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Open AccessArticle

Palmitate-Induced Cardiac Lipotoxicity Is Relieved by the Redox-Active Motif of SELENOT through Improving Mitochondrial Function and Regulating Metabolic State

Cells 2023, 12(7), 1042; https://doi.org/10.3390/cells12071042 (registering DOI) - 29 Mar 2023

Abstract

Cardiac lipotoxicity is an important contributor to cardiovascular complications during obesity. Given the fundamental role of the endoplasmic reticulum (ER)-resident Selenoprotein T (SELENOT) for cardiomyocyte differentiation and protection and for the regulation of glucose metabolism, we took advantage of a small peptide (PSELT), [...] Read more.

Cardiac lipotoxicity is an important contributor to cardiovascular complications during obesity. Given the fundamental role of the endoplasmic reticulum (ER)-resident Selenoprotein T (SELENOT) for cardiomyocyte differentiation and protection and for the regulation of glucose metabolism, we took advantage of a small peptide (PSELT), derived from the SELENOT redox-active motif, to uncover the mechanisms through which PSELT could protect cardiomyocytes against lipotoxicity. To this aim, we modeled cardiac lipotoxicity by exposing H9c2 cardiomyocytes to palmitate (PA). The results showed that PSELT counteracted PA-induced cell death, lactate dehydrogenase release, and the accumulation of intracellular lipid droplets, while an inert form of the peptide (I-PSELT) lacking selenocysteine was not active against PA-induced cardiomyocyte death. Mechanistically, PSELT counteracted PA-induced cytosolic and mitochondrial oxidative stress and rescued SELENOT expression that was downregulated by PA through FAT/CD36 (cluster of differentiation 36/fatty acid translocase), the main transporter of fatty acids in the heart. Immunofluorescence analysis indicated that PSELT also relieved the PA-dependent increase in CD36 expression, while in SELENOT-deficient cardiomyocytes, PA exacerbated cell death, which was not mitigated by exogenous PSELT. On the other hand, PSELT improved mitochondrial respiration during PA treatment and regulated mitochondrial biogenesis and dynamics, preventing the PA-provoked decrease in PGC1-α and increase in DRP-1 and OPA-1. These findings were corroborated by transmission electron microscopy (TEM), revealing that PSELT improved the cardiomyocyte and mitochondrial ultrastructures and restored the ER network. Spectroscopic characterization indicated that PSELT significantly attenuated infrared spectral-related macromolecular changes (i.e., content of lipids, proteins, nucleic acids, and carbohydrates) and also prevented the decrease in membrane fluidity induced by PA. Our findings further delineate the biological significance of SELENOT in cardiomyocytes and indicate the potential of its mimetic PSELT as a protective agent for counteracting cardiac lipotoxicity. Full article

(This article belongs to the Special Issue Oxidative Stress and Antioxidant Strategies: Relationships and Cellular Pathways for Human Health)

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Open AccessArticle

Theoretical Advancements on a Few New Dependence Models Based on Copulas with an Original Ratio Form

by

Christophe Chesneau

Modelling 2023, 4(2), 102-132; https://doi.org/10.3390/modelling4020008 (registering DOI) - 29 Mar 2023

Abstract

Copulas are well-known tools for describing the relationship between two or more quantitative variables. They have recently received a lot of attention, owing to the variable dependence complexity that appears in heterogeneous modern problems. In this paper, we offer five new copulas based [...] Read more.

Copulas are well-known tools for describing the relationship between two or more quantitative variables. They have recently received a lot of attention, owing to the variable dependence complexity that appears in heterogeneous modern problems. In this paper, we offer five new copulas based on a common original ratio form. All of them are defined with a single tuning parameter, and all reduce to the independence copula when this parameter is equal to zero. Wide admissible domains for this parameter are established, and the mathematical developments primarily rely on non-trivial limits, two-dimensional differentiations, suitable factorizations, and mathematical inequalities. The corresponding functions and characteristics of the proposed copulas are looked at in some important details. In particular, as common features, it is shown that they are diagonally symmetric, but not Archimedean, not radially symmetric, and without tail dependence. The theory is illustrated with numerical tables and graphics. A final part discusses the multi-dimensional variation of our original ratio form. The contributions are primarily theoretical, but they provide the framework for cutting-edge dependence models that have potential applications across a wide range of fields. Some established two-dimensional inequalities may be of interest beyond the purposes of this paper. Full article

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Open AccessArticle

Modelling of Electric Bus Operation and Charging Process: Potential Contribution of Local Photovoltaic Production

by

Nathanael Dougier

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Berk Celik

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Salim-Kinnou Chabi-Sika

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Manuela Sechilariu

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Fabrice Locment

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Justin Emery

Appl. Sci. 2023, 13(7), 4372; https://doi.org/10.3390/app13074372 (registering DOI) - 29 Mar 2023

Abstract

The transition from diesel to electric buses allows the reduction of greenhouse gas emissions. However, the impacts of charging strategies on the quality of bus services and the utility grid must be assessed to ensure the feasibility of the energy transition in the [...] Read more.

The transition from diesel to electric buses allows the reduction of greenhouse gas emissions. However, the impacts of charging strategies on the quality of bus services and the utility grid must be assessed to ensure the feasibility of the energy transition in the public transportation sector. This study investigates the performances of different locations and sizes of charging infrastructures by presenting the comprehensive modelling of a bus network. It also estimates the potential benefits of a local photovoltaic (PV) production to reduce negative impacts on the utility grid. The presented approach is used for modelling one urban bus line in Compiègne, France, and simulations are performed for various case studies. The results demonstrate that the proposed method allows analysing the impact of the charging process on the quality of bus services by determining the delays of arrivals. The simulations also show the impacts of charger placement on bus on-board battery capacity, total peak power demand of battery charging, and PV self-consumption ratio. The amount of PV energy used directly to charge buses remains low, although it varies between scenarios. PV energy during winter is not sufficient to fully charge buses; however, it can be enough with additional stationary storage in the summer. Full article

(This article belongs to the Special Issue Photovoltaic Power System: Modeling and Performance Analysis)

Open AccessArticle

Dynamical Systems Analysis of f(Q) Gravity

by

Christian Böhmer

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Erik Jensko

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Ruth Lazkoz

Universe 2023, 9(4), 166; https://doi.org/10.3390/universe9040166 (registering DOI) - 29 Mar 2023

Abstract

Modified gravity theories can be used for the description of homogeneous and isotropic cosmological models through the corresponding field equations. These can be cast into systems of autonomous differential equations because of their sole dependence on a well-chosen time variable, be it the [...] Read more.

Modified gravity theories can be used for the description of homogeneous and isotropic cosmological models through the corresponding field equations. These can be cast into systems of autonomous differential equations because of their sole dependence on a well-chosen time variable, be it the cosmological time, or an alternative. For that reason, a dynamical systems approach offers a reliable route to study those equations. Through a model-independent set of variables, we are able to study all

f (Q)

modified gravity models. The drawback of the procedure is a more complicated constraint equation. However, it allows the dynamical system to be formulated in fewer dimensions than using other approaches. We focus on a recent model of interest, the power-exponential model, and generalize the fluid content of the model. Full article

(This article belongs to the Special Issue Modified Gravity Approaches to the Tensions of ΛCDM)

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Open AccessArticle

Effect of Metal Complexing on Mn–Fe/TS-1 Catalysts for Selective Catalytic Reduction of NO with NH₃

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Molecules 2023, 28(7), 3068; https://doi.org/10.3390/molecules28073068 (registering DOI) - 29 Mar 2023

Abstract

TS-1 zeolite with desirable pore structure, an abundance of acidic sites, and good thermal stability promising as a support for the selective catalytic reduction of NO with NH₃ (NH₃-SCR). Herein, a series of Mn–Fe/TS-1 catalysts have been synthesized, adopting tetraethylenepentamine [...] Read more.

TS-1 zeolite with desirable pore structure, an abundance of acidic sites, and good thermal stability promising as a support for the selective catalytic reduction of NO with NH₃ (NH₃-SCR). Herein, a series of Mn–Fe/TS-1 catalysts have been synthesized, adopting tetraethylenepentamine (TEPA) as a metal complexing agent using the one-pot hydrothermal method. The introduced TEPA can not only increase the loading of active components but also prompts the formation of a hierarchical structure through decreasing the size of TS-1 nanocrystals to produce intercrystalline mesopores during the hydrothermal crystallization process. The optimized Mn–Fe/TS-1(R-2) catalyst shows remarkable NH₃-SCR performance. Moreover, it exhibits excellent resistance to H₂O and SO₂ at low temperatures. The characterization results indicate that Mn–Fe/TS-1(R-2) possesses abundant surface Mn⁴⁺ and Fe²⁺ and chemisorbed oxygen, strong reducibility, and a high Brønsted acid amount. For comparison, Mn–Fe/TiO₂ displays a narrower active temperature window due to its poor thermostability. Full article

(This article belongs to the Special Issue Synthesis and Applications of Transition Metal Complexes)

Open AccessArticle

Effects of Dietary Intervention Using Spirulina at Graded Levels on Productive Performance and Physiological Status of Quail Birds Reared under Elevated Temperatures

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Agriculture 2023, 13(4), 789; https://doi.org/10.3390/agriculture13040789 (registering DOI) - 29 Mar 2023

Abstract

The current study aimed to explore the effect of Spirulina platensis (SP) inclusion at various levels in quail diets, in terms of their production performance, physiological traits, stress measurements, and immunological parameters under heat stress (HS) conditions. Four hundred Japanese quail (Coturnix [...] Read more.

The current study aimed to explore the effect of Spirulina platensis (SP) inclusion at various levels in quail diets, in terms of their production performance, physiological traits, stress measurements, and immunological parameters under heat stress (HS) conditions. Four hundred Japanese quail (Coturnix japonica) chicks, one day old, were equally distributed into forty wire cages, and the cages were placed in two chambers with environmentally controlled systems (20 cages in each chamber). From 21 to 42 d of age, the quails were randomly subjected to a factorial design of two HS treatments × four SP treatments. To induce HS treatments in the quails, the first chamber was maintained at a thermoneutral temperature of 24 °C (TN group), while the temperature of the second chamber was elevated to 35 °C during the daytime (9:00–17:00 h), followed by a thermoneutral temperature for the remaining 24 h cycle (HS group). The birds in each chamber were further allocated into four SP treatments (5 replicate cages × 10 birds per cage in each treatment), where the quails were fed on a basal diet that included 0, 5, 10, or 15 g/kg SP (SP0, SP5, SP10, and SP15 groups, respectively). After exposure to the HS, a significant (p < 0.05) reduction of 5% in body weight and 9% in both weight gain and feed intake was recorded, and the slaughter performance of the quails was adversely (p < 0.05) affected. In addition, HS significantly (p < 0.05) impaired the physiological traits (total protein, albumin, globulin, alanine transferase, aspartate transferase, creatinine, uric acid, cholesterol, and triglycerides) and immunological parameters (total white blood cells, heterophil to lymphocyte ratio, and T- and B-lymphocyte stimulation indexes), but increased the stress measurements (corticosterone, malondialdehyde, interleukin-1β, and tumor necrosis factor-α). In contrast, most of these parameters were linearly (p < 0.05) improved by increasing the SP levels in the diets of the TN quail group. When the SP was included in the diets of the HS quail group, the deleterious effects of HS on the alanine and aspartate transferase activities, creatinine, uric acid, triglycerides, corticosterone, interleukin-1β, and tumor necrosis factor-α levels, heterophil to lymphocyte ratio, and T- and B-lymphocyte stimulation indexes were remarkably (p < 0.05) relieved. These results concluded that SP nutritional application can improve the production performance and the overall physiological homeostasis of the Japanese quail, especially when suffering from heat stress. Full article

(This article belongs to the Special Issue Effects of Dietary Interventions on Poultry Production)

Open AccessReview

Update on the Utility of Optical Coherence Tomography in the Analysis of the Optic Nerve Head in Highly Myopic Eyes with and without Glaucoma

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Bachar Kudsieh

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José Ignacio Fernández-Vigo

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Ignacio Flores-Moreno

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Jorge Ruiz-Medrano

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Maria Garcia-Zamora

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Muhsen Samaan

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Jose Maria Ruiz-Moreno

J. Clin. Med. 2023, 12(7), 2592; https://doi.org/10.3390/jcm12072592 (registering DOI) - 29 Mar 2023

Abstract

Glaucoma diagnosis in highly myopic subjects by optic nerve head (ONH) imaging is challenging as it is difficult to distinguish structural defects related to glaucoma from myopia-related defects in these subjects. Optical coherence tomography (OCT) has evolved to become a routine examination at [...] Read more.

Glaucoma diagnosis in highly myopic subjects by optic nerve head (ONH) imaging is challenging as it is difficult to distinguish structural defects related to glaucoma from myopia-related defects in these subjects. Optical coherence tomography (OCT) has evolved to become a routine examination at present, providing key information in the assessment of glaucoma based on the study of the ONH. However, the correct segmentation and interpretation of the ONH data employing OCT is still a challenge in highly myopic patients. High-resolution OCT images can help qualitatively and quantitatively describe the structural characteristics and anatomical changes in highly myopic subjects with and without glaucoma. The ONH and peripapillary area can be analyzed to measure the myopic atrophic-related zone, the existence of intrachoroidal cavitation, staphyloma, and ONH pits by OCT. Similarly, the lamina cribosa observed in the OCT images may reveal anatomical changes that justify visual defects. Several quantitative parameters of the ONH obtained from OCT images were proposed to predict the progression of visual defects in glaucoma subjects. Additionally, OCT images help identify factors that may negatively influence the measurement of the retinal nerve fiber layer (RNFL) and provide better analysis using new parameters, such as Bruch’s Membrane Opening-Minimum Rim Width, which serves as an alternative to RNFL measurements in highly myopic subjects due to its superior diagnostic ability. Full article

(This article belongs to the Special Issue Clinical Utility of Optical Coherence Tomography in Ophthalmology)

Open AccessArticle

A Simple Neural-Network-Based Decoder for Short Binary Linear Block Codes

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Appl. Sci. 2023, 13(7), 4371; https://doi.org/10.3390/app13074371 (registering DOI) - 29 Mar 2023

Abstract

The conventional soft decision decoding (SDD) methods require various hard decision decoders (HDDs) based on different codes or re-manipulate the generator matrix by the complicated Gaussian elimination technique according to the bit reliability. This paper presents a general multi-class neural network (NN)-based decoder [...] Read more.

The conventional soft decision decoding (SDD) methods require various hard decision decoders (HDDs) based on different codes or re-manipulate the generator matrix by the complicated Gaussian elimination technique according to the bit reliability. This paper presents a general multi-class neural network (NN)-based decoder for the short linear block codes, where no HDD and Gaussian elimination are required once the NN is constructed. This network architecture performs multi-classification to select the messages with high occurrence probabilities and chooses the best codeword on a maximum likelihood basis. Simulation results show that the developed approach outperforms the existing deep neural network (DNN)-based decoders in terms of decoding time and bit error rate (BER). The error-correcting performance is also superior to the conventional Chase-II algorithm and is close to the ordered statistics decoding (OSD) in most cases. For Bose–Chaudhuri–Hocquenghem (BCH) codes, the SNR is improved by 1dB to 4dB as the BER is 10⁻⁴. For the (23, 12) quadratic residue (QR) code, the SNR is improved by 2dB when the BER is 10⁻³. The developed NN-based decoder is quite general and applicable to various short linear block codes with good BER performance. Full article

Open AccessArticle

Temporal Multimodal Data-Processing Algorithms Based on Algebraic System of Aggregates

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Algorithms 2023, 16(4), 186; https://doi.org/10.3390/a16040186 (registering DOI) - 29 Mar 2023

Abstract

In many tasks related to an object’s observation or real-time monitoring, the gathering of temporal multimodal data is required. Such data sets are semantically connected as they reflect different aspects of the same object. However, data sets of different modalities are usually stored [...] Read more.

In many tasks related to an object’s observation or real-time monitoring, the gathering of temporal multimodal data is required. Such data sets are semantically connected as they reflect different aspects of the same object. However, data sets of different modalities are usually stored and processed independently. This paper presents an approach based on the application of the Algebraic System of Aggregates (ASA) operations that enable the creation of an object’s complex representation, referred to as multi-image (MI). The representation of temporal multimodal data sets as the object’s MI yields simple data-processing procedures as it provides a solid semantic connection between data describing different features of the same object, process, or phenomenon. In terms of software development, the MI is a complex data structure used for data processing with ASA operations. This paper provides a detailed presentation of this concept. Full article

(This article belongs to the Collection Feature Paper in Algorithms and Complexity Theory)

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Open AccessSystematic Review

MRONJ Treatment Strategies: A Systematic Review and Two Case Reports

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Angelo Michele Inchingolo

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Merigrazia Campanelli

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Alessio Danilo Inchingolo

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Gianna Dipalma

Appl. Sci. 2023, 13(7), 4370; https://doi.org/10.3390/app13074370 (registering DOI) - 29 Mar 2023

Abstract

MRONJ is a serious drug-related side effect that is most common in people using antiresorptive and/or angiogenic medications. Therapy options for this condition include conservative treatments, surgical procedures with varied degrees of invasiveness, and adjuvant therapies. The aim of the present study is [...] Read more.

MRONJ is a serious drug-related side effect that is most common in people using antiresorptive and/or angiogenic medications. Therapy options for this condition include conservative treatments, surgical procedures with varied degrees of invasiveness, and adjuvant therapies. The aim of the present study is to identify the most successful and promising therapy alternatives available to clinicians. PubMed, Cochrane, Scopus, Web of Science, and Embase were searched for works on our topic published between 8 January 2006 and 8 January 2023. The search was restricted to randomized clinical trials, retrospective studies, clinical studies, and case series involving human subjects with at least five cases and no age restriction on participants. A total of 2657 was found. After the selection process, the review included 32 publications for qualitative analysis. Although conservative treatments (pharmacological, laser, and minimally invasive surgery) are effective in the early stages of MRONJs or as a supplement to traditional surgical resection therapy, most studies emphasize the importance of surgical treatment for the resolution or downstaging of advanced lesions. Fluorescence-guided surgery, PRP, PRF, CGF, piezosurgery, VEGF, hyaluronic acid, and ozone therapy all show significant potential for improving treatment outcomes. Full article

(This article belongs to the Special Issue Dentistry, Orthodontics and Maxillo-Facial Surgery, Traditional and Smart Approaches)

Open AccessArticle

Study on the Dynamic Generation of Subcooled Water Using a Compact Heat Exchanger

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Pengwei Cheng

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Kaijian Wang

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Solomon Sinkolongo

Appl. Sci. 2023, 13(7), 4369; https://doi.org/10.3390/app13074369 (registering DOI) - 29 Mar 2023

Abstract

The dynamic generation of ice slurry from subcooled water is one of the most promising ways to make ice; this process is utilized widely in ice storage air-conditioning systems. However, the random occurrence of ice blockage during the generation of subcooled water using [...] Read more.

The dynamic generation of ice slurry from subcooled water is one of the most promising ways to make ice; this process is utilized widely in ice storage air-conditioning systems. However, the random occurrence of ice blockage during the generation of subcooled water using conventional heat exchangers prevents the increase in subcooling, thereby reducing the efficiency of the release of the subcooled water and converting it into ice slurry. A more efficient approach to reducing the fluid passage time is to employ a compact heat exchanger with a highly efficient heat transfer performance, a heat transfer length of only 21.5 mm, and a hydraulic diameter of 0.32 mm. A compact heat exchanger was used to build a dynamic generation setup for subcooled water, and 40 wt% of non-freezing liquid and tap water was used as the working fluid for heat exchange to generate subcooled water. The results show that the compact heat exchanger can achieve a greater subcooling degree (3.8 K) and longer duration (108 min). This study further explored the potential for dynamic ice making from deep, subcooled water and improved the overall structure of the compact heat exchanger used. The experimental setup is recommended based on the analysis of the results. Full article

(This article belongs to the Special Issue The10th Asian Conference on Refrigeration and Air-Conditioning (ACRA2022))

Open AccessArticle

Certain Properties and Applications of Convoluted Δ_h Multi-Variate Hermite and Appell Sequences

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Shahid Ahmad Wani

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Ibtehal Alazman

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Badr Saad T. Alkahtani

Symmetry 2023, 15(4), 828; https://doi.org/10.3390/sym15040828 (registering DOI) - 29 Mar 2023

Abstract

This study follows the line of research that by employing the monomiality principle, new outcomes are produced. Thus, in line with prior facts, our aim is to introduce the

Δ_{h}

multi-variate Hermite Appell polynomials [...] Read more.

This study follows the line of research that by employing the monomiality principle, new outcomes are produced. Thus, in line with prior facts, our aim is to introduce the

Δ_{h}

multi-variate Hermite Appell polynomials

_{Δ_{h}}_{H} A_{m}^{[r]} (q_{1}, q_{2}, \dots, q_{r}; h)

. Further, we obtain their recurrence sort of relations by using difference operators. Furthermore, symmetric identities satisfied by these polynomials are established. The operational rules are helpful in demonstrating the novel characteristics of the polynomial families and thus operational principle satisfied by these polynomials is derived and will prove beneficial for future observations. Further, a few members of the

Δ_{h}

Appell polynomial family are considered and their corresponding results are derived accordingly. Full article

(This article belongs to the Special Issue New Advances in Special Functions and Their Applications in Science and Mathematics)

Open AccessCommunication

Progressive Motor and Non-Motor Symptoms in Park7 Knockout Zebrafish

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Lakshmi Narasimha Murthy Chavali

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Sushma N. Grellscheid

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Kari E. Fladmark

Int. J. Mol. Sci. 2023, 24(7), 6456; https://doi.org/10.3390/ijms24076456 (registering DOI) - 29 Mar 2023

Abstract

DJ-1 is a redox sensitive protein with a wide range of functions related to oxidative stress protection. Mutations in the park7 gene, which codes for DJ-1 are associated with early onset familial Parkinson’s disease and increased astrocytic DJ-1 levels are found in pathologic [...] Read more.

DJ-1 is a redox sensitive protein with a wide range of functions related to oxidative stress protection. Mutations in the park7 gene, which codes for DJ-1 are associated with early onset familial Parkinson’s disease and increased astrocytic DJ-1 levels are found in pathologic tissues from idiopathic Parkinson’s disease. We have previously established a DJ-1 knockout zebrafish line that developed normally, but with aging the DJ-1 null fish had a lowered level of tyrosine hydroxylase, respiratory mitochondrial failure and a lower body mass. Here we have examined the DJ-1 knockout from the early adult stage and show that loss of DJ-1 results in a progressive, age-dependent increase in both motoric and non-motoric symptoms associated to Parkinson’s disease. These changes coincide with changes in mitochondrial and mitochondrial associated proteins. Recent studies have suggested that a decline in NAD+ can contribute to Parkinson’s disease and that supplementation of NAD+ precursors may delay disease progression. We found that the brain NAD+/NADH ratio decreased in aging zebrafish but did not correlate with DJ-1 induced altered behavior. Differences were first observed at the late adult stage in which NAD+ and NADPH levels were decreased in DJ-1 knockouts. Considering the experimental power of zebrafish and the development of Parkinson’s disease-related symptoms in the DJ-1 null fish, this model can serve as a useful tool both to understand the progression of the disease and the effect of suggested treatments. Full article

(This article belongs to the Special Issue Insights into Park7 (DJ-1), a Multifunctional Protein Links to Parkinson Disease)

Open AccessArticle

Grain Refinement Mechanism of 5A06 Aluminum Alloy Sheets during Cold Rotary Forging

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Materials 2023, 16(7), 2754; https://doi.org/10.3390/ma16072754 (registering DOI) - 29 Mar 2023

Abstract

This paper studies the grain refinement mechanisms of 5A06 aluminum alloy sheets in cold rotary forging (CRF). The results show that the grains are clearly refined from 25.1 µm to 11.8 µm during the CRF process. The grain refinement mechanism can be divided [...] Read more.

This paper studies the grain refinement mechanisms of 5A06 aluminum alloy sheets in cold rotary forging (CRF). The results show that the grains are clearly refined from 25.1 µm to 11.8 µm during the CRF process. The grain refinement mechanism can be divided into two modes: (1) The grains with a small Schmid factor (SF) are activated by multi-slip systems, and dense dislocations are segregated along the boundaries of interior regions with different slip systems, which results in a rapidly increasing strain localization along these boundaries. Since the strain localization restrains the coordinate slip deformation between different interior regions, the grains are directly separated into several finer grains. (2) The grains with a large SF are primarily activated by a single slip system, and the dislocation migrates smoothly along most microband boundaries. Then, a more severe lattice rotation causes a transformation to a hard orientation and multi-slip system activation, which contributes to an increase in the rapid misorientation across microband boundaries and thus promotes significant SF grain refinement. Full article

Open AccessArticle

Analysis of Cantilever Triple-Layer Piezoelectric Harvester (CTLPH): Non-Resonance Applications

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Mojtaba Ghodsi

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Morteza Mohammadzaheri

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Payam Soltani

Energies 2023, 16(7), 3129; https://doi.org/10.3390/en16073129 (registering DOI) - 29 Mar 2023

Abstract

In this research, a design guideline for a kinetic energy converter using a cantilever triple-layer piezoelectric harvester (CTLPH) for low-frequency applications is presented. By combining the constitutive and internal energy equations, the analytical equations for harvested voltage and power were developed. It was [...] Read more.

In this research, a design guideline for a kinetic energy converter using a cantilever triple-layer piezoelectric harvester (CTLPH) for low-frequency applications is presented. By combining the constitutive and internal energy equations, the analytical equations for harvested voltage and power were developed. It was also found that frequency of motion, applied tip force, piezoelectric coefficients, geometrical dimensions, and mechanical properties of layers play significant roles in the performance of the harvester. Having characterised the voltage regulator module, LTC3588, the dependency of output voltage on both the storage and output capacitors of the LTC3588 was investigated. An experimental measurement using the optical method was carried out to determine the applied tip force. Furthermore, the performance of the CTLPH in low frequencies (< 3.3 Hz) for various resistive loads was investigated. It was found that both excitation frequency and external resistance load are effective on the maximum generated power. The developed CTLPH shows the optimum power of 17.31at the external resistance of 20 kΩ, which is highly appropriate for micropower devices with at least 3.2 Hz of kinetic vibration in their environment. Full article

(This article belongs to the Special Issue Recent Advances and Future Challenges in Energy Applications and Control of Piezoelectric Actuators)

Open AccessArticle

Measurement Properties of the Dutch Multifactor Fatigue Scale in Early and Late Rehabilitation of Acquired Brain Injury in Denmark

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Frederik Lehman Dornonville de la Cour

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Trine Schow

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Tonny Elmose Andersen

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Annemarie Hilkjær Petersen

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Gry Zornhagen

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Annemarie C. Visser-Keizer

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Anne Norup

J. Clin. Med. 2023, 12(7), 2587; https://doi.org/10.3390/jcm12072587 (registering DOI) - 29 Mar 2023

Abstract

Fatigue is a major issue in neurorehabilitation without a gold standard for assessment. The purpose of this study was to evaluate measurement properties of the five subscales of the self-report questionnaire the Dutch Multifactor Fatigue Scale (DMFS) among Danish adults with acquired brain [...] Read more.

Fatigue is a major issue in neurorehabilitation without a gold standard for assessment. The purpose of this study was to evaluate measurement properties of the five subscales of the self-report questionnaire the Dutch Multifactor Fatigue Scale (DMFS) among Danish adults with acquired brain injury. A multicenter study was conducted (N = 149, 92.6% with stroke), including a stroke unit and three community-based rehabilitation centers. Unidimensionality and measurement invariance across rehabilitation settings were tested using confirmatory factor analysis. External validity with Depression Anxiety Stress Scales (DASS-21) and the EQ-5D-5L was investigated using correlational analysis. Results were mixed. Unidimensionality and partial invariance were supported for the Impact of Fatigue, Mental Fatigue, and Signs and Direct Consequences of Fatigue, range: RMSEA = 0.07–0.08, CFI = 0.94–0.99, ω = 0.78–0.90. Coping with Fatigue provided poor model fit, RMSEA = 0.15, CFI = 0.81, ω = 0.46, and Physical Fatigue exhibited local dependence. Correlations among the DMFS, DASS-21, and EQ-5D-5L were in expected directions but in larger magnitudes compared to previous research. In conclusion, three subscales of the DMFS are recommended for assessing fatigue in early and late rehabilitation, and these may facilitate the targeting of interventions across transitions in neurorehabilitation. Subscales were strongly interrelated, and the factor solution needs evaluation. Full article

(This article belongs to the Special Issue New Perspectives in Rehabilitation after Traumatic Brain Injury: Volume 2)

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Open AccessArticle

Novel Strategy for Surface Modification of Titanium Implants towards the Improvement of Osseointegration Property and Antibiotic Local Delivery

by

Isabela da Rocha Silva

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Aline Tavares da Silva Barreto

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Renata Santos Seixas

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Paula Nunes Guimarães Paes

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Juliana do Nascimento Lunz

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Rossana Mara da Silva Moreira Thiré

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Paula Mendes Jardim

Materials 2023, 16(7), 2755; https://doi.org/10.3390/ma16072755 (registering DOI) - 29 Mar 2023

Abstract

The topography and chemical composition modification of titanium (Ti) implants play a decisive role in improving biocompatibility and bioactivity, accelerating osseointegration, and, thus, determining clinical success. In spite of the development of surface modification strategies, bacterial contamination is a common cause of failure. [...] Read more.

The topography and chemical composition modification of titanium (Ti) implants play a decisive role in improving biocompatibility and bioactivity, accelerating osseointegration, and, thus, determining clinical success. In spite of the development of surface modification strategies, bacterial contamination is a common cause of failure. The use of systemic antibiotic therapy does not guarantee action at the contaminated site. In this work, we proposed a surface treatment for Ti implants that aim to improve their osseointegration and reduce bacterial colonization in surgery sites due to the local release of antibiotic. The Ti discs were hydrothermally treated with 3M NaOH solution to form a nanostructured layer of titanate on the Ti surface. Metronidazole was impregnated on these nanostructured surfaces to enable its local release. The samples were coated with poly(vinyl alcohol)—PVA films with different thickness to evaluate a possible control of drug release. Gamma irradiation was used to crosslink the polymer chains to achieve hydrogel layer formation and to sterilize the samples. The samples were characterized by XRD, SEM, FTIR, contact angle measurements, “in vitro” bioactivity, and drug release analysis. The alkaline hydrothermal treatment successfully produced intertwined, web-like nanostructures on the Ti surface, providing wettability and bioactivity to the Ti samples (Ti + TTNT samples). Metronidazole was successfully loaded and released from the Ti + TTNT samples coated or not with PVA. Although the polymeric film acted as a physical barrier to drug delivery, all groups reached the minimum inhibitory concentration for anaerobic bacteria. Thus, the surface modification method presented is a potential approach to improve the osseointegration of Ti implants and to associate local drug delivery with dental implants, preventing early infections and bone failure. Full article

(This article belongs to the Special Issue Novel Dental Implant Coatings for Better Implant-Bone Integration Properties)

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Open AccessReview

Non-Classical Intercellular Communications: Basic Mechanisms and Roles in Biology and Medicine

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Natalia Polyakova

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Maria Kalashnikova

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Alexander Belyavsky

Int. J. Mol. Sci. 2023, 24(7), 6455; https://doi.org/10.3390/ijms24076455 (registering DOI) - 29 Mar 2023

Abstract

In multicellular organisms, interactions between cells and intercellular communications form the very basis of the organism’s survival, the functioning of its systems, the maintenance of homeostasis and adequate response to the environment. The accumulated experimental data point to the particular importance of intercellular [...] Read more.

In multicellular organisms, interactions between cells and intercellular communications form the very basis of the organism’s survival, the functioning of its systems, the maintenance of homeostasis and adequate response to the environment. The accumulated experimental data point to the particular importance of intercellular communications in determining the fate of cells, as well as their differentiation and plasticity. For a long time, it was believed that the properties and behavior of cells were primarily governed by the interactions of secreted or membrane-bound ligands with corresponding receptors, as well as direct intercellular adhesion contacts. In this review, we describe various types of other, non-classical intercellular interactions and communications that have recently come into the limelight—in particular, the broad repertoire of extracellular vesicles and membrane protrusions. These communications are mediated by large macromolecular structural and functional ensembles, and we explore here the mechanisms underlying their formation and present current data that reveal their roles in multiple biological processes. The effects mediated by these new types of intercellular communications in normal and pathological states, as well as therapeutic applications, are also discussed. The in-depth study of novel intercellular interaction mechanisms is required for the establishment of effective approaches for the control and modification of cell properties both for basic research and the development of radically new therapeutic strategies. Full article

(This article belongs to the Special Issue Intercellular and Intracellular Communication in Human Health and Disease 2.0)

Open AccessArticle

Excitement and Concerns of Young Radiation Oncologists over Automatic Segmentation: A French Perspective

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Cancers 2023, 15(7), 2040; https://doi.org/10.3390/cancers15072040 (registering DOI) - 29 Mar 2023

Abstract

Introduction: Segmentation of organs at risk (OARs) and target volumes need time and precision but are highly repetitive tasks. Radiation oncology has known tremendous technological advances in recent years, the latest being brought by artificial intelligence (AI). Despite the advantages brought by AI [...] Read more.

Introduction: Segmentation of organs at risk (OARs) and target volumes need time and precision but are highly repetitive tasks. Radiation oncology has known tremendous technological advances in recent years, the latest being brought by artificial intelligence (AI). Despite the advantages brought by AI for segmentation, some concerns were raised by academics regarding the impact on young radiation oncologists’ training. A survey was thus conducted on young french radiation oncologists (ROs) by the SFjRO (Société Française des jeunes Radiothérapeutes Oncologues). Methodology: The SFjRO organizes regular webinars focusing on anatomical localization, discussing either segmentation or dosimetry. Completion of the survey was mandatory for registration to a dosimetry webinar dedicated to head and neck (H & N) cancers. The survey was generated in accordance with the CHERRIES guidelines. Quantitative data (e.g., time savings and correction needs) were not measured but determined among the propositions. Results: 117 young ROs from 35 different and mostly academic centers participated. Most centers were either already equipped with such solutions or planning to be equipped in the next two years. AI segmentation software was mostly useful for H & N cases. While for the definition of OARs, participants experienced a significant time gain using AI-proposed delineations, with almost 35% of the participants saving between 50–100% of the segmentation time, time gained for target volumes was significantly lower, with only 8.6% experiencing a 50–100% gain. Contours still needed to be thoroughly checked, especially target volumes for some, and edited. The majority of participants suggested that these tools should be integrated into the training so that future radiation oncologists do not neglect the importance of radioanatomy. Fully aware of this risk, up to one-third of them even suggested that AI tools should be reserved for senior physicians only. Conclusions: We believe this survey on automatic segmentation to be the first to focus on the perception of young radiation oncologists. Software developers should focus on enhancing the quality of proposed segmentations, while young radiation oncologists should become more acquainted with these tools. Full article

(This article belongs to the Special Issue Unlocking the Potential of AI and Big Data in Cancer Research: Advances and Applications)

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Open AccessSystematic Review

Fluorescence and Intraoperative Ultrasound as Surgical Adjuncts for Brain Metastases Resection: What Do We Know? A Systematic Review of the Literature

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Cancers 2023, 15(7), 2047; https://doi.org/10.3390/cancers15072047 (registering DOI) - 29 Mar 2023

Abstract

(1) Background: brain metastases (BMs) are the most common neoplasm of the central nervous system; despite the high incidence of this type of tumour, to date there is no universal consensus on the most effective treatment in patients with BMs, even if surgery [...] Read more.

(1) Background: brain metastases (BMs) are the most common neoplasm of the central nervous system; despite the high incidence of this type of tumour, to date there is no universal consensus on the most effective treatment in patients with BMs, even if surgery still plays a primary role. Despite this, the adjunct systems that help to reach the GTR, which are well structured for other tumour forms such as ultrasound and fluorescence systems, are not yet well employed and standardised in surgical practice. The aim of this review is to provide a picture of the current state-of-art of the roles of iOUS and intraoperative fluorescence to better understand their potential roles as surgical tools.(2) Methods: to reach this goal, the PubMed database was searched using the following string as the keyword: (((Brain cerebral metastasis [MeSH Major Topic])OR (brain metastasis, [MeSH Major Topic])) AND ((5-ala, [MeSH Terms]) OR (Aminolevulinicacid [All fields]) OR (fluorescein, [MeSH Terms]) OR (contrast enhanced ultrasound [MeSH Terms])OR ((intraoperative ultrasound. [MeSH Terms]))) AND (english [Filter]) AND ((english [Filter]) AND(2010:2022 [pdat])) AND (english [Filter]). (3) Results: from our research, a total of 661 articles emerged; of these, 57 were selected. 21 of these included BMs generically as a secondary class for comparisons with gliomas, without going deeply into specific details. Therefore, for our purposes, 36 articles were considered. (4) Conclusions: with regard to BMs treatment and their surgical adjuncts, there is still much to be explored. This is mainly related to the heterogeneity of patients, the primary tumour histology and the extent of systemic disease; regardless, surgery plays a paramount role in obtaining a local disease control, and more standardised surgical protocols need to be made, with the aim of optimizing the use of the available surgical adjuncts and in order to increase the rate of GTR. Full article

(This article belongs to the Special Issue Advanced Research in Metastatic Brain Tumors)

Open AccessArticle

Surgical Approach to Liver Metastases in GEP-NET in a Tertiary Reference Center

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Cancers 2023, 15(7), 2048; https://doi.org/10.3390/cancers15072048 (registering DOI) - 29 Mar 2023

Abstract

Indications for liver resection in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NET) vary from liver resection with curative intent to tumor debulking or tissue sampling for histopathological characterization. With increasing expertise, the number of minimally invasive liver surgeries (MILS) in GEP-NET patients has increased. [...] Read more.

Indications for liver resection in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NET) vary from liver resection with curative intent to tumor debulking or tissue sampling for histopathological characterization. With increasing expertise, the number of minimally invasive liver surgeries (MILS) in GEP-NET patients has increased. However, the influence on the oncological outcome has hardly been described. The clinicopathological data of patients who underwent liver resection for hepatic metastases of GEP-NET at the Department of Surgery, Charité—Universitätsmedizin Berlin, were analyzed. Propensity score matching (PSM) was performed to compare MILS with open liver surgery (OLS). In total, 22 patients underwent liver surgery with curative intent, and 30 debulking surgeries were analyzed. Disease-free survival (DFS) was longer than progression-free survival (PFS) (10 vs. 24 months), whereas overall survival (OS) did not differ significantly (p = 0.588). Thirty-nine (75%) liver resections were performed as OLS, and thirteen (25%) as MILS. After PSM, a shorter length of hospital stay was found for the MILS group (14 vs. 10 d, p = 0.034), while neither DFS/PFS nor OS differed significantly. Both curative intended and cytoreductive resection of hepatic GEP-NET metastases achieved excellent outcomes. MILS led to a reduced length of hospital, while preserving a good oncological outcome. Full article

(This article belongs to the Special Issue Diagnosis and Treatment of Gastroenteropancreatic Neuroendocrine Neoplasms)

Open AccessArticle

In Vitro Anti-Inflammatory and Vasculoprotective Effects of Red Cell Extract from the Black Sea Urchin Arbacia lixula

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Maria Annunziata Carluccio

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Patrizia Pagliara

Nutrients 2023, 15(7), 1672; https://doi.org/10.3390/nu15071672 (registering DOI) - 29 Mar 2023

Abstract

Sea urchins have emerged as an important source of bioactive compounds with anti-inflammatory and antioxidant properties relevant to human health. Since inflammation is a crucial pathogenic process in the development and progression of atherosclerosis, we here assessed the potential anti-inflammatory and vasculoprotective effects [...] Read more.

Sea urchins have emerged as an important source of bioactive compounds with anti-inflammatory and antioxidant properties relevant to human health. Since inflammation is a crucial pathogenic process in the development and progression of atherosclerosis, we here assessed the potential anti-inflammatory and vasculoprotective effects of coelomic red-cell methanolic extract of the black sea urchin Arbacia lixula in an in vitro model of endothelial cell dysfunction. Human microvascular endothelial cells (HMEC-1) were pretreated with A. lixula red-cell extract (10 and 100 μg/mL) before exposure to the pro-inflammatory cytokine tumor necrosis factor (TNF)-α. The extract was non-toxic after 24 h cell treatment and was characterized by antioxidant power and phenol content. The TNF-α-stimulated expression of adhesion molecules (VCAM-1, ICAM-1) and cytokines/chemokines (MCP-1, CCL-5, IL-6, IL-8, M-CSF) was significantly attenuated by A. lixula red-cell extract. This was functionally accompanied by a reduction in monocyte adhesion and chemotaxis towards activated endothelial cells. At the molecular level, the tested extract significantly counteracted the TNF-α-stimulated activation of the pro-inflammatory transcription factor NF-κB. These results provide evidence of potential anti-atherosclerotic properties of A. lixula red-cell extract, and open avenues in the discovery and development of dietary supplements and/or drugs for the prevention or treatment of cardiovascular diseases. Full article

(This article belongs to the Special Issue Marine Nutraceuticals and Human Health)

Open AccessArticle

Effects of Oat β-Glucan on the Textural and Sensory Properties of Low-Fat Set Type Pea Protein Yogurt

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Molecules 2023, 28(7), 3067; https://doi.org/10.3390/molecules28073067 (registering DOI) - 29 Mar 2023

Abstract

This study investigated the effect of oat β-glucan as a fat substitute on the structure formation, texture, and sensory properties of pea protein yogurt. The results showed that the incorporation of 0.5% β-glucan significantly accelerated the lactic acid bacteria-induced fermentation, with the time [...] Read more.

This study investigated the effect of oat β-glucan as a fat substitute on the structure formation, texture, and sensory properties of pea protein yogurt. The results showed that the incorporation of 0.5% β-glucan significantly accelerated the lactic acid bacteria-induced fermentation, with the time for reaching the target pH of 4.6 shortened from 3.5 h to 3 h (p < 0.05); increased the plastic module (G’) from 693 Pa to 764 Pa when fermenting 3 h (p < 0.05); and enhanced the water-holding capacity from 77.29% to 82.15% (p < 0.05). The identification of volatile organic compounds (VOCs) in low-fat pea protein yogurt by GC-IMS revealed a significant decrease in aldehydes and a significant increase in alcohols, ketones and acids in the pea yogurt after fermentation (p < 0.05). Among them, the levels of acetic acid, acetone, 2,3-butanedione, 3-hydroxy-2-butanone, and ethyl acetate all significantly increased with the addition of oat β-glucan (p < 0.05), thereby providing prominent fruity, sweet, and creamy flavors, respectively. Combined with the results of sensory analysis, the quality characteristics of pea protein yogurt with 1% oil by adding 1% oat β-glucan were comparable to the control sample with 3% oil. Therefore, oat β-glucan has a good potential for fat replacement in pea protein yogurt. Full article

(This article belongs to the Special Issue Extraction, Modification, Functionality and Bioactivity of Plant Proteins for a Healthy and Sustainable Food System)

Open AccessArticle

Effect of LNR-g-MMA on the Mechanical Properties and Lifetime Estimation of PLA/PP Blends

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Kraiwut Wisetkhamsai

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Weerawat Patthaveekongka

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Wanvimon Arayapranee

Polymers 2023, 15(7), 1712; https://doi.org/10.3390/polym15071712 (registering DOI) - 29 Mar 2023

Abstract

Polylactide (PLA) polymer, polypropylene (PP) polymer, and a PLA/PP (70:30 wt%) blend, with liquid natural rubber-−graft−methyl methacrylate (LNR−g−MMA) of 0.0, 2.5, 5.0, and 10.0 phr as compatibilizers, were prepared by internal mixing and compression molding. The effect of LNR-g-MMA content on the morphology, [...] Read more.

Polylactide (PLA) polymer, polypropylene (PP) polymer, and a PLA/PP (70:30 wt%) blend, with liquid natural rubber-−graft−methyl methacrylate (LNR−g−MMA) of 0.0, 2.5, 5.0, and 10.0 phr as compatibilizers, were prepared by internal mixing and compression molding. The effect of LNR-g-MMA content on the morphology, mechanical properties, water absorption, thermal degradation, and a lifetime of blends based on PLA and PP was investigated. Scanning electron microscopy (SEM) revealed that the PLA/PP blend underwent phase separation, and the presence of LNR−g−MMA in the PLA/PP blend showed a more homogenized and refined blend morphology. Hence, the addition of LNR−g−MMA was used as a compatibilizer to induce miscibility in the PLA/PP blend. The values of tensile strength, elongation at break, and impact strength of the polymer blends increased, whereas water absorption values decreased with increased LNR−g−MMA content. Thermal degradation kinetics was studied over a temperature range of 50–800 °C with multiple heating rates. The results demonstrated that the thermal stability of blends without LNR-g-MMA was greater than that of blends with LNR−g−MMA and that the thermal stability decreased with increasing LNR−g−MMA content. The activation energy (E_a) was calculated by using the Kissinger–Akahira–Sunose method. The E_a value of PLA was much lower than that of PP, and incorporating PP in the PLA matrix increased the E_a. The addition of LNR−g−MMA to the PLA/PP blend decreased the E_a. The lifetime of PLA/PP blends was reduced with the addition of LNR−g−MMA. Full article

(This article belongs to the Special Issue Durability and Degradation of Polymeric Materials II)

Open AccessArticle

Multiparametric Quantitative Analysis of Photodamage to Skin Using Optical Coherence Tomography

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Sensors 2023, 23(7), 3589; https://doi.org/10.3390/s23073589 (registering DOI) - 29 Mar 2023

Abstract

Ultraviolet (UV) irradiation causes 90% of photodamage to skin and long-term exposure to UV irradiation is the largest threat to skin health. To study the mechanism of UV-induced photodamage and the repair of sunburnt skin, the key problem to solve is how to [...] Read more.

Ultraviolet (UV) irradiation causes 90% of photodamage to skin and long-term exposure to UV irradiation is the largest threat to skin health. To study the mechanism of UV-induced photodamage and the repair of sunburnt skin, the key problem to solve is how to non-destructively and continuously evaluate UV-induced photodamage to skin. In this study, a method to quantitatively analyze the structural and tissue optical parameters of artificial skin (AS) using optical coherence tomography (OCT) was proposed as a way to non-destructively and continuously evaluate the effect of photodamage. AS surface roughness was achieved based on the characteristic peaks of the intensity signal of the OCT images, and this was the basis for quantifying AS cuticle thickness using Dijkstra’s algorithm. Local texture features within the AS were obtained through the gray-level co-occurrence matrix method. A modified depth-resolved algorithm was used to quantify the 3D scattering coefficient distribution within AS based on a single-scattering model. A multiparameter assessment of AS photodamage was carried out, and the results were compared with the MTT experiment results and H&E staining. The results of the UV photodamage experiments showed that the cuticle of the photodamaged model was thicker (56.5%) and had greater surface roughness (14.4%) compared with the normal cultured AS. The angular second moment was greater and the correlation was smaller, which was in agreement with the results of the H&E staining microscopy. The angular second moment and correlation showed a good linear relationship with the UV irradiation dose, illustrating the potential of OCT in measuring internal structural damage. The tissue scattering coefficient of AS correlated well with the MTT results, which can be used to quantify the damage to the bioactivity. The experimental results also demonstrate the anti-photodamage efficacy of the vitamin C factor. Quantitative analysis of structural and tissue optical parameters of AS by OCT enables the non-destructive and continuous detection of AS photodamage in multiple dimensions. Full article

(This article belongs to the Section Optical Sensors)

Open AccessArticle

Prevalence, Resistance Patterns and Biofilm Production Ability of Bacterial Uropathogens from Cases of Community-Acquired Urinary Tract Infections in South Italy

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Francesca Paola Sasso

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Arianna Petrillo

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Marco Guida

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Marilena Galdiero

Pathogens 2023, 12(4), 537; https://doi.org/10.3390/pathogens12040537 (registering DOI) - 29 Mar 2023

Abstract

Community-acquired urinary tract infections represent the most common infectious diseases in the community setting. Knowing the antibiotic resistance patterns of uropathogens is crucial for establishing empirical treatment. The aim of the current study is to determine the incidence of the causative agents of [...] Read more.

Community-acquired urinary tract infections represent the most common infectious diseases in the community setting. Knowing the antibiotic resistance patterns of uropathogens is crucial for establishing empirical treatment. The aim of the current study is to determine the incidence of the causative agents of UTIs and their resistance profiles. Patients of all ages and both sexes were enrolled in the study, and admitted to San Ciro Diagnostic Center in Naples between January 2019 and Jun 2020. Bacterial identification and antibiotic susceptibility testing were carried out using Vitek 2 system. Among the 2741 urine samples, 1702 (62.1%) and 1309 (37.9%) were negative and positive for bacterial growth, respectively. Of 1309 patients with infection, 760 (73.1%) were females and 279 (26.9 %) were males. The greatest number of positive cases were found in the in the elderly (>61 years). Regarding uropathogens, 1000 (96.2%) were Gram-negative while 39 (3.8%) were Gram-positive strains. The three most isolated pathogenic strains were Escherichia coli (72.2%), Klebsiella pneumoniae (12.4%), and Proteus mirabilis (9.0%). Strong biofilm formation ability was observed in about 30% of the tested isolates. The low resistance rates recorded against nitrofurantoin, fosfomycin, piperacillin–tazobactam, and gentamicin could suggest them as the most appropriate therapies for CA-UTIs. Full article

Open AccessArticle

Safety, Pharmacokinetic and Pharmacodynamic Evaluation of Teverelix for the Treatment of Hormone-Sensitive Advanced Prostate Cancer: Phase 2 Loading-Dose-Finding Studies

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Carol M. MacLean

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Albertas Ulys

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Feliksas Jankevičius

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Žilvinas Saladžinskas

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Steve van Os

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Finn Larsen

Medicina 2023, 59(4), 681; https://doi.org/10.3390/medicina59040681 (registering DOI) - 29 Mar 2023

Abstract

Background and objectives: Teverelix drug product (DP) is a gonadotropin-releasing hormone antagonist in development for the treatment of patients with prostate cancer in whom androgen deprivation therapy is indicated. The aim of this paper is to present the results of five Phase [...] Read more.

Background and objectives: Teverelix drug product (DP) is a gonadotropin-releasing hormone antagonist in development for the treatment of patients with prostate cancer in whom androgen deprivation therapy is indicated. The aim of this paper is to present the results of five Phase 2 studies that assessed the pharmacokinetics, pharmacodynamics, efficacy and safety of different loading dose regimens of teverelix DP. Methods: Five single-arm, uncontrolled clinical trials were conducted in patients with advanced prostate cancer. The five different loading dose regimens of teverelix DP tested were (a) a single 90 mg subcutaneous (SC) injection of teverelix DP given on 3 consecutive days (Days 0, 1 and 2); (b) a single 90 mg intramuscular (IM) injection of teverelix DP given 7 days apart (Days 0 and 7); (c) a single 120 mg SC injection of teverelix DP given on 2 consecutive days (Days 0 and 1); (d) 2 × 60 mg SC injections of teverelix DP given on 3 consecutive days (Days 0, 1 and 2), and (e) 2 × 90 mg SC injections of teverelix DP given on 3 consecutive days (Days 0, 1 and 2). The primary efficacy parameter was the duration of action of an initial loading dose regimen in terms of suppression of testosterone to below the castration level (0.5 ng/mL). Results: Eighty-two patients were treated with teverelix DP. Two regimens (90 mg and 180 mg SC on 3 consecutive days) had a mean duration of castration of 55.32 days and 68.95 days with > 90% of patients having testosterone levels < 0.5 ng/mL at Day 28. The mean onset of castration for the SC regimens ranged from 1.10 to 1.77 days, while it was slower (2.4 days) with IM administration. The most common adverse event (AE) was injection site reaction. No AEs of severe intensity were reported. Conclusions: Teverelix DP is safe and well tolerated. Castrate levels of testosterone can be rapidly achieved following the subcutaneous injection of teverelix DP on 3 consecutive days. Streamlining of the administration of the loading dose and identifying a suitable maintenance dose will be investigated in future trials. Full article

Open AccessArticle

Sclerotioloids A−C: Three New Alkaloids from the Marine-Derived Fungus Aspergillus sclerotiorum ST0501

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Mar. Drugs 2023, 21(4), 219; https://doi.org/10.3390/md21040219 (registering DOI) - 29 Mar 2023

Abstract

Alkaloids, as one of the largest classes of natural products with diverse structures, are an important source of innovative medicines. Filamentous fungi, especially those derived from the marine environment, are one of the major producers of alkaloids. In this study, three new alkaloids, [...] Read more.

Alkaloids, as one of the largest classes of natural products with diverse structures, are an important source of innovative medicines. Filamentous fungi, especially those derived from the marine environment, are one of the major producers of alkaloids. In this study, three new alkaloids, sclerotioloids A−C (1−3), along with six known analogs (4−9), were obtained under the guidance of the MS/MS-based molecular networking from the marine-derived fungus, Aspergillus sclerotiorum ST0501, collected from the South China Sea. Their chemical structures were elucidated by comprehensive analysis of the spectroscopic data, including 1D and 2D NMR and HRESIMS. Additionally, the configuration of compound 2 was unambiguously determined by X-ray single crystal diffraction, and that of compound 3 was determined by the TDDFT-ECD approach. Sclerotioloid A (1) represents the first example of 2,5-diketopiperazine alkaloid with a rare terminal alkyne. Sclerotioloid B (2) showed the inhibition of NO production induced by lipopolysaccharide (LPS), with an inhibition rate of 28.92% higher than that of dexamethasone (25.87%). These results expanded the library of fungal-derived alkaloids and further prove the potential of marine fungi in the generation of alkaloids with new scaffolds. Full article

(This article belongs to the Special Issue A Theme Issue Honoring Professor Peter Proksch's 70th Birthday: Bioactive Compounds from the Ocean)

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