest concentration of sulbactam in the liver and kidney samples of the AS group and the mixture group appeared at 1 h after drug withdrawal. Between 1 h and 12 h post discontinuation, the total amount of amoxicillin, amoxicilloic acid, and amoxicillin diketopiperazine in the two tissues decreased rapidly, and the elimination half-life of the AS group was significantly higher than that in the mixture group (p < 0.05); the residual amount of sulbactam also decreased rapidly, and the elimination half-life was not significantly different (p > 0.05). In 72 h urine samples, the total excretion rates were 60.61 ± 2.13% and 62.62 ± 1.73% in the AS group and mixture group, respectively. The total excretion rates of fecal samples (at 72 h) for the AS group and mixture group were 9.54 ± 0.26% and 10.60 ± 0.24%, respectively. These results showed that the total quantity of amoxicillin, amoxicilloic acid, and amoxicillin diketopiperazine was eliminated more slowly in the liver and kidney of the AS group than those of the mixture group and that the excretion rate through urine and feces was essentially the same for both groups. The residual elimination pattern of the hybrid molecule in rats determined in this study provides a theoretical basis for the in-depth development and application of hybrid molecules, as well as guidelines for the development of similar drugs. Full article
23 pages, 681 KiB  
Article
Monocytic Differentiation of Human Acute Myeloid Leukemia Cells: A Proteomic and Phosphoproteomic Comparison of FAB-M4/M5 Patients with and without Nucleophosmin 1 Mutations
by Frode Selheim, Elise Aasebø, Håkon Reikvam, Øystein Bruserud and Maria Hernandez-Valladares
Int. J. Mol. Sci. 2024, 25(10), 5080; https://doi.org/10.3390/ijms25105080 (registering DOI) - 07 May 2024
Abstract
Even though morphological signs of differentiation have a minimal impact on survival after intensive cytotoxic therapy for acute myeloid leukemia (AML), monocytic AML cell differentiation (i.e., classified as French/American/British (FAB) subtypes M4/M5) is associated with a different responsiveness both to Bcl-2 inhibition (decreased [...] Read more.
Even though morphological signs of differentiation have a minimal impact on survival after intensive cytotoxic therapy for acute myeloid leukemia (AML), monocytic AML cell differentiation (i.e., classified as French/American/British (FAB) subtypes M4/M5) is associated with a different responsiveness both to Bcl-2 inhibition (decreased responsiveness) and possibly also bromodomain inhibition (increased responsiveness). FAB-M4/M5 patients are heterogeneous with regard to genetic abnormalities, even though monocytic differentiation is common for patients with Nucleophosmin 1 (NPM1) insertions/mutations; to further study the heterogeneity of FAB-M4/M5 patients we did a proteomic and phosphoproteomic comparison of FAB-M4/M5 patients with (n = 13) and without (n = 12) NPM1 mutations. The proteomic profile of NPM1-mutated FAB-M4/M5 patients was characterized by increased levels of proteins involved in the regulation of endocytosis/vesicle trafficking/organellar communication. In contrast, AML cells without NPM1 mutations were characterized by increased levels of several proteins involved in the regulation of cytoplasmic translation, including a large number of ribosomal proteins. The phosphoproteomic differences between the two groups were less extensive but reflected similar differences. To conclude, even though FAB classification/monocytic differentiation are associated with differences in responsiveness to new targeted therapies (e.g., Bcl-2 inhibition), our results shows that FAB-M4/M5 patients are heterogeneous with regard to important biological characteristics of the leukemic cells. Full article
(This article belongs to the Special Issue Proteomics and Its Applications in Disease 2.0)
28 pages, 4172 KiB  
Review
Biopolymer Materials in Triboelectric Nanogenerators: A Review
by Qiliang Zhu, Enqi Sun, Zequan Zhao, Tong Wu, Shuchang Meng, Zimeng Ma, Shoaib Muhammad, Hafeez Ur Rehman, Xia Cao and Ning Wang
Polymers 2024, 16(10), 1304; https://doi.org/10.3390/polym16101304 (registering DOI) - 07 May 2024
Abstract
In advancing the transition of the energy sector toward heightened sustainability and environmental friendliness, biopolymers have emerged as key elements in the construction of triboelectric nanogenerators (TENGs) due to their renewable sources and excellent biodegradability. The development of these TENG devices is of [...] Read more.
In advancing the transition of the energy sector toward heightened sustainability and environmental friendliness, biopolymers have emerged as key elements in the construction of triboelectric nanogenerators (TENGs) due to their renewable sources and excellent biodegradability. The development of these TENG devices is of significant importance to the next generation of renewable and sustainable energy technologies based on carbon-neutral materials. This paper introduces the working principles, material sources, and wide-ranging applications of biopolymer-based triboelectric nanogenerators (BP-TENGs). It focuses on the various categories of biopolymers, ranging from natural sources to microbial and chemical synthesis, showcasing their significant potential in enhancing TENG performance and expanding their application scope, while emphasizing their notable advantages in biocompatibility and environmental sustainability. To gain deeper insights into future trends, we discuss the practical applications of BP-TENG in different fields, categorizing them into energy harvesting, healthcare, and environmental monitoring. Finally, the paper reveals the shortcomings, challenges, and possible solutions of BP-TENG, aiming to promote the advancement and application of biopolymer-based TENG technology. We hope this review will inspire the further development of BP-TENG towards more efficient energy conversion and broader applications. Full article
12 pages, 415 KiB  
Article
Quantitative Determination of Biogenic Element Contents and Phytochemicals of Broccoli (Brassica oleracea var. italica) Cooked Using Different Techniques
by Fahad AlJuhaimi, Isam A. Mohamed Ahmed, Mehmet Musa Özcan, Nurhan Uslu and Zainab Albakry
Plants 2024, 13(10), 1283; https://doi.org/10.3390/plants13101283 (registering DOI) - 07 May 2024
Abstract
In this study, the effect of different cooking techniques on broccoli moisture, total phenolic, total flavonoid, and radical scavenging capacity results, polyphenol contents, and their quantitative values was investigated. The total phenolic quantities of fresh and cooked broccoli samples were assessed to be [...] Read more.
In this study, the effect of different cooking techniques on broccoli moisture, total phenolic, total flavonoid, and radical scavenging capacity results, polyphenol contents, and their quantitative values was investigated. The total phenolic quantities of fresh and cooked broccoli samples were assessed to be between 36.32 (conventional boiling) and 423.39 mg GAE/100 g (microwave heating). The radical scavenging activities of the broccoli samples were reported between 2.55 (conventional boiling) and 4.99 mmol/kg (microwave heating). In addition, catechin and rutin quantities of the fresh and cooked broccoli samples were measured to be between 2.24 (conventional boiling) and 54.48 mg/100 g (microwave heating), and between 0.55 (conventional boiling) and 16.33 mg/100 g (microwave heating), respectively. The most abundant elements in fresh and cooked broccoli samples were K, Ca, P, S, and Mg. The results showed some changes depending on cooking techniques compared to the control. The bioactive properties of broccoli samples cooked by means of conventional boiling, boiling in vacuum bag, and high-pressure boiling were established to be lower compared to the fresh sample. Catechin, 3,4-dihydroxybenzoic acid, rutin, and gallic acid were the key phenolic compounds of fresh and cooked broccoli samples. The phenolic components of broccoli were significantly affected by the applied cooking techniques. The highest protein in broccoli samples was determined in the broccoli sample cooked by boiling in a vacuum bag. There were statistically significant changes among the mineral results of broccoli cooked with different cooking methods. Full article
18 pages, 637 KiB  
Article
Maximum Packing of    λ-Fold Complete 3-Uniform Hypergraph with a Special Tetrahedron
by Yuzhe Zhu and  Hongtao Zhao
Mathematics 2024, 12(10), 1421; https://doi.org/10.3390/math12101421 (registering DOI) - 07 May 2024
Abstract
Let Kv(3)=(V,E) be the complete 3-uniform hypergraph, where the vertex set is V={x1,x2,,xv}, in which the edge set E [...] Read more.
Let Kv(3)=(V,E) be the complete 3-uniform hypergraph, where the vertex set is V={x1,x2,,xv}, in which the edge set E is of all triples. Let ST denote the special tetrahedron with four edges, where each edge contains three vertices of degree 2. In this paper, we consider the decomposition and packing of a complete 3-uniform hypergraph of an λ-fold special tetrahedron. Firstly, the necessary conditions for the existence of the λ-fold ST-decomposition are discussed in four distinct cases. Secondly, according to the recursive constructions, the required designs of small orders are found. For hypergraphs with large orders, they can be recursively generated using some designs of small orders. Then, it is proven that the above necessary conditions are sufficient. Finally, we prove that a maximum ST-packing of a complete 3-uniform hypergraph Kv(3) exists for all v6 and λ1 Full article
13 pages, 327 KiB  
Article
Treatment Outcomes in Patients with Muscular Temporomandibular Joint Disorders: A Prospective Case-Control Study
by Rossana Izzetti, Elisabetta Carli, Stefano Gennai, Maria Rita Giuca, Filippo Graziani and Marco Nisi
Dent. J. 2024, 12(5), 129; https://doi.org/10.3390/dj12050129 (registering DOI) - 07 May 2024
Abstract
Muscular temporomandibular joint disorders (M-TMDs) encompass a wide range of painful muscular conditions, which can provoke functional limitation and severely affect quality of life. The aim of the present study was to assess the treatment outcomes in patients affected by M-TMDs in terms [...] Read more.
Muscular temporomandibular joint disorders (M-TMDs) encompass a wide range of painful muscular conditions, which can provoke functional limitation and severely affect quality of life. The aim of the present study was to assess the treatment outcomes in patients affected by M-TMDs in terms of pain scores assessed with pressure pain threshold (PPT). The levels of depression, anxiety, and the Oral Health Impact Profile were also assessed and compared to healthy controls. Patients with a clinical diagnosis of M-TMDs and a control group of healthy subjects were enrolled. At baseline, OHIP-14, PHQ-9, and GAD-7 were administered. PPT was registered at the level of masseter and temporalis muscles. The patients affected by M-TMDs were then treated with oral splints and physio-kinesiotherapy following a standardized treatment protocol. At the 6-month follow-up of M-TMD-affected patients, PPT was registered, and the questionnaires were re-administered to evaluate treatment outcomes. In total, sixty patients and sixty controls were enrolled. The treatment of M-TMDs produced a significant improvement in PPT at the level of the masseter muscle. OHIP-14 at baseline in the M-TMD group was significantly higher compared to the control group (p < 0.05). At the 6-month follow-up, a significant reduction in OHIP-14 scores was registered, although with higher scores compared to the control group (p < 0.05). PHQ-9 was significantly higher at baseline in the M-TMD group (p < 0.05) and decreased to values comparable to the control group after treatment. GAD-7 presented statistically significant differences between the control group and M-TMD patients at baseline (p < 0.05) and between pre- and post-treatment in the M-TMD group. Following treatment, the GAD-7 scores were comparable to the control group. The symptom burden associated with M-TMDs negatively affects quality of life, with higher oral health impairment and a tendency towards depression and anxiety compared to healthy subjects. Following treatment, an improvement in both PPT and quality of life was observed. Full article
21 pages, 1355 KiB  
Article
Predicting the Pathway Involvement of Metabolites Based on Combined Metabolite and Pathway Features
by Erik D. Huckvale and Hunter N. B. Moseley
Metabolites 2024, 14(5), 266; https://doi.org/10.3390/metabo14050266 (registering DOI) - 07 May 2024
Abstract
A major limitation of most metabolomics datasets is the sparsity of pathway annotations for detected metabolites. It is common for less than half of the identified metabolites in these datasets to have a known metabolic pathway involvement. Trying to address this limitation, machine [...] Read more.
A major limitation of most metabolomics datasets is the sparsity of pathway annotations for detected metabolites. It is common for less than half of the identified metabolites in these datasets to have a known metabolic pathway involvement. Trying to address this limitation, machine learning models have been developed to predict the association of a metabolite with a “pathway category”, as defined by a metabolic knowledge base like KEGG. Past models were implemented as a single binary classifier specific to a single pathway category, requiring a set of binary classifiers for generating the predictions for multiple pathway categories. This past approach multiplied the computational resources necessary for training while diluting the positive entries in the gold standard datasets needed for training. To address these limitations, we propose a generalization of the metabolic pathway prediction problem using a single binary classifier that accepts the features both representing a metabolite and representing a pathway category and then predicts whether the given metabolite is involved in the corresponding pathway category. We demonstrate that this metabolite–pathway features pair approach not only outperforms the combined performance of training separate binary classifiers but demonstrates an order of magnitude improvement in robustness: a Matthews correlation coefficient of 0.784 ± 0.013 versus 0.768 ± 0.154. Full article
(This article belongs to the Special Issue Machine Learning Applications in Metabolomics Analysis)
19 pages, 483 KiB  
Article
Novel Distance Measures of q-Rung Orthopair Fuzzy Sets and Their Applications
by Donglai Wang, Yige Yuan, Zhe Liu, Sijia Zhu and Zhifang Sun
Symmetry 2024, 16(5), 574; https://doi.org/10.3390/sym16050574 (registering DOI) - 07 May 2024
Abstract
The q-rung orthopair fuzzy sets (q-ROFSs), a novel concept for processing vague information, offer a more potent and all-encompassing method compared to traditional fuzzy sets, intuitionistic fuzzy sets, and Pythagorean fuzzy sets. The inclusion of the parameter q allows for [...] Read more.
The q-rung orthopair fuzzy sets (q-ROFSs), a novel concept for processing vague information, offer a more potent and all-encompassing method compared to traditional fuzzy sets, intuitionistic fuzzy sets, and Pythagorean fuzzy sets. The inclusion of the parameter q allows for the q-rung orthopair fuzzy sets to capture a broader range of uncertainty of information. In this paper, we present two novel distance measures for q-ROFSs inspired by the Jensen–Shannon divergence, called DJS_2D and DJS_3D, and we analyze some properties they satisfy, such as non-degeneracy, symmetry, boundedness, and triangular inequality. Then, the normalized distance measures, called DJS_2D˜ and DJS_3D˜, are proposed and we verify their rationality through numerical experiments. Finally, we apply the proposed distance measures to practical scenarios, including pattern recognition and multicriteria decision-making, and the results demonstrate the effectiveness of the proposed distance measures. Full article
(This article belongs to the Special Issue Recent Developments on Fuzzy Sets Extensions)
26 pages, 1210 KiB  
Article
Characterization and Photocatalytic and Antibacterial Properties of Ag- and TiOx-Based (x = 2, 3) Composite Nanomaterials under UV Irradiation
by Nicola Morante, Veronica Folliero, Federica Dell’Annunziata, Nicoletta Capuano, Antonietta Mancuso, Katia Monzillo, Massimiliano Galdiero, Diana Sannino and Gianluigi Franci
Materials 2024, 17(10), 2178; https://doi.org/10.3390/ma17102178 (registering DOI) - 07 May 2024
Abstract
Metal and metal oxide nanostructured materials have been chemically and physically characterized and tested concerning methylene blue (MB) photoremoval and UV antibacterial activity against Escherichia coli and Staphylococcus aureus. In detail, silver nanoparticles and commercial BaTiO3 nanoparticles were modified to obtain [...] Read more.
Metal and metal oxide nanostructured materials have been chemically and physically characterized and tested concerning methylene blue (MB) photoremoval and UV antibacterial activity against Escherichia coli and Staphylococcus aureus. In detail, silver nanoparticles and commercial BaTiO3 nanoparticles were modified to obtain nanocomposites through sonicated sol–gel TiO2 synthesis and the photodeposition of Ag nanoparticles, respectively. The characterization results of pristine nanomaterials and synthetized photocatalysts revealed significant differences in specific surface area (SSA), the presence of impurities in commercial Ag nanoparticles, an anatase phase with brookite traces for TiO2-based nanomaterials, and a mixed cubic–tetragonal phase for BaTiO3. Silver nanoparticles exhibited superior antibacterial activity at different dosages; however, they were inactive in the photoremoval of the dye. The silver–TiOx nanocomposite demonstrated an activity in the UV photodegradation of MB and UV inhibition of bacterial growth. Specifically, TiO2/AgNP (30–50 nm) reduced growth by 487.5 and 1.1 × 103 times for Escherichia coli and Staphylococcus aureus, respectively, at a dose of 500 ug/mL under UV irradiation. Full article
(This article belongs to the Special Issue State-of-the-Art of Materials Science and Engineering in Italy)
12 pages, 2017 KiB  
Article
Cross-Water–Air Optical Wireless Communication Using Orthogonal Time–Frequency Space Modulation
by Dianbin Lian, Yan Gao and Jie Lian
Symmetry 2024, 16(5), 571; https://doi.org/10.3390/sym16050571 (registering DOI) - 07 May 2024
Abstract
This paper examines the communication difficulties encountered in cross-media wireless optical transmission through simulated research on the utilization of orthogonal time and frequency space (OTFS) modulation technology. Our analysis and comparison demonstrate that OTFS significantly improves the reliability and throughput of data transmission [...] Read more.
This paper examines the communication difficulties encountered in cross-media wireless optical transmission through simulated research on the utilization of orthogonal time and frequency space (OTFS) modulation technology. Our analysis and comparison demonstrate that OTFS significantly improves the reliability and throughput of data transmission in intricate multipath channel settings. In contrast to conventional orthogonal frequency division multiplexing (OFDM) technology, OTFS displays better resilience and transmission effectiveness. We foresee additional enhancements and progress in OTFS technology to present a sturdier and more efficient resolution for wireless communication, thereby providing valuable perspectives and encouragement for associated research initiatives. Our results underscore the capability of OTFS technology to transform wireless communication systems in demanding multipath channel conditions. Full article
(This article belongs to the Special Issue Symmetry and Its Application in Wireless Communication)
18 pages, 3760 KiB  
Article
Inhibition of Shikimate Kinase from Methicillin-Resistant Staphylococcus aureus by Benzimidazole Derivatives. Kinetic, Computational, Toxicological, and Biological Activity Studies
by Lluvia Rios-Soto, Alicia Hernández-Campos, David Tovar-Escobar, Rafael Castillo, Erick Sierra-Campos, Mónica Valdez-Solana, Alfredo Téllez-Valencia and Claudia Avitia-Domínguez
Int. J. Mol. Sci. 2024, 25(10), 5077; https://doi.org/10.3390/ijms25105077 (registering DOI) - 07 May 2024
Abstract
Antimicrobial resistance (AMR) is one of the biggest threats in modern times. It was estimated that in 2019, 1.27 million deaths occurred around the globe due to AMR. Methicillin-resistant Staphylococcus aureus (MRSA) strains, a pathogen considered of high priority by the World Health [...] Read more.
Antimicrobial resistance (AMR) is one of the biggest threats in modern times. It was estimated that in 2019, 1.27 million deaths occurred around the globe due to AMR. Methicillin-resistant Staphylococcus aureus (MRSA) strains, a pathogen considered of high priority by the World Health Organization, have proven to be resistant to most of the actual antimicrobial treatments. Therefore, new treatments are required to be able to manage this increasing threat. Under this perspective, an important metabolic pathway for MRSA survival, and absent in mammals, is the shikimate pathway, which is involved in the biosynthesis of chorismate, an intermediate for the synthesis of aromatic amino acids, folates, and ubiquinone. Therefore, the enzymes of this route have been considered good targets to design novel antibiotics. The fifth step of the route is performed by shikimate kinase (SK). In this study, an in-house chemical library of 170 benzimidazole derivatives was screened against MRSA shikimate kinase (SaSK). This effort led to the identification of the first SaSK inhibitors, and the two inhibitors with the greatest inhibition activity (C1 and C2) were characterized. Kinetic studies showed that both compounds were competitive inhibitors with respect to ATP and non-competitive for shikimate. Structural analysis through molecular docking and molecular dynamics simulations indicated that both inhibitors interacted with ARG113, an important residue involved in ATP binding, and formed stable complexes during the simulation period. Biological activity evaluation showed that both compounds were able to inhibit the growth of a MRSA strain. Mitochondrial assays showed that both compounds modify the activity of electron transport chain complexes. Finally, ADMETox predictions suggested that, in general, C1 and C2 can be considered as potential drug candidates. Therefore, the benzimidazole derivatives reported here are the first SaSK inhibitors, representing a promising scaffold and a guide to design new drugs against MRSA. Full article
(This article belongs to the Special Issue Recent Advances: Heterocycles in Drugs and Drug Discovery 2.0)
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18 pages, 1403 KiB  
Article
Interaction of Protons with Noble-Gas Atoms: Total and Differential Cross Sections
by Musab Al-Ajaleen and Károly Tőkési
Atoms 2024, 12(5), 28; https://doi.org/10.3390/atoms12050028 (registering DOI) - 07 May 2024
Abstract
We present a classical treatment of the ionization and electron-capture processes in the interaction of protons with neutral noble-gas atoms, namely, Ne, Ar, Kr, and Xe. We used a three-body classical-trajectory Monte Carlo (CTMC) method to calculate the total (TCS) and differential (DCS) [...] Read more.
We present a classical treatment of the ionization and electron-capture processes in the interaction of protons with neutral noble-gas atoms, namely, Ne, Ar, Kr, and Xe. We used a three-body classical-trajectory Monte Carlo (CTMC) method to calculate the total (TCS) and differential (DCS) cross sections of single-electron processes. The Garvey-type model potential was employed in the CTMC model to describe the collision between the projectile and the target, accounting for the screening effect of the inactive electrons. The TCSs are evaluated for impact energies in the energy range between 0.2 keV and 50 MeV for a number of sub-shells of the targets. The ionization DCS are evaluated for an impact energy of 35 keV, focusing on the outer sub-shells only. We found that our ionization and electron-capture TCSs are in very good agreement with the previous theoretical and experimental data for all targets. Moreover, we presented single (SDCS)- and double (DDCS)-differential cross sections as a function of the energy and ejection angle of the ionized electron for all collision systems. Full article
(This article belongs to the Section Atomic, Molecular and Nuclear Spectroscopy and Collisions)
18 pages, 679 KiB  
Article
Evaluation of the Metabolite Profile of Fish Oil Omega-3 Fatty Acids (n-3 FAs) in Micellar and Enteric-Coated Forms—A Randomized, Cross-Over Human Study
by Afoke Ibi, Chuck Chang, Yun Chai Kuo, Yiming Zhang, Min Du, Yoon Seok Roh, Roland Gahler, Mary Hardy and Julia Solnier
Metabolites 2024, 14(5), 265; https://doi.org/10.3390/metabo14050265 (registering DOI) - 07 May 2024
Abstract
This study evaluated the differences in the metabolite profile of three n-3 FA fish oil formulations in 12 healthy participants: (1) standard softgels (STD) providing 600 mg n-3 FA; (2) enteric-coated softgels (ENT) providing 600 mg n-3 FA; (3) a new micellar formulation [...] Read more.
This study evaluated the differences in the metabolite profile of three n-3 FA fish oil formulations in 12 healthy participants: (1) standard softgels (STD) providing 600 mg n-3 FA; (2) enteric-coated softgels (ENT) providing 600 mg n-3 FA; (3) a new micellar formulation (LMF) providing 374 mg n-3 FA. The pharmacokinetics (PKs), such as the area under the plot of plasma concentration (AUC), and the peak blood concentration (Cmax) of the different FA metabolites including HDHAs, HETEs, HEPEs, RvD1, RvD5, RvE1, and RvE2, were determined over a total period of 24 h. Blood concentrations of EPA (26,920.0 ± 10,021.0 ng/mL·h) were significantly higher with respect to AUC0-24 following LMF treatment vs STD and ENT; when measured incrementally, blood concentrations of total n-3 FAs (EPA/DHA/DPA3) up to 11 times higher were observed for LMF vs STD (iAUC 0-24: 16,150.0 ± 5454.0 vs 1498.9 ± 443.0; p ≤ 0.0001). Significant differences in n-3 metabolites including oxylipins were found between STD and LMF with respect to 12-HEPE, 9-HEPE, 12-HETE, and RvD1; 9-HEPE levels were significantly higher following the STD vs. ENT treatment. Furthermore, within the scope of this study, changes in blood lipid levels (i.e., cholesterol, triglycerides, LDL, and HDL) were monitored in participants for up to 120 h post-treatment; a significant decrease in serum triglycerides was detected in participants (~20%) following the LMF treatment; no significant deviations from the baseline were detected for all the other lipid biomarkers in any of the treatment groups. Despite a lower administered dose, LMF provided higher blood concentrations of n-3 FAs and certain anti-inflammatory n-3 metabolites in human participants—potentially leading to better health outcomes. Full article
(This article belongs to the Section Nutrition and Metabolism)
18 pages, 1093 KiB  
Article
Dip-Bump Structure in Proton’s Single Diffractive Dissociation at the Large Hadron Collider
by László Jenkovszky, Rainer Schicker and István Szanyi
Universe 2024, 10(5), 208; https://doi.org/10.3390/universe10050208 (registering DOI) - 07 May 2024
Abstract
By extending the dipole Pomeron (DP) model, successful in describing elastic nucleon–nucleon scattering, to proton single diffractive dissociation (SD), we predict a dip-bump structure in the squared four-momentum transfer (t) distribution of proton’s SD. Structures in the t distribution of single [...] Read more.
By extending the dipole Pomeron (DP) model, successful in describing elastic nucleon–nucleon scattering, to proton single diffractive dissociation (SD), we predict a dip-bump structure in the squared four-momentum transfer (t) distribution of proton’s SD. Structures in the t distribution of single diffractive dissociation are predicted around t=4 GeV2 at LHC energies in the range of 3 GeV2|t| 7 GeV2. Apart from the dependence on s (total energy squared) and t (squared momentum transfer), we predict also a dependence on missing masses. We include the minimum set of Regge trajectories, namely the Pomeron and the Odderon, indispensable at the LHC. Further generalization, e.g., by the inclusion of non-leading Regge trajectories, is straightforward. The present model contains two types of Regge trajectories: those connected with tchannel exchanges (the Pomeron, the Odderon, and non-leading (secondary) reggeons) appearing at small and moderate t, where they are real and nearly linear, as well as direct-channel trajectories α(M2) related to missing masses. In this paper, we concentrate on structures in t neglecting (for the time being) resonances in M2. Full article
(This article belongs to the Special Issue Multiparticle Dynamics)
16 pages, 520 KiB  
Article
Factors Influencing Long-Term Local Recurrence, Distant Metastasis, and Survival in Patients with Soft Tissue Sarcoma of the Extremities Treated with Radiotherapy
by Arthur Lebas, Clara Le Fevre, Waisse Waissi, Isabelle Chambrelant, David Brinkert and Georges Noel
Cancers 2024, 16(10), 1789; https://doi.org/10.3390/cancers16101789 (registering DOI) - 07 May 2024
Abstract
Introduction: The prognostic factors for extremity soft-tissue sarcomas (ESTSs) treated with multimodal surgery and radiotherapy (RT) remain a subject of debate across diverse and heterogeneous studies. Methods: We retrospectively analyzed nonmetastatic ESTS patients treated with RT between 2007 and 2020 in Strasbourg, France. [...] Read more.
Introduction: The prognostic factors for extremity soft-tissue sarcomas (ESTSs) treated with multimodal surgery and radiotherapy (RT) remain a subject of debate across diverse and heterogeneous studies. Methods: We retrospectively analyzed nonmetastatic ESTS patients treated with RT between 2007 and 2020 in Strasbourg, France. We assessed local control (LC), distant control (DC), overall survival (OS), and complications. Results: A total of 169 patients diagnosed with localized ESTS were included. The median age was 64 years (range 21–94 years). ESTS primarily occurred proximally (74.6%) and in the lower limbs (71%). Most tumors were grade 2–3 (71.1%), deep-seated (86.4%), and had R0 margins (63.9%). Most patients were treated with helical tomotherapy (79.3%). The median biologically effective dose (BED) prescribed was 75 BEDGy4 (range 45.0–109.9). The median follow-up was 5.5 years. The 5- and 10-year LC, DC, and OS rates were 91.7%, 76.8%, and 83.8% and 84.2%, 74.1%, and 77.6%, respectively. According to the univariate analysis, LC was worse for patients who received less than 75 BEDGy4 (p = 0.015). Deep tumors were associated with worse OS (p < 0.05), and grade 2–3 and undifferentiated pleomorphic sarcoma (UPS) were linked to both shorter DC and shorter OS (p < 0.05). IMRT was associated with longer LC than 3DRT (p = 0.018). Multivariate analysis revealed that patients with liposarcoma had better OS (p < 0.05) and that patients with distant relapse had shorter OS (p < 0.0001). Conclusion: RT associated with surgical resection was well tolerated and was associated with excellent long-term rates of LC, DC, and OS. Compared with 3DRT, IMRT improved local control. Liposarcoma was a favorable prognostic factor for OS. Intermediate- and high-grade tumors and deep tumors were associated with lower DC and OS. Full article
(This article belongs to the Special Issue Multimodality Management of Sarcomas)
24 pages, 617 KiB  
Review
Protein Oxidation in Aging and Alzheimer’s Disease Brain
by Rukhsana Sultana and D. Allan Butterfield
Antioxidants 2024, 13(5), 574; https://doi.org/10.3390/antiox13050574 (registering DOI) - 07 May 2024
Abstract
Proteins are essential molecules that play crucial roles in maintaining cellular homeostasis and carrying out biological functions such as catalyzing biochemical reactions, structural proteins, immune response, etc. However, proteins also are highly susceptible to damage by reactive oxygen species (ROS) and reactive nitrogen [...] Read more.
Proteins are essential molecules that play crucial roles in maintaining cellular homeostasis and carrying out biological functions such as catalyzing biochemical reactions, structural proteins, immune response, etc. However, proteins also are highly susceptible to damage by reactive oxygen species (ROS) and reactive nitrogen species (RNS). In this review, we summarize the role of protein oxidation in normal aging and Alzheimer’s disease (AD). The major emphasis of this review article is on the carbonylation and nitration of proteins in AD and mild cognitive impairment (MCI). The oxidatively modified proteins showed a strong correlation with the reported changes in brain structure, carbohydrate metabolism, synaptic transmission, cellular energetics, etc., of both MCI and AD brains compared to the controls. Some proteins were found to be common targets of oxidation and were observed during the early stages of AD, suggesting that those changes might be critical in the onset of symptoms and/or formation of the pathological hallmarks of AD. Further studies are required to fully elucidate the role of protein oxidation and nitration in the progression and pathogenesis of AD. Full article
30 pages, 590 KiB  
Article
A Nonlinear Programming Approach to Solving Interval-Valued Intuitionistic Hesitant Noncooperative Fuzzy Matrix Games
by Shuvasree Karmakar and Mijanur Rahaman Seikh
Symmetry 2024, 16(5), 573; https://doi.org/10.3390/sym16050573 (registering DOI) - 07 May 2024
Abstract
Initially, fuzzy sets and intuitionistic fuzzy sets were used to address real-world problems with imprecise data. Eventually, the notion of the hesitant fuzzy set was formulated to handle decision makers’ reluctance to accept asymmetric information. However, in certain scenarios, asymmetric information is gathered [...] Read more.
Initially, fuzzy sets and intuitionistic fuzzy sets were used to address real-world problems with imprecise data. Eventually, the notion of the hesitant fuzzy set was formulated to handle decision makers’ reluctance to accept asymmetric information. However, in certain scenarios, asymmetric information is gathered in terms of a possible range of acceptance and nonacceptance by players rather than specific values. Furthermore, decision makers exhibit some hesitancy regarding this information. In such a situation, all the aforementioned expansions of fuzzy sets are unable to accurately represent the scenario. The purpose of this article is to present asymmetric information situations in which the range of choices takes into account the hesitancy of players in accepting or not accepting information. To illustrate these problems, we develop matrix games that consider the payoffs of interval-valued intuitionistic hesitant fuzzy elements (IIHFEs). Dealing with these types of fuzzy programming problems requires a significant amount of effort. To solve these matrix games, we formulate two interval-valued intuitionistic hesitant fuzzy programming problems. Preserving the hesitant nature of the payoffs to determine the optimal strategies, these two problems are transformed into two nonlinear programming problems. This transformation involves using mathematical operations for IIHFEs. Here, we construct a novel aggregation operator of IIHFEs, viz., min-max operators of IIHFEs. This operator is suitable for applying the developed methodology. The cogency and applicability of the proposed methodology are verified through a numerical example based on the situation of conflict between hackers and defenders to prevent damage to cybersecurity. To validate the superiority of the proposed model along with the computed results, we provide comparisons with the existing models. Full article
(This article belongs to the Special Issue Recent Developments on Fuzzy Sets Extensions)
21 pages, 1207 KiB  
Article
A Differentially Private Framework for the Dynamic Heterogeneous Redundant Architecture System in Cyberspace
by Yilin Kang, Qiao Zhang, Bingbing Jiang and Youjun Bu
Electronics 2024, 13(10), 1805; https://doi.org/10.3390/electronics13101805 (registering DOI) - 07 May 2024
Abstract
With the development of information technology, tremendous vulnerabilities and backdoors have evolved, causing inevitable and severe security problems in cyberspace. To fix them, the endogenous safety and security (ESS) theory and one of its practices, the Dynamic Heterogeneous Redundant (DHR) architecture, are proposed. [...] Read more.
With the development of information technology, tremendous vulnerabilities and backdoors have evolved, causing inevitable and severe security problems in cyberspace. To fix them, the endogenous safety and security (ESS) theory and one of its practices, the Dynamic Heterogeneous Redundant (DHR) architecture, are proposed. In the DHR architecture, as an instance of the multi-heterogeneous system, a decision module is designed to obtain intermediate results from heterogeneous equivalent functional executors. However, privacy-preserving is not paid attention to in the architecture, which may cause privacy breaches without compromising the ESS theory. In this paper, based on differential privacy (DP), a theoretically rigorous privacy tool, we propose a privacy-preserving DHR framework called DP-DHR. Gaussian random noise is injected into each (online) executor output in DP-DHR to guarantee DP, but it also makes the decision module unable to choose the final result because each executor output is potentially correct even if it is compromised by adversaries. To weaken this disadvantage, we propose the advanced decision strategy and the hypersphere clustering algorithm to classify the perturbed intermediate results into two categories, candidates and outliers, where the former is closer to the correct value than the latter. Finally, the DP-DHR is proven to guarantee DP, and the experimental results also show that the utility is not sacrificed for the enhancement of privacy by much (a ratio of 4–7% on average), even in the condition of some executors (less than one-half) being controlled by adversaries. Full article
18 pages, 1296 KiB  
Article
Characteristics of RNA Stabilizer RNApro for Peripheral Blood Collection
by Stefano Gambarino, Ilaria Galliano, Anna Clemente, Cristina Calvi, Paola Montanari, Anna Pau, Maddalena Dini and Massimiliano Bergallo
Diagnostics 2024, 14(10), 971; https://doi.org/10.3390/diagnostics14100971 (registering DOI) - 07 May 2024
Abstract
Peripheral blood is the most practical tissue for human immune system gene expression profiling because it is easily accessible, whereas the site of primary infection in certain diseases may not be easily accessible. Due to the ex vivo instability of RNA transcripts, a [...] Read more.
Peripheral blood is the most practical tissue for human immune system gene expression profiling because it is easily accessible, whereas the site of primary infection in certain diseases may not be easily accessible. Due to the ex vivo instability of RNA transcripts, a key challenge in the gene expression analysis of blood samples is the rapid sample handling and stabilization of the mRNA by adding an RNA preservative (PAXgeneTM Blood RNA Tubes, TempusTM Blood RNA tubes, RNAlater Stabilization Reagent, RNAgard® Blood Tubes). BioMole (Turin, Italy) has developed a novel blood stabilizer, called RNApro, in which RNA is stabilized during phlebotomy and sample storage. In this study, RNApro performance intended as RNA yield, integrity, and stability was evaluated. Our results show that blood samples stored at −80 °C and re-extracted after 7 years show no differences in terms of quantity, quality, and amplificability. The samples in the RNAlater stabilization solution can be stored at room temperature for up to one week or at 4 °C for up to one month. Similar results can also be observed for PAXgene tubes, Tempus tubes, and RNAgard tubes. In agreement with these data, the RNApro stabilization solution preserves the RNA from degradation for up to 1 month at 4 °C and 1 week at room temperature. RNApro can be stored indifferently at −80, −20, 4 °C, or room temperature for up to 2 months after, and then could be stored at −80 °C for up to seven years. In summary, our study is the first to analyze the performance of an RNA stabilizer called RNApro. We can conclude that several studies have shown significant differences in gene expression analysis when the sample was preserved in different RNA stabilizers. Therefore, it is desirable to standardize the method of nucleic acid conservation when comparing data from transcriptomic analyses. Full article
(This article belongs to the Section Clinical Laboratory Medicine)
15 pages, 829 KiB  
Article
Texture and Twinning Evolution of Cold-Rolled Industrial Pure Zirconium
by Yuan Liu, Yiming Li, Weimin Mao, Huiyi Bai, Qi Fang, Yunping Ji and Huiping Ren
Processes 2024, 12(5), 948; https://doi.org/10.3390/pr12050948 (registering DOI) - 07 May 2024
Abstract
Industrial pure zirconium plays an essential role as a structural material in the nuclear energy sector. Understanding the deformation mechanisms is crucial for effectively managing the plasticity and texture evolution of industrial pure zirconium. In the present study, the texture and microstructure evolution [...] Read more.
Industrial pure zirconium plays an essential role as a structural material in the nuclear energy sector. Understanding the deformation mechanisms is crucial for effectively managing the plasticity and texture evolution of industrial pure zirconium. In the present study, the texture and microstructure evolution of industrial pure zirconium during the cold-rolling process have been characterized by XRD, EBSD, and TEM. The influences of various twins on texture evolution have also been simulated by the reaction stress model. The effects of slip and twinning on the deformation behavior and texture evolution have been discussed based on crystallographic and experimental considerations. Cold rolling yields a typical bimodal texture, resulting in the preferential <2110>//RD orientation. The activation of the deformation mechanisms during cold rolling follows the sequential trend of slip, twinning, local slip. Experimental characterization and reaction stress simulation illustrate that T1 twins dominate in the early stage, whereas C2 twins develop at the later stage of the cold-rolling process. Twinning, especially the T1 twin, contributes to the formation of the {0001}<1010> orientation. Full article
(This article belongs to the Special Issue Digital Research and Development of Materials and Processes)
19 pages, 3527 KiB  
Article
Research on Disinformation in Academic Studies: Perspectives through a Bibliometric Analysis
by Nuria Navarro-Sierra, Silvia Magro-Vela and Raquel Vinader-Segura
Publications 2024, 12(2), 14; https://doi.org/10.3390/publications12020014 (registering DOI) - 07 May 2024
Abstract
Disinformation is a phenomenon of concern to all political systems, as it poses a threat to freedom and democracy through the manipulation of public opinion aimed at eroding institutions. This paper presents a bibliometric and systematized study which allows the establishment of a [...] Read more.
Disinformation is a phenomenon of concern to all political systems, as it poses a threat to freedom and democracy through the manipulation of public opinion aimed at eroding institutions. This paper presents a bibliometric and systematized study which allows the establishment of a comprehensive view of the research and current state of academic investigations on disinformation. To this end, a content analysis of the scientific articles indexed in Scopus up to 31 December 2023 has been carried out based on three categories of analysis: journals, authors and investigations. Similarly, a systematic study of the 50 most cited articles in this sample was performed in order to gain a deeper understanding of the nature, motivations and methodological approaches of these investigations. The results indicate that disinformation is a research topic which has gained great interest in the academic community since 2018, with special mention to the impact of COVID-19 and the vaccines against this disease. Thus, it can be concluded that disinformation is an object of study which attracts significant attention and which must be approached from transdisciplinarity to respond to a phenomenon of great complexity. Full article
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