bluuebunny/crossref_metadata_2025 huggingface dataset:
Damage Identification for Railway Tracks Using Onboard Monitoring Systems in In-Service Vehicles and Data Science
Authors: Traquinho Nelson , Vale Cecília , Ribeiro Diogo , Meixedo Andreia , Montenegro Pedro , Mosleh Araliya , Calçada Rui
Published: October 2023

Nowadays, railway track monitoring strategies are based on the use of railway inspection vehicles and wayside dynamic monitoring systems. The latter sometimes requires traffic disruption, as well as higher time and cost-consumption activities, and the use of dedicated inspection vehicles is less economical and efficient as the use of in-service vehicles. Furthermore, the use of non-automated algorithms faces challenges when it comes to early damage detection in railway infrastructure, considering operational, environmental, and big data aspects, and may lead to false alarms. To overcome these challenges, the application of artificial intelligence (AI) algorithms for early detection of track defects using accelerations, measured by dynamic monitoring systems in in-service railway vehicles is attracting the attention of railway managers. In this paper, an AI-based methodology based on axle box acceleration signals is applied for the early detection of distributed damage to track in terms of the longitudinal level and lateral alignment. The methodology relies on feature extraction using an autoregressive model, data normalization using principal component analysis, data fusion and feature discrimination using Mahalanobis distance and outlier analysis, considering eight onboard accelerometers. For the numerical simulations, 75 undamaged and 45 damaged track scenarios are considered. The alert limit state defined in the European Standard for assessing track geometry quality is also assumed as a threshold. It was found that the detection accuracy of the AI-based methodology for different sensor layouts and types of damage is greater than 94%, which is acceptable.
Age of Information Cost Minimization with No Buffers, Random Arrivals and Unreliable Channels: A PCL-Indexability Analysis
Authors: Niño-Mora José
Published: October 2023

Over the last decade, the Age of Information has emerged as a key concept and metric for applications where the freshness of sensor-provided data is critical. Limited transmission capacity has motivated research on the design of tractable policies for scheduling information updates to minimize Age of Information cost based on Markov decision models, in particular on the restless multi-armed bandit problem (RMABP). This allows the use of Whittle’s popular index policy, which is often nearly optimal, provided indexability (index existence) is proven, which has been recently accomplished in some models. We aim to extend the application scope of Whittle’s index policy in a broader AoI scheduling model. We address a model with no buffers incorporating random packet arrivals, unreliable channels, and nondecreasing AoI costs. We use sufficient indexability conditions based on partial conservation laws previously introduced by the author to establish the model’s indexability and evaluate its Whittle index in closed form under discounted and average cost criteria. We further use the index formulae to draw insights on how scheduling priority depends on model parameters.
Hidden Markov Model Based on Logistic Regression
Authors: Lee Byeongheon , Park Joowon , Kim Yongku
Published: October 2023

A hidden Markov model (HMM) is a useful tool for modeling dependent heterogeneous phenomena. It can be used to find factors that affect real-world events, even when those factors cannot be directly observed. HMMs differ from traditional methods by using state variables and mixture distributions to model the hidden states. This allows HMMs to find relationships between variables even when the variables cannot be directly observed. HMM can be extended, allowing the transition probabilities to depend on covariates. This makes HMMs more flexible and powerful, as they can be used to model a wider range of sequential data. Modeling covariates in a hidden Markov model is particularly difficult when the dimension of the state variable is large. To avoid these difficulties, Markovian properties are achieved by implanting the previous state variables to the logistic regression model. We apply the proposed method to find the factors that affect the hidden state of matsutake mushroom growth, in which it is hard to find covariates that directly affect matsutake mushroom growth in Korea. We believe that this method can be used to identify factors that are difficult to find using traditional methods.
Default Probabilities and the Credit Spread of Mexican Companies: The Modified Merton Model
Authors: Morales-Bañuelos Paula , Fernández-Anaya Guillermo
Published: October 2023

This study aims to identify the model that best approximates the credit spread that should be fixed on debt instruments issued by both companies listed on the Mexican Stock Market, considering the particularities of the Mexican market. Five models were analyzed: Merton’s model, Brownian Motion Model, Power Law Brownian Motion Model, Bloomberg’s model, and the model presented in this paper, which includes the conformable derivatives, taking as a reference the change in the variable as other authors have done, and the Bloomberg corporate default risk model (DRSK) for publics firms. We concluded that the modified Merton model approximates, to a greater extent, the credit spreads that fix on a prime rate on the loans granted to Mexican non-financial companies.
Music through Curve Insights
Authors: Gul Shai
Published: October 2023

This manuscript endeavors to establish a framework for the mapping of music onto a three-dimensional structure. Our objective is to transform the guitar choruses of Beatles songs into curves, with each chorus corresponding to its respective curve. We aim to investigate and characterize the intricacy of each song by employing mathematical techniques derived from differential geometry, specifically focusing on the total curvature of the chorus curve. Given that a single song may possess varying chord progressions in different verses, the performer can determine the geometric representation they aim to convey through the number of loops and the direction of the curve. The overarching objective of our study is to enable viewers to identify specific songs or motives by visually examining an object and exploring its geometric properties. Furthermore, we posit that these ideas can provide composers with a fresh perspective on their own musical compositions while also granting non-professional audiences a glimpse into the intricacies involved in the process of composing.
Early and Late Complications after Cataract Surgery in Patients with Uveitis
Authors: Bajraktari Gentian , Jukić Tomislav , Kalauz Miro , Oroz Martin , Radolović Bertetić Andrea , Vukojević Nenad
Published: October 2023

Background and Objectives: Uveitis, a prevalent eye disorder characterized by inflammatory processes, often leads to cataract formation and significant visual impairment. This study aimed to evaluate preoperative conditions and postoperative outcomes following cataract surgery in uveitis patients. Materials and Methods: A retrospective study was conducted at the University Hospital Center Rebro Zagreb, Croatia, involving uveitis patients who underwent cataract surgery between 2013 and 2022. Eligible patients had uveitic cataracts affecting visual acuity or posterior segment visualization in a “quiet eye” and were disease-inactive for at least three months. Patients with certain pre-existing ocular conditions were excluded. The data collected included patient demographics, uveitis type, preoperative therapy, preexisting lesions, and postoperative outcomes such as visual acuity, intraocular pressure, central macular thickness, and complications. Statistical analysis was performed to identify risk factors associated with complications. Results: This study included 105 patients. The most common uveitis types were idiopathic uveitis, HLA-B27-associated uveitis, and JIA uveitis. After cataract surgery, there was a significant improvement in visual acuity at various time points, with 90% of eyes showing improvement. Intraocular pressure decreased over time. Central macular thickness increased at three months post-surgery but remained stable thereafter. Early and late complications were observed in 52.4% and 63.8% of eyes, respectively. The most common complications were posterior capsular opacification (53.3%), macular edema (26.6%), and epiretinal membrane formation (9.52%). The factors associated with complications varied between early and late stages but included age, age at the onset of uveitis, and the uveitis type. Conclusions: In patients with quiescent uveitis undergoing cataract surgery, significant visual improvement was achieved. This study highlights the importance of careful patient selection, preoperative and postoperative inflammation management, and precise surgical techniques. Although complications were common, the risk of capsular opacification, macular edema, and epiretinal membrane formation after surgery increased. However, future investigations should address this study’s limitations and further refine perioperative strategies.
Effect of the Degree of Li3PO4 Vapor Dissociation on the Ionic Conductivity of LiPON Thin Films
Authors: Kamenetskikh Alexander , Gavrilov Nikolay , Ershov Alexey , Tretnikov Petr
Published: October 2023

Thin films of solid-state lithium-ion electrolytes show promise for use in small-sized autonomous power sources for micro- and nanoelectronic elements. The high rate of vacuum-plasma synthesis (~0.5 μm/h) of lithium phosphor-oxynitride (LiPON) films with an ionic conductivity of ~2·10−6 S/cm is achieved through anodic evaporation of Li3PO4 in a low-pressure arc. The microstructure and ionic conductivity of LiPON films are influenced by the proportion of free lithium in the vapor flow. This paper presents the results of a study on the plasma composition during anodic evaporation of Li3PO4 in a discharge with a self-heating hollow cathode and a crucible anode. A method is proposed for adjusting the free lithium concentration in the gas-vapor (Li3PO4 + N2/Ar) discharge plasma based on changing the frequency of collisions of electrons with Li3PO4 vapor in the anodic region of the discharge. It is demonstrated that an increase in the proportion of free lithium in the flow of deposited particles leads to an enhancement in the concentration and mobility of lithium ions in the deposited films and, subsequently, an improvement in the ionic conductivity of LiPON films.
Ongoing Progress on Pervaporation Membranes for Ethanol Separation
Authors: Imad Muhammad , Castro-Muñoz Roberto
Published: October 2023

Ethanol, a versatile chemical extensively employed in several fields, including fuel production, food and beverage, pharmaceutical and healthcare industries, and chemical manufacturing, continues to witness expanding applications. Consequently, there is an ongoing need for cost-effective and environmentally friendly purification technologies for this organic compound in both diluted (ethanol-water–) and concentrated solutions (water-ethanol–). Pervaporation (PV), as a membrane technology, has emerged as a promising solution offering significant reductions in energy and resource consumption during the production of high-purity components. This review aims to provide a panorama of the recent advancements in materials adapted into PV membranes, encompassing polymeric membranes (and possible blending), inorganic membranes, mixed-matrix membranes, and emerging two-dimensional-material membranes. Among these membrane materials, we discuss the ones providing the most relevant performance in separating ethanol from the liquid systems of water–ethanol and ethanol–water, among others. Furthermore, this review identifies the challenges and future opportunities in material design and fabrication techniques, and the establishment of structure–performance relationships. These endeavors aim to propel the development of next-generation pervaporation membranes with an enhanced separation efficiency.
Involvement of the Macrophage Migration Inhibitory Factor (MIF) in Lipedema
Authors: Vasella Mauro , Wolf Stefan , Francis Eamon C. , Grieb Gerrit , Pfister Pablo , Reid Gregory , Bernhagen Jürgen , Lindenblatt Nicole , Gousopoulos Epameinondas , Kim Bong-Sung
Published: October 2023

Lipedema is a chronic disorder that mainly affects women. It is often misdiagnosed, and its etiology remains unknown. Recent research indicates an accumulation of macrophages and a shift in macrophage polarization in lipedema. One known protein superfamily that contributes to macrophage accumulation and polarization is the macrophage migration inhibitory factor (MIF) family. MIF-1 and MIF-2 are ubiquitously expressed and also regulate inflammatory processes in adipose tissue. In this study, the expression of MIF-1, MIF-2 and CD74—a common receptor for both cytokines—was analyzed in tissue samples of 11 lipedema and 11 BMI-matched, age-matched and anatomically matched control patients using qPCR and immunohistochemistry (IHC). The mRNA expression of MIF-1 (mean 1.256; SD 0.303; p = 0.0485) and CD74 (mean 1.514; SD 0.397; p = 0.0097) were significantly elevated in lipedema patients, while MIF-2 expression was unaffected (mean 1.004; SD 0.358; p = 0.9718). The IHC analysis corroborated the results for CD74 expression on a cellular level. In conclusion, our results provide first evidence for a potential involvement of the MIF family, presumably via the MIF-1-CD74 axis, in lipedema.
Heterogeneous Habitats in Taiga Forests with Different Important Values of Constructive Species Changes Bacterial Beta Diversity
Authors: Zhou Tian , Wu Song , Pan Hong , Lu Xinming , Du Jun , Yang Libin
Published: October 2023

As a crucial link between the aboveground and belowground components of forest ecosystems, soil bacterial communities are extremely sensitive to changes in plant communities and soil conditions. To investigate the impact of the difference of constructive species on soil bacterial communities in taiga forests, we conducted a vegetation survey at the international monitoring plot of the Larix gmelinii forests in the Great Khingan Mountains and calculated the important value of Larix gmelinii to determine experimental groups based on this survey. Subsequently, we collected soil samples for high-throughput sequencing to analyze how the soil bacterial community composition and diversity changed, and which factors affected them. The results showed that taiga forests with different important values of Larix gmelinii had heterogeneous habitats, in which the soil AP content significantly increased, and the SOC, MBC, pH, and C/N content decreased significantly (p < 0.05). A total of 32 phyla, 91 classes, 200 orders, 308 families, 496 genera, and 975 species of soil bacteria were obtained by sequencing. Among them, Proteobacteria, Actinobacteriota, and Acidobacteriota were the dominant phyla, and Mycobacterium was the dominant genus, and the relative abundance of each bacterial group was varied. The beta diversity of soil bacteria showed extremely significant differences (p = 0.001), with SOC, C/N, MBC, AP, TN, pH, AN, and WC being the main influencing factors. Functional prediction analysis showed that chemoheterotrophy and aerobic chemoheterotrophy were the main bacterial functional groups, and the relative abundance of each functional group was significantly different (p < 0.05). Overall, taiga forests with differences in constructive species had heterogeneous habitats, which changed the community composition, beta diversity, and potential functions of soil bacteria.
Multidrug-Resistant and Extensively Drug-Resistant Escherichia coli in Sewage in Kuwait: Their Implications
Authors: Redha Mahdi , Al Sweih Noura , Albert M.
Published: October 2023

In Kuwait, some sewage is discharged into the sea untreated, causing a health risk. Previously, we investigated the presence of pathogenic E. coli among the 140 isolates of E. coli cultured from the raw sewage from three sites in Kuwait. The aim of the current study was to characterize the antimicrobial resistance of these isolates and the implications of resistance. Susceptibility to 15 antibiotic classes was tested. Selected genes mediating resistance to cephalosporins and carbapenems were sought. ESBL and carbapenemase production were also determined. Two virulent global clones, ST131 and ST648, were sought. A total of 136 (97.1%), 14 (10.0%), 128 (91.4%), and 2 (1.4%) isolates were cephalosporin-resistant, carbapenem-resistant, multidrug-resistant (MDR), and extensively drug-resistant (XDR), respectively. Among the cephalosporin-resistant isolates, ampC, blaTEM, blaCTX-M, blaOXA-1, and blaCMY-2 were found. Eighteen (12.9%) samples were ESBL producers. All carbapenem-resistant isolates were negative for carbapenemase genes (blaOXA-48, blaIMP, blaGES, blaVIM, blaNDM, and blaKPC), and for carbapenemase production. Resistance rates in carbapenem-resistant isolates to many other antibiotics were significantly higher than in susceptible isolates. A total of four ST131 and ST648 isolates were detected. The presence of MDR and XDR E. coli and global clones in sewage poses a threat in treating E. coli infections.
An Ultrafast UPLC–MS/MS Method for Characterizing the In Vitro Metabolic Stability of Acalabrutinib
Authors: Attwa Mohamed W. , Bakheit Ahmed H. , Abdelhameed Ali S. , Kadi Adnan A.
Published: October 2023

Acalabrutinib, commercially known as Calquence®, is a pharmacological molecule that has robust inhibitory activity against Bruton tyrosine kinase. The medicine in question was carefully developed by the esteemed pharmaceutical company AstraZeneca. The FDA granted authorization on 21 November 2019 for the utilization of acalabrutinib (ACB) in the treatment of small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL) in adult patients. The aim of this study was to develop a UPLC–MS/MS method that is effective, accurate, environmentally sustainable, and has a high degree of sensitivity. The methodology was specifically developed with the intention of quantifying ACB in human liver microsomes (HLMs). The methodology described above was subsequently utilized to assess the metabolic stability of ACB in HLMs in an in vitro environment. The validation procedures for the UPLC–MS/MS method in the HLMs were conducted in accordance with the bioanalytical method validation criteria established by the U.S.- DA. The utilization of the StarDrop software (version 6.6), which integrates the P450 metabolic module and DEREK software (KB 2018 1.1), was employed for the purpose of evaluating the metabolic stability and identifying potential hazardous alarms associated with the chemical structure of ACB. The calibration curve, as established by the ACB, demonstrated a linear correlation across the concentration range of 1 to 3000 ng/mL in the matrix of HLMs. The present study conducted an assessment of the accuracy and precision of the UPLC–MS/MS method in quantifying inter-day and intra-day fluctuations. The inter-day accuracy demonstrated a spectrum of values ranging from −1.00% to 8.36%, whilst the intra-day accuracy presented a range of values spanning from −2.87% to 4.11%. The t1/2 and intrinsic clearance (Clint) of ACB were determined through in vitro testing to be 20.45 min and 39.65 mL/min/kg, respectively. The analysis concluded that the extraction ratio of ACB demonstrated a moderate level, thus supporting the recommended dosage of ACB (100 mg) to be administered twice daily for the therapeutic treatment of persons suffering from B-cell malignancies. Several computational tools have suggested that introducing minor structural alterations to the butynoyl group, particularly the alpha, beta-unsaturated amide moiety, or substituting this group during the drug design procedure, could potentially enhance the metabolic stability and safety properties of novel derivatives in comparison to ACB.
Synthesis and Characterization of Bipyridyl-(Imidazole)n Mn(II) Compounds and Their Evaluation as Potential Precatalysts for Water Oxidation
Authors: Mu Ge , Gaynor Ryan B. , McIntyre Baylee N. , Donnadieu Bruno , Creutz Sidney E.
Published: October 2023

Metalloenzymes make extensive use of manganese centers for oxidative catalysis, including water oxidation; the need to develop improved synthetic catalysts for these processes has long motivated the development of bioinspired manganese complexes. Herein, we report a series of bpy-(imidazole)n (n = 1 or 2) (bpy = 2,2′-bipyridyl) ligands and their Mn2+ complexes. Four Mn2+ complexes are structurally characterized using single-crystal X-ray diffraction, revealing different tridentate and tetradentate ligand coordination modes. Cyclic voltammetry of the complexes is consistent with ligand-centered reductions and metal-centered oxidations, and UV-vis spectroscopy complemented by TD-DFT calculations shows primarily ligand-centered transitions with minor contributions from charge-transfer type transitions at higher energies. In solution, ESI-MS studies provide evidence for ligand reorganization, suggesting complex speciation behavior. The oxidation of the complexes in the presence of water is probed using cyclic voltammetry, but the low stability of the complexes in aqueous solution leads to decomposition and precludes their ultimate application as aqueous electrocatalysts. Possible reasons for the low stability and suggestions for improvement are discussed.
Pyrrole-Based Enaminones as Building Blocks for the Synthesis of Indolizines and Pyrrolo[1,2-a]pyrazines Showing Potent Antifungal Activity
Authors: Miranda-Sánchez Diter , Escalante Carlos H. , Andrade-Pavón Dulce , Gómez-García Omar , Barrera Edson , Villa-Tanaca Lourdes , Delgado Francisco , Tamariz Joaquín
Published: October 2023

As a new approach, pyrrolo[1,2-a]pyrazines were synthesized through the cyclization of 2-formylpyrrole-based enaminones in the presence of ammonium acetate. The enaminones were prepared with a straightforward method, reacting the corresponding alkyl 2-(2-formyl-1H-pyrrol-1-yl)acetates, 2-(2-formyl-1H-pyrrol-1-yl)acetonitrile, and 2-(2-formyl-1H-pyrrol-1-yl)acetophenones with DMFDMA. Analogous enaminones elaborated from alkyl (E)-3-(1H-pyrrol-2-yl)acrylates were treated with a Lewis acid to afford indolizines. The antifungal activity of the series of substituted pyrroles, pyrrole-based enaminones, pyrrolo[1,2-a]pyrazines, and indolizines was evaluated on six Candida spp., including two multidrug-resistant ones. Compared to the reference drugs, most test compounds produced a more robust antifungal effect. Docking analysis suggests that the inhibition of yeast growth was probably mediated by the interaction of the compounds with the catalytic site of HMGR of the Candida species.
Analysis of Volatile Compounds in Processed Cream Cheese Models for the Prediction of “Fresh Cream” Aroma Perception
Authors: Caille Coline , Boukraâ Mariem , Rannou Cécile , Villière Angélique , Catanéo Clément , Lethuaut Laurent , Lagadec-Marquez Araceli , Bechaux Julia , Prost Carole
Published: October 2023

Controlling flavor perception by analyzing volatile and taste compounds is a key challenge for food industries, as flavor is the result of a complex mix of components. Machine-learning methodologies are already used to predict odor perception, but they are used to a lesser extent to predict aroma perception. The objectives of this work were, for the processed cream cheese models studied, to (1) analyze the impact of the composition and process on the sensory perception and VOC release and (2) predict “fresh cream” aroma perception from the VOC characteristics. Sixteen processed cream cheese models were produced according to a three-factor experimental design: the texturing agent type (κ-carrageenan, agar-agar) and level and the heating time. A R-A-T-A test on 59 consumers was carried out to describe the sensory perception of the cheese models. VOC release from the cheese model boli during swallowing was investigated with an in vitro masticator (Oniris device patent), followed by HS-SPME-GC-(ToF)MS analysis. Regression trees and random forests were used to predict “fresh cream” aroma perception, i.e., one of the main drivers of liking of processed cheeses, from the VOC release during swallowing. Agar-agar cheese models were perceived as having a “milk” odor and favored the release of a greater number of VOCs; κ-carrageenan samples were perceived as having a “granular” and “brittle” texture and a “salty” and “sour” taste and displayed a VOC retention capacity. Heating induced firmer cheese models and promoted Maillard VOCs responsible for “cooked” and “chemical” aroma perceptions. Octa-3,5-dien-2-one and octane-2,3-dione were the two main VOCs that contributed positively to the “fresh cream” aroma perception. Thus, regression trees and random forests are powerful statistical tools to provide a first insight into predicting the aroma of cheese models based on VOC characteristics.
Terminal Residue and Dietary Risk Assessment of Atrazine and Isoxaflutole in Corn Using High-Performance Liquid Chromatography–Tandem Mass Spectrometry
Authors: Cao Junli , Pei Tao , Wang Yonghui , Qin Shu , Qi Yanli , Ren Pengcheng , Li Jindong
Published: October 2023

Isoxaflutole and atrazine are representative pesticides for weed control in corn fields. Formulations containing these two pesticides have been registered in China, and their residues may threaten food safety and human health. In this study, a method for simultaneous determination of isoxaflutole, atrazine, and their metabolites in fresh corn, corn kernels, and corn straw was established based on modified QuEChERS pre-treatment and high-performance liquid chromatography–tandem mass spectrometry (HPLC–MS/MS). The linearity of seven compounds was good (R2 ≥ 0.9912), and the matrix effect was 48.5–77.1%. At four spiked levels of 0.01, 0.02, 0.05, and 0.5 mg kg−1, all compounds’ average recovery was 76% to 116%, with relative standard deviation (RSD) less than 18.9%. Field experiments were conducted in Liaoning, Heilongjiang, Inner Mongolia, Shanxi, Beijing, and Yunnan provinces to study the terminal residues. The terminal residues of all compounds were below the LOQ (0.01 mg kg−1) in fresh corn and corn kernels, and atrazine residues in corn straw ranged from <0.05 mg kg−1 to 0.17 mg kg−1. Finally, a dietary risk assessment was conducted based on residues from field trials, food consumption, and acceptable daily intake (ADI). For all populations, the chronic dietary risk probability (RQc) of atrazine was between 0.0185% and 0.0739%, while that of isoxaflutole was 0.0074–0.0296%, much lower than 100%. The results may provide scientific guidance for using isoxaflutole and atrazine in corn field ecosystems.
Editorial for the Special Issue: “Spatial Structure of Minerals”
Authors: Wu Dun , Hu Guangqing , Gao Yuhang
Published: October 2023

The spatial structure of minerals is a fundamental factor in determining the morphology, physical properties, and genesis of minerals [...]
Mitochondria-Targeted Lipid Nanoparticles Loaded with Rotenone as a New Approach for the Treatment of Oncological Diseases
Authors: Vasileva Leysan , Gaynanova Gulnara , Kuznetsova Darya , Valeeva Farida , Lyubina Anna , Amerhanova Syumbelya , Voloshina Alexandra , Sibgatullina Guzel , Samigullin Dmitry , Petrov Konstantin , Zakharova Lucia
Published: October 2023

This research is based on the concept that mitochondria are a promising target for anticancer therapy, including thatassociated with the use of oxidative phosphorylation blockers (mitochondrial poisons). Liposomes based on L-α-phosphatidylcholine (PC) and cholesterol (Chol) modified with cationic surfactants with triphenylphosphonium (TPPB-n, where n = 10, 12, 14, and 16) and imidazolium (IA-n(OH), where n = 10, 12, 14, and 16) head groups were obtained. The physicochemical characteristics of liposomes at different surfactant/lipid molar ratios were determined by dynamic/electrophoretic light scattering, transmission electron microscopy, and spectrophotometry. The hydrodynamic diameter of all the systems was within 120 nm with a polydispersity index of no more than 0.24 even after 2 months of storage. It was shown that cationization of liposomes leads to an increase in the internalization of nanocontainers in pancreatic carcinoma (PANC-1) and duodenal adenocarcinoma (HuTu 80) cells compared with unmodified liposomes. Also, using confocal microscopy, it was shown that liposomes modified with TPPB-14 and IA-14(OH) statistically better colocalize with the mitochondria of tumor cells compared with unmodified ones. At the next stage, the mitochondrial poison rotenone (ROT) was loaded into cationic liposomes. It was shown that the optimal loading concentration of ROT is 0.1 mg/mL. The Korsmeyer–Peppas and Higuchi kinetic models were used to describe the release mechanism of ROT from liposomes in vitro. A significant reduction in the IC50 value for the modified liposomes compared with free ROT was shown and, importantly, a higher degree of selectivity for the HuTu 80 cell line compared with the normal cells (SI value is 307 and 113 for PC/Chol/TPPB-14/ROT and PC/Chol/IA-14(OH)/ROT, respectively) occurred. It was shown that the treatment of HuTu 80 cells with ROT-loaded cationic liposomal formulations leads to a dose-dependent decrease in the mitochondrial membrane potential.
Relationships between Maternal Folic Acid Supplementation and GATA4 Gene Polymorphisms in Patients with Non-Chromosomal Congenital Heart Disease: A Hospital-Based Case–Control Study in China
Authors: Chen Letao , Yang Tubao , Wang Tingting , Sun Mengting , Qin Jiabi
Published: October 2023

This study aimed to investigate the relationships between maternal FA supplementation and nine single-nucleotide variants of the GATA4 gene in non-chromosomal CHD and further explore the gene–environment interactions associated with CHD. A total of 585 CHD patients and 600 controls were recruited in the case–control study. Maternal FA (FA-containing multivitamin) supplementation information and nine polymorphisms of the GATA4 gene were collected in this study. Adjusted ORs (aOR) and their 95% confidence intervals (CIs) were calculated using proper statistical methods to analyze the relationships between the two main exposures of interest with respect to CHD. After adjusting the suspicious confounding factors, a significantly increased risk for CHD in offspring was found with non-FA supplementation before/during the pregnancy to CHD in offspring (aOR = 1.58, 95% CI: 1.01–2.48). We suggested taking FA supplementation before/during the pregnancy to prevent CHD in offspring, especially in the preconception period (aOR = 0.53, 95% CI: 0.32–0.90). The genetic results showed that the polymorphisms of rs4841588, rs12458, and rs904018 under specific genotypes and genetic models were significantly related to CHD. The gene–environment interaction between rs10108052 and FA supplementation before/during pregnancy could increase the risk of CHD (aOR = 5.38, 95% CI: 1.67–17.09, Pinteraction = 0.004). Relationships between maternal FA supplementation and specific polymorphisms of the GATA4 gene, as well as the gene–environment interaction, were significantly associated with CHD in offspring.
Improvement of Locomotion Caused by Lactococcus lactis subsp. lactis in the Model Organism Caenorhabditis elegans
Authors: Ali Mohammad Shaokat , Ahmed Shamima , Takeuchi Shino , Wada Takayuki , Kage-Nakadai Eriko
Published: October 2023

Lactococcus lactis subsp. lactis exhibits probiotic properties in humans. Considering that Caenorhabditis elegans can be used to study the effects of microorganisms on animal behavior, owing to its simple nervous system, we assessed the impacts of two strains of Lactococcus lactis subsp. Lactis—a non-nisin-producing strain, NBRC 100933 (LL100933), and a nisin-producing strain, NBRC 12007 (LL12007)—on the lifespan, locomotion, reproductive capacity of, and lipid accumulation in, C. elegans. The lifespan of adult C. elegans fed a mixture (1:1) of Escherichia coli OP50 and LL100933 or LL12007 did not show a significant increase compared to that of the group fed a standard diet of E. coli OP50. However, the nematodes fed Lactococcus strains showed notable enhancement in their locomotion at all of the tested ages. Further, the beneficial effects of LL100933 and LL12007 were observed in the daf-16 mutants, but not in the skn-1 and pmk-1 mutants. The lipid accumulation in the worms of the Lactococcus-fed group was lower than that in the control group at all experimental ages. Overall, LL100933 and LL12007 enhance the locomotor behavior of C. elegans, likely by modulating the PMK-1/p38 MAPK and SKN-1/Nrf2 transcription factors.
Nutrient-Based Approaches for Melanoma: Prevention and Therapeutic Insights
Authors: Dong Yucheng , Wei Jiaxin , Yang Fan , Qu Yang , Huang Jiuzuo , Shi Di
Published: October 2023

Melanoma, a prevalent and lethal form of skin cancer, remains a formidable challenge in terms of prevention and treatment. While significant progress has been made in understanding its pathogenesis and treatment, the quest for effective prevention strategies and therapeutic approaches remains ongoing. Considering the increased advancements in understanding the dynamic interplay between nutrients and melanoma, we aim to offer a refreshed perspective on nutrient-based approaches for melanoma prevention and adjunctive therapy. In contrast to other studies, we have innovatively provided a detailed exposition of the nutrients’ influences on melanoma prognosis and treatment. This review firstly examines various nutrients, including antioxidants (namely vitamins A, D, C, and E; selenium; and caffeine), polyunsaturated fatty acids, and flavonoids, for their effects and underlying mechanisms in reducing melanoma risk. Among these nutrients, caffeine shows the most promising potential, as it is supported by multiple cohort studies for its protective effect against melanoma. In contrast, there is a certain degree of inconsistency in the research of other nutrients, possibly due to inherent differences between animal studies and epidemiological research, as well as variations in the definition of nutrient intake. To comprehensively investigate the impact of nutrients on melanoma progression and therapeutic approaches, the following sections will explore how nutrients influence immune responses and other physiological processes. While there is robust support from cell and animal studies regarding the immunomodulatory attributes of vitamins D and zinc, the anti-angiogenic potential of polyphenols, and the cell growth-inhibitory effects of flavonoids, the limited availability of human-based research substantially constrains their practical relevance in clinical contexts. As for utilizing nutrients in adjuvant melanoma treatments, multiple approaches have garnered clinical research support, including the utilization of vitamin D to decrease the postoperative recurrence rates among melanoma patients and the adoption of a high-fiber diet to enhance the effectiveness of immunotherapy. In general, the effects of most nutrients on reducing the risk of melanoma are not entirely clear. However, several nutrients, including vitamin D and dietary fiber, have demonstrated their potential to improve the melanoma prognosis and enhance the treatment outcomes, making them particularly deserving of clinical attention. A personalized and interdisciplinary approach, involving dermatologists, oncologists, nutritionists, and researchers, holds the promise of optimizing melanoma treatment strategies.
Palliative Care in Portugal—From Intention to Reality, What Is Yet to Be Accomplished
Authors: Marques Paulo , Rêgo Francisca , Nunes Rui
Published: October 2023

Objectives: This article focuses on exploring the evolution of palliative care in Portugal. Ten years after the approval of its Basic Law, the aim was to investigate the quality of the path followed and the guidelines that could promote its development. Thus, this study sought to identify (a) the goals of the current members of parliament concerning palliative care, (b) the major priorities that should guide the development of palliative care in the coming decade, (c) the facilitating or hindering factors to accelerating the process, and (d) to propose consensually agreed measures for the integral development of palliative care within the health system. Methods: The qualitative data analysis was performed through the reading of the literature and interviews conducted via Zoom with several intentionally chosen participants. The data extracted from the previous studies were analyzed in a focus group. The NVivo® 10 was used for the data processing and categorization. Results: Three key themes emerged concerning the current status of palliative care: the policymakers, the health professionals, and the society. This first line of structuring is explained by a second set of categories, namely, (a) the knowledge about palliative care; and (b) palliative care organization from the policymakers’ perspective. In the health professionals’ domain: (a) knowledge about palliative care, (b) clinical training, and (c) medical specialty. Finally, in society: (a) knowledge about palliative care. Significance of the results: Advancing general education, increasing the qualitative training for different health professionals, reformulating the laws supporting them, promoting the flexibility of the implementation methodologies, and establishing a medical specialty are crucial to achieving the proposed goal. This study was not registered.
Case Report and Literature Review: Bisphosphonate, Sirolimus, and Atenolol Treatment in a 4-Year-Old Child Diagnosed with Gorham–Stout Disease
Authors: Park Su Jin , Yoo Jae Won , Ahn Moon Bae
Published: October 2023

We report a 4-year-old with Gorham–Stout disease (GSD) who was treated with a combination of bisphosphonate, sirolimus, and atenolol. A previously healthy 4-year-old girl presented with back pain after falling on her back 2 months prior. Thoracolumbar spine X-ray revealed diffuse compression spinal fractures in T9-L2. Magnetic resonance imaging (MRI) confirmed multiple compression fractures at T9-L5 and revealed a paraspinal mass along the T1-L1 level. Based on clinical, radiological, and histopathological findings, Gorham–Stout disease was diagnosed. Treatment with sirolimus (0.5 mg twice daily, 1.6 mg/m2) was initiated and intravenous bisphosphonate (pamidronate, 1 mg/kg for 3 days, total 3 mg/kg every 4 months) was added for back pain; she had immediate improvement in back pain. After 9 months with this treatment, she had a mild increase in paraspinal lymphangiomatosis and aggravation in T9-L5 compression fractures; atenolol was administered. The patient underwent 11 months of combination treatment with bisphosphonate, sirolimus, and atenolol, and MRI showed mild degree of reduction in the paraspinal lesions at L1-L5. The patient is currently in stable condition with no back pain or side effects. The triple combination treatment with bisphosphonate, sirolimus, and atenolol may be helpful in stabilizing the disease course of GSD.
Influence of Extrudate-Based Textural Properties on Pellet Molding Quality
Authors: Tian Wenxiu , Li Xue , Li Wenjie , Xue Aile , Zheng Minyue , Lin Xiao , Hong Yanlong
Published: October 2023

As the precursor of pellets, the extrudate has a direct impact on the molding quality of the pellets. Therefore, the correlation between the surface roughness of the extrudates and the molding quality of pellets with pure microcrystalline cellulose (MCC) formulations and those containing traditional Chinese medicine (TCM) formulations was explored. MCC was used as a pelleting agent, mixer torque rheometry (MTR) was used to guide the optimal dosage of the wetting agent, and TCM extracts (drug loadings of 20% to 40%) were selected as model drugs to prepare the extrudates and pellets under the same extrusion spheronization process conditions. The surface roughness and texture parameters of extrudates were analyzed via a microscope and texture analyzer, respectively, and the quality of pellets was evaluated. The extrudate roughness of the pure MCC prescription decreased and then increased with increasing water addition, while the extrudate roughness of the prescription containing TCM extracts tended to increase and then decrease. The addition of water affected the extrudate properties, with TCM extract molecules filling gaps in the MCC structure, leading to rough surfaces. The extrudate roughness of the TCM prescriptions was significantly greater than that of the pure MCC prescriptions at optimal water addition levels, resulting in ideal pellets.
Novel Imaging Probes: From Design to Applications
Authors: Chen Kuo-Ting
Published: October 2023

Molecular imaging has emerged as a powerful tool for clinical diagnosis [...]
Comparative Investigation into the Roles of Imipenem:Cyclodextrin Complexation and Antibiotic Combination in Combatting Antimicrobial Resistance in Gram-Negative Bacteria
Authors: Farhan Sara Mahmoud , El-Baky Rehab Mahmoud Abd , Ahmed Hala Rady , Fathalla Zeinab , Alamri Ali , Abdelkader Hamdy , Fatease Adel Al
Published: October 2023

Extensively drug-resistant (XDR), multidrug-resistant (MDR) and pandrug-resistant (PDR) Gram-negative microorganisms (GNBs) are considered a significant global threat. β-lactam and aminoglycoside combinations and imipenem:cyclodextrin inclusion complexes were studied for the treatment of lethal GNBs. This is because of the broad empiric coverage of the two drugs and their possession of different spectra of activity. Two cyclodextrins (β- and hydroxy propyl β-cyclodextrins) were utilized for inclusion complex formation with imipenem using the physical and kneading methods. In silico investigation using the molecular docking and Fourier-infrared spectroscopy (FTIR) were employed to estimate binding constant and confirm complex formation, respectively. The in vitro effects of amikacin and imipenem combination in comparison to the effect of imipenem-β- and hydroxy propyl β-cyclodextrin (CD) complexes against Klebsiella spp. and Acinetobacter baumannii were studied. The isolated microorganisms’ antimicrobial responsiveness to various antibiotics (19 antibiotics) was evaluated. It was found that piperacillin/tazobactam and gentamycin (resistance rates were 33.3% and 34%, respectively) were the most effective antimicrobials. The in vitro studies have been performed by the checkerboard technique and time-killing assay. The studied combination of amikacin and imipenem showed a substantial drop in bacterial count (p < 0.05). The in vitro studies demonstrated a synergism for the investigated combination. Conventional PCR was used in molecular studies to identify the resistance genes bla IMP and aac (6′)-Ib. The blaIMP and aac (6′)-Ib were recorded in 38.2% and 3.6% of the studied isolates, respectively. The in vitro studies showed synergistic effects among the tested antibiotics with FICIs of ≤0.5. Finally, the study compared the reduction in bacterial count between the tested antibiotic combinations and imipenem:CD physical and kneaded mixtures. Imipenem:CD inclusion complexes demonstrated a significant bacterial count reduction over the antibiotic combination. These results highlight the emerging role of CDs as safe biofunctional excipients in the combat against superbug bacterial resistance.
Resensitisation of Methicillin-Resistant Staphylococcus aureus to Conventional Antibiotics in the Presence of an Engineered Enzybiotic
Authors: Manoharadas Salim , Al-Rayes Basel F. , Almuzaini Mohammed Abdulaziz M. , Almohammadi Yasser Muteq
Published: October 2023

Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most dreadful pathogens relevant in community and nosocomial-related infections around the world. Resensitising MRSA to antibiotics, once it became resistant, was a tough choice due to the high adaptability of this bacteria to savage conditions. This study aimed to create a chimeric enzybiotic against MRSA and test its efficiency, either individually or in combination with antibiotics. The novel enzybiotic BAC100 was constructed by fusing the catalytic domain from the bacteriocin BacL1 from Enterococcus faecalis with the cell-wall-binding domain from protein P17 of Staphylococcus aureus bacteriophage ϕ44AHJD. Apart from its partial lone activity, BAC100 was found to resensitise the MRSA strain to traditional antibiotics, including ampicillin and tetracycline. Both drugs were able to reduce live MRSA cells by 85 and 90%, respectively, within 60 min of treatment together with BAC100. However, no significant activity was observed against MRSA when these drugs were tested independently, pointing to the inherent resistance of MRSA against these conventional antibiotics. To our knowledge, this is one of the first instances where an engineered enzybiotic was found to resensitise MRSA to conventional antibiotics. This study will pave the way for the development of similar peptides that can be used together with antibiotics against gruesome pathogens of clinical importance.
Evaluation of Oromucosal Natural Gum-Based Emulgels as Novel Strategy for Photodynamic Therapy of Oral Premalignant Lesions
Authors: Szymańska Emilia , Potaś Joanna , Baranowski Marcin , Czarnomysy Robert , Sulewska Magdalena Ewa , Basa Anna , Pietruska Małgorzata , Bielawski Krzysztof , Winnicka Katarzyna
Published: October 2023

Photodynamic therapy (PDT) recently has been shown as a promising option in the treatment of premalignant lesions of the soft oral tissues. Effective delivery of photosensitizer is challenging due to poor drug adherence to the oromucosal epithelium. In the present work, emulgels composed of natural polysaccharide gums (tragacanth, xanthan and gellan) were evaluated as novel oromucosal platforms of delta-aminolevulinic acid (ALA) for PDT. Apart from mucoadhesive and textural analysis, the specific steps involved studies on drug penetration behavior and safety profile using a three-dimensional human oral epithelium model (HOE). All designed emulgels presented greater mucoadhesiveness when compared to commercial oromucosal gel. Incorporation of ALA affected textural properties of emulgels, and tragacanth/xanthan formulation with greater hardness and cohesiveness exhibited a protective function against the mechanical tongue stress. Permeability studies revealed that ALA is capable of penetrating across oromucosal epithelium by passive transport and all formulations promoted its absorption rate when compared to a commercial topical product with ALA. Importantly, the combination of tragacanth and xanthan profoundly enhanced photosensitizer retention in the buccal epithelium. Tested samples performed negligible reduction in cell viability and moderately low IL-1β release, confirming their non-irritancy and compatibility with HOE. Overall, the presented findings indicate that tragacanth/xanthan emulgel holds promise as an oromucosal ALA-carrier for PDT strategy.
Molecular Insights to the Structure-Interaction Relationships of Human Proton-Coupled Oligopeptide Transporters (PepTs)
Authors: Luo Yining , Gao Jingchun , Jiang Xukai , Zhu Ling , Zhou Qi Tony , Murray Michael , Li Jian , Zhou Fanfan
Published: October 2023

Human proton-coupled oligopeptide transporters (PepTs) are important membrane influx transporters that facilitate the cellular uptake of many drugs including ACE inhibitors and antibiotics. PepTs mediate the absorption of di- and tri-peptides from dietary proteins or gastrointestinal secretions, facilitate the reabsorption of peptide-bound amino acids in the kidney, and regulate neuropeptide homeostasis in extracellular fluids. PepT1 and PepT2 have been the most intensively investigated of all PepT isoforms. Modulating the interactions of PepTs and their drug substrates could influence treatment outcomes and adverse effects with certain therapies. In recent studies, topology models and protein structures of PepTs have been developed. The aim of this review was to summarise the current knowledge regarding structure-interaction relationships (SIRs) of PepTs and their substrates as well as the potential applications of this information in therapeutic optimisation and drug development. Such information may provide insights into the efficacy of PepT drug substrates in patients, mechanisms of drug–drug/food interactions and the potential role of PepTs targeting in drug design and development strategies.