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Purine stretches, sequences of adenine (A) and guanine (G) in DNA, play critical roles in binding regulatory protein factors and influence gene expression by affecting DNA folding. This study investigates the relationship between purine stretches and cancer development, considering the aromaticity of purines, quantified by methods like Hückel's rule and NICS calculations, and the importance of the flanking sequence context. A pronounced avoidance of long purine stretches by typical cancer mutations was observed in public data on the intergenic regions of cancer patients, suggesting a role of intergenic sequences in chromatin reorganization and gene regulation. A statistically significant shortening of purine stretches in cancerous tumors (p value < 0.0001) was found. The insights into the aromatic nature of purines and their stacking energies explain the role of purine stretches in DNA structure, contributing to their role in cancer progression. This research lays the groundwork for understanding the nature of purine stretches, emphasizing their importance in gene regulation and chromatin restructuring, and offers potential avenues for novel cancer therapies and insights into cancer etiology.
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Mutação , Neoplasias , Purinas , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Purinas/metabolismo , DNA/genética , DNA/metabolismo , Cromatina/metabolismo , Cromatina/genéticaRESUMO
The green synthesis of zinc oxide nanoparticles (ZnO NPs) using plants has grown in significance in recent years. ZnO NPs were synthesized in this work via a chemical precipitation method with Jasminum sambac (JS) leaf extract serving as a capping agent. These NPs were characterized using UV-vis spectroscopy, FT-IR, XRD, SEM, TEM, TGA, and DTA. The results from UV-vis and FT-IR confirmed the band gap energies (3.37 eV and 3.50 eV) and the presence of the following functional groups: CN, OH, C=O, and NH. A spherical structure and an average grain size of 26 nm were confirmed via XRD. The size and surface morphology of the ZnO NPs were confirmed through the use of SEM analysis. According to the TEM images, the ZnO NPs had an average mean size of 26 nm and were spherical in shape. The TGA curve indicated that the weight loss starts at 100 °C, rising to 900 °C, as a result of the evaporation of water molecules. An exothermic peak was seen during the DTA analysis at 480 °C. Effective antibacterial activity was found at 7.32 ± 0.44 mm in Gram-positive bacteria (S. aureus) and at 15.54 ± 0.031 mm in Gram-negative (E. coli) bacteria against the ZnO NPs. Antispasmodic activity: the 0.3 mL/mL sample solution demonstrated significant reductions in stimulant effects induced by histamine (at a concentration of 1 µg/mL) by (78.19%), acetylcholine (at a concentration of 1 µM) by (67.57%), and nicotine (at a concentration of 2 µg/mL) by (84.35%). The antipyretic activity was identified using the specific Shodhan vidhi method, and their anti-inflammatory properties were effectively evaluated with a denaturation test. A 0.3 mL/mL sample solution demonstrated significant reductions in stimulant effects induced by histamine (at a concentration of 1 µg/mL) by 78.19%, acetylcholine (at a concentration of 1 µM) by 67.57%, and nicotine (at a concentration of 2 µg/mL) by 84.35%. These results underscore the sample solution's potential as an effective therapeutic agent, showcasing its notable antispasmodic activity. Among the administered doses, the 150 mg/kg sample dose exhibited the most potent antipyretic effects. The anti-inflammatory activity of the synthesized NPs showed a remarkable inhibition percentage of (97.14 ± 0.005) at higher concentrations (250 µg/mL). Furthermore, a cytotoxic effect was noted when the biologically synthesized ZnO NPs were introduced to treated cells.
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Antipiréticos , Jasminum , Nanopartículas , Óxido de Zinco , Óxido de Zinco/farmacologia , Parassimpatolíticos , Acetilcolina , Escherichia coli , Histamina , Nicotina , Espectroscopia de Infravermelho com Transformada de Fourier , Staphylococcus aureus , Anti-Inflamatórios/farmacologia , Antibacterianos/farmacologia , Extratos Vegetais/farmacologiaRESUMO
This work aimed to develop and characterize a water-soluble, high-release active pharmaceutical ingredient (API) composite based on the practically water-insoluble API N-butyl-N-methyl-1-phenylpyrrolo[1,2-a]pyrazine-3-carboxamide (GML-3), a substance with antidepressant and anxiolytic action. This allows to ensure the bioavailability of the medicinal product of combined action. Composites obtained by the method of creating amorphous solid dispersions, where polyvinylpyrrolidone (PVP) or Soluplus® was used as a polymer, were studied for crystallinity, stability and the release of API from the composite into purified water. The resulting differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD), and dissolution test data indicate that the resulting composites are amorphous at 1:15 API: polymer ratios for PVP and 1:5 for Soluplus®, which ensures the solubility of GML-3 in purified water and maintaining the supercritical state in solution.
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Polímeros , Povidona , Polímeros/química , Solubilidade , Povidona/química , Água , Pirazinas , Varredura Diferencial de Calorimetria , Difração de Raios XRESUMO
In Cre site-specific recombination, the synaptic intermediate is a recombinase homotetramer containing a pair of loxP DNA target sites. The enzyme system's strand-exchange mechanism proceeds via a Holliday-junction (HJ) intermediate; however, the geometry of DNA segments in the synapse has remained highly controversial. In particular, all crystallographic structures are consistent with an achiral, planar Holliday-junction (HJ) structure, whereas topological assays based on Cre-mediated knotting of plasmid DNAs are consistent with a right-handed chiral junction. We use the kinetics of loop closure involving closely spaced (131-151 bp) loxP sites to investigate the in-aqueo ensemble of conformations for the longest-lived looped DNA intermediate. Fitting the experimental site-spacing dependence of the loop-closure probability, J, to a statistical-mechanical theory of DNA looping provides evidence for substantial out-of-plane HJ distortion, which unequivocally stands in contrast to the square-planar intermediate geometry from Cre-loxP crystal structures and those of other int-superfamily recombinases. J measurements for an HJ-isomerization-deficient Cre mutant suggest that the apparent geometry of the wild-type complex is consistent with temporal averaging of right-handed and achiral structures. Our approach connects the static pictures provided by crystal structures and the natural dynamics of macromolecules in solution, thus advancing a more comprehensive dynamic analysis of large nucleoprotein structures and their mechanisms.
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DNA/química , Integrases/química , Recombinação Genética , Cinética , Modelos Moleculares , Conformação de Ácido NucleicoRESUMO
The Cre-recombination system has become an important tool for genetic manipulation of higher organisms and a model for site-specific DNA-recombination mechanisms employed by the λ-Int superfamily of recombinases. We report a novel quantitative approach for characterizing the probability of DNA-loop formation in solution using time-dependent ensemble Förster resonance energy transfer measurements of intra- and inter-molecular Cre-recombination kinetics. Our method uses an innovative technique for incorporating multiple covalent modifications at specific sites in covalently closed DNA. Because the mechanism of Cre recombinase does not conform to a simple kinetic scheme, we employ numerical methods to extract rate constants for fundamental steps that pertain to Cre-mediated loop closure. Cre recombination does not require accessory proteins, DNA supercoiling or particular metal-ion cofactors and is thus a highly flexible system for quantitatively analyzing DNA-loop formation in vitro and in vivo.
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DNA/química , Integrases/metabolismo , Recombinação Genética , Transferência Ressonante de Energia de Fluorescência , Integrases/química , Cinética , Modelos Moleculares , Conformação de Ácido NucleicoRESUMO
Biobased plastics provide a sustainable alternative to conventional food packaging materials, thereby reducing the environmental impact. The present study investigated the effectiveness of chitosan with varying levels of Moringa oleifera seed powder (MOSP) and tannic acid (TA). Chitosan (CS) biocomposite films with tannic acid acted as a cross-linker, and Moringa oleifera seed powder served as reinforcement. To enhance food packaging and film performance, Moringa oleifera seed powder was introduced at various loadings of 1.0, 3.0, 5.0, and 10.0 wt.%. Fourier-transform infrared spectroscopy, X-ray diffraction, and scanning electron microscopy analyses were performed to study the structure and morphology of the CS/TA/MOSP films. The scanning electron microscopy results confirmed that chitosan/TA with 10.0 wt.% of MOSP produced a lightly miscible droplet/matrix structure. Furthermore, mechanical properties, swelling, water solubility, optical barrier, and water contact angle properties of the film were also calculated. With increasing Moringa oleifera seed powder contents, the biocomposite films' antimicrobial and antifungal activity increased at the 10.0 wt.% MOSP level; all of the observed bacteria [Staphylococcus aureus (S. aureus), Escherichia coli (E. coli), Aspergillus niger (A. niger), and Candida albicans (C. albicans)] had a notably increased percentage of growth. The film, with 10.0 wt.% MOSP content, effectively preserves strawberries' freshness, making it an ideal food packaging material.
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The synthesis of Al-ZnO nanoparticles (NPs) was achieved using a green synthesis approach, utilizing leaf extract from Anisomeles indica (L.) in a straightforward co-precipitation method. The goal of this study was to investigate the production of Al-ZnO nanoparticles through the reduction and capping method utilizing Anisomeles indica (L.) leaf extract. The powder X-ray diffraction, UV spectroscopy, Fourier transform infrared spectroscopy, and scanning electron microscopy with EDAX analysis were used to analyze the nanoparticles. X-ray diffraction analysis confirmed the presence of spherical structures with an average grain size of 40 nm in diameter, while UV-visible spectroscopy revealed a prominent absorption peak at 360 nm. FTIR spectra demonstrated the presence of stretching vibrations associated with O-H, N-H, C=C, C-N, and C=O as well as C-Cl groups indicating their involvement in the reduction and stabilization of nanoparticles. SEM image revealed the presence of spongy, spherical, porous agglomerated nanoparticles, confirming the chemical composition of Al-ZnO nanoparticles through the use of the EDAX technique. Al-ZnO nanoparticles showed increased bactericidal activity against both Gram-positive and Gram-negative bacteria. The antioxidant property of the green synthesized Al-ZnO nanoparticles was confirmed by DPPH radical scavenging with an IC50 value of 23.52 indicating excellent antioxidant capability. Green synthesized Al-ZnO nanoparticles were shown in in vivo studies on HeLa cell lines to be effective for cancer treatment. Additionally, α-amylase inhibition assay and α-glucosidase inhibition assay demonstrated their potent anti-diabetic activities. Moving forward, the current methodology suggests that the presence of phenolic groups, flavonoids, and amines in Al-ZnO nanoparticles synthesized with Anisomeles indica (L.) extract exhibit significant promise for eliciting biological responses, including antioxidant and anti-diabetic effects, in the realms of biomedical and pharmaceutical applications.
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In this research work, a coated paper was prepared with poly (butylene adipate-co-terephthalate) (PBAT) film to explore its use in eco-friendly food packaging. The paper was coated with PBAT film for packaging using hot pressing, a production method currently employed in the packaging industry. The coated papers were evaluated for their structural, mechanical, thermal, and barrier properties. The structural morphology and chemical analysis of the coated paper confirmed the consistent formation of PBAT bi-layered on paper surfaces. Surface coating with PBAT film increased the water resistance of the paper samples, as demonstrated by tests of barrier characteristics, including the water vapor transmission rate (WVTR), oxygen transmission rate (OTR), and water contact angle (WCA) of water drops. The transmission rate of the clean paper was 2010.40 cc m-2 per 24 h for OTR and 110.24 g m-2 per 24 h for WVTR. If the PBAT-film was coated, the value decreased to 91.79 g m-2 per 24 h and 992.86 cc m-2 per 24 h. The hydrophobic nature of PBAT, confirmed by WCA measurements, contributed to the enhanced water resistance of PBAT-coated paper. This result presents an improved PBAT-coated paper material, eliminating the need for adhesives and allowing for the fabrication of bi-layered packaging.
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The structural and electro-thermophysical characteristics of organosilicon elastomers modified with multilayer carbon nanotubes (MWCNTs) synthesized on Co-Mo/Al2O3-MgO and metallic (Cu or Ni) microparticles have been studied. The structures were analyzed with scanning electron microscopy (SEM), transmission electron microscopy (TEM), Raman spectroscopy, and energy-dispersive X-ray spectroscopy (EDX). The main focus of this study was the influence of metallic dispersed fillers on the resistance of a modified elastomer with Cu and Ni to the degradation of electrophysical parameters under the action of applied electrical voltage. The distribution of the temperature field on the surface of a modified polymer composite with metallic micro-dimensional structures has been recorded. The collected data demonstrate the possibility of controlling the degradation caused by electrical voltage. It has been found that repeated on/off turns of the elastomer with an MWCNTs on 50 and 100 cycles leads to a deterioration in the properties of the conductive elastomer from the available power of 1.1 kW/m2 (-40 °C) and, as a consequence, a decrease in the power to 0.3 kW/m2 (-40 °C) after 100 on/off cycles. At the same time, the Ni additive allows increasing the power by 1.4 kW/m2 (-40 °C) and reducing the intensity of the degradation of the conductive structures (after 100 on/off cycles up to 1.2 kW/m2 (-40 °C). When Ni is replaced by Cu, the power of the modified composite in the heating mode increases to 1.6 kW/m2 (-40 °C) and, at the same time, the degradation of the conductive structures in the composite decreases in the mode of cyclic offensives (50 and 100 cycles) (1.5 kW/m2 (-40 °C)). It was found that the best result in terms of heat removal is typical for an elastomer sample with an MWCNTs and Cu (temperature reaches 93.9 °C), which indicates an intensification of the heat removal from the most overheated places of the composite structure. At the same time, the maximum temperature for the Ni additives reaches 86.7 °C. A sample without the addition of a micro-sized metal is characterized by the local unevenness of the temperature field distribution, which causes undesirable internal overheating and destruction of the current-conducting structures based on the MWCNTs. The maximum temperature at the same time reaches a value of 49.8 °C. The conducted studies of the distribution of the micro-sizes of Ni and Cu show that Cu, due to its larger particles, improves internal heat exchange and intensifies heat release to the surface of the heater sample, which improves the temperature regime of the MWCNTs and, accordingly, increases resistance to electrophysical degradation.
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The development of new drugs derived from plant sources is of significant interest in modern pharmacy. One of the promising plant sources for introduction into pharmaceuticals is Tripleurospermum inodorum (L.) Sch. Bip., also known as Tripleurospermum perforatum (Merat.) M. This plant has been shown to possess various biological activities, including anti-inflammatory, antimicrobial, and antimycotic activities, among others. However, a review of the current literature reveals a paucity of studies investigating the chemical composition of the herb Tripleurospermum inodorum (L.) Sch. Bip. This study presents the development of a method for obtaining an extract of the herb Tripleurospermum inodorum (L.) Sch. Bip. enriched with flavonoids, harvested before flowering and butonization. This study focused on determining the optimal conditions for extraction, including the concentration of the extractant (ethanol), extraction time, raw material/extractant ratio, extraction frequency, complexation reaction time, amount of aluminum chloride solution, and amount of diluted acetic acid. The results indicate that herbs harvested during this specific period exhibited a higher flavonoid content compared to those collected during butonization and flowering. Moreover, this study demonstrated that the flavonoid content could exceed 7% mg REq/100 g D.W. through a one-hour extraction process. Furthermore, the flavonoid content was found to be 7.65 ± 0.03 mg REq/100 g D.W. following a three-minute ultrasound-assisted extraction process, followed by thermal extraction. A qualitative analysis identified a variety of phenolic compounds in the extract, such as chlorogenic acid, 5-O-p-coumaroylquinic acid, 1-O-p-coumaroylquinic acid, luteolin-7-glucoside, quercetin-3-glucoside, luteolin-7-rutinoside, 3,5-O-dicaffeoylquinic acid, quercetin-3-O-malonylglucoside, apigenin-7-glucoside, luteolin-3-malonylglucoside, cynarin, rhamnetin-3-(O-dimethyl rhamnosyl glucosylglucoside), and luteolin. Moreover, this study demonstrated the antimicrobial, anti-inflammatory, anticoagulant, anti-aggregation, and antioxidant activities of the aqueous alcoholic extract from T. inodorum herb (ETIH) against pathogens such as Staphylococcus aureus, Escherichia coli, and Candida albicans. Additionally, the extract exhibited comparable anti-inflammatory effects on diclofenac sodium. These findings contribute to the understanding of the potential pharmacological applications of the developed herb extract.
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Anodized aluminum oxide (AAO) molds were used for the production of large-area and inexpensive superhydrophobic polymer films. A controlled anodization methodology was developed for the fabrication of hierarchical micro-nanoporous (HMN) AAO imprint molds (HMN-AAO), where phosphoric acid was used as both an electrolyte and a widening agent. Heat generated upon repetitive high-voltage (195 V) anodization steps is effectively dissipated by establishing a cooling channel. On the HMN-AAO, within the hemispherical micropores, arrays of hexagonal nanopores are formed. The diameter and depth of the micro- and nanopores are 18/8 and 0.3/1.25 µm, respectively. The gradual removal of micropatterns during etching in both the vertical and horizontal directions is crucial for fabricating HMN-AAO with a high aspect ratio. HMN-AAO rendered polycarbonate (PC) and polymethyl methacrylate (PMMA) films with respective water contact angles (WCAs) of 153° and 151°, respectively. The increase in the WCA is 80% for PC (85°) and 89% for PMMA (80°). On the PC and PMMA films, mechanically robust arrays of nanopillars are observed within the hemispherical micropillars. The micro-nanopillars on these polymer films are mechanically robust and durable. Regular nanoporous AAO molds resulted in only a hydrophobic polymer film (WCA = 113-118°). Collectively, the phosphoric acid-based controlled anodization strategy can be effectively utilized for the manufacturing of HMN-AAO molds and roll-to-roll production of durable superhydrophobic surfaces.
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This research aims to use energy harvested from conductive materials to power microelectronic components. The proposed method involves using vibration-based energy harvesting to increase the natural vibration frequency, reduce the need for battery replacement, and minimise chemical waste. Piezoelectric transduction, known for its high-power density and ease of application, has garnered significant attention. Additionally, graphene, a non-piezoelectric material, exhibits good piezoelectric properties. The research explores a novel method of printing graphene material using 3D printing, specifically Direct Ink Writing (DIW) and fused deposition modelling (FDM). Both simulation and experimental techniques were used to analyse energy harvesting. The experimental technique involved using the cantilever beam-based vibration energy harvesting method. The results showed that the DIW-derived 3D-printed prototype achieved a peak power output of 12.2 µW, surpassing the 6.4 µW output of the FDM-derived 3D-printed prototype. Furthermore, the simulation using COMSOL Multiphysics yielded a harvested output of 0.69 µV.
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When cultivating on wheat bran or deactivated fungal mycelium as a model of "natural growth", the ability of Trichoderma to synthesize extracellular L-lysine-α-oxidase (LysO) simultaneously with cell-wall-degrading enzymes (proteases, xylanase, glucanases, chitinases, etc.), responsible for mycoparasitism, was shown. LysO, in turn, causes the formation of H2O2 and pipecolic acid. These compounds are known to be signaling molecules and play an important role in the induction and development of systemic acquired resistance in plants. Antagonistic effects of LysO have been demonstrated against phytopathogenic fungi and Gram-positive or Gram-negative bacteria with dose-dependent cell death. The antimicrobial effect of LysO decreased in the presence of catalase. The generating intracellular ROS in the presence of LysO was also shown in both bacteria and fungi, which led to a decrease in viable cells. These results suggest that the antimicrobial activity of LysO is due to two factors: the formation of exogenous hydrogen peroxide as a product of the enzymatic oxidative deamination of L-lysine and the direct interaction of LysO with the cell wall of the micro-organisms. Thus, LysO on its own enhances the potential of the producer in the environment; namely, the enzyme complements the strategy of the fungus in biocontrol and indirectly participates in inducing SAR and regulating the relationship between pathogens and plants.
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A DNA structure, known as triple-stranded DNA, is made up of three oligonucleotide chains that wind around one another to form a triple helix (TFO). Hoogsteen base pairing describes how triple-stranded DNA may be built at certain conditions by the attachment of the third strand to an RNA, PNA, or DNA, which might all be employed as oligonucleotide chains. In each of these situations, the oligonucleotides can be employed as an anchor, in conjunction with a specific bioactive chemical, or as a messenger that enables switching between transcription and replication through the triplex-forming zone. These data are also considered since various illnesses have been linked to the expansion of triplex-prone sequences. In light of metabolic acidosis and associated symptoms, some consideration is given to the impact of several low-molecular-weight compounds, including pH on triplex production in vivo. The review is focused on the development of biomedical oligonucleotides with triplexes.
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Rising waste construction, agricultural actions, and manufacturing sewages all contribute to heavy metal accumulation in water resources. Humans consume heavy metals-contaminated substances to make sustenance, which equally ends up in the food circle. Cleaning of these vital properties, along with the prevention of new pollution, has long been required to evade negative strength consequences. Most wastewater treatment techniques are widely acknowledged to be costly and out of the grasp of governments and small pollution mitigation businesses. Utilizing hyper-accumulator plants that are extremely resilient to heavy metals in the environment/soil, phytoremediation is a practical and promising method for eliminating heavy metals from contaminated environments. This method extracts, degrades, or detoxifies harmful metals using green plants. The three phytoremediation techniques of phytostabilization, phytoextraction, and phytovolatilization have been used extensively for soil remediation. Regarding their ability to be used on a wide scale, conventional phytoremediation methods have significant limitations. Hence, biotechnological attempts to change plants for heavy metal phytoremediation methods are extensively investigated in order to increase plant effectiveness and possible use of improved phytoremediation approaches in the country of India. This review focuses on the advances and significance of phytoremediation accompanied by the removal of various harmful heavy metal contaminants. Similarly, sources, heavy metals status in India, impacts on nature and human health, and variables influencing the phytoremediation of heavy metals have all been covered.
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Applications of DNA-containing nanomaterials (DNA-NMs) in science and technology are currently attracting increasing attention in the fields of medicine, environment, engineering, etc. Such objects have become important for various branches of science and industries due to their outstanding characteristics such as small size, high controllability, clustering actions, and strong permeability. For these reasons, DNA-NMs deserve a review with respect to their recent advancements. On the other hand, precise cluster control, targeted drug distribution in vivo, and cellular micro-nano operation remain as problems. This review summarizes the recent progress in DNA-NMs and their crossover and integration into multiple disciplines (including in vivo/in vitro, microcircles excisions, and plasmid oligomers). We hope that this review will motivate relevant practitioners to generate new research perspectives and boost the advancement of nanomanipulation.
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The development of reliable and effective functional materials that can be used in various technological fields and environmental conditions is one of the goals of modern nanotechnology. Heating elements' manufacturing requires understanding the laws of heat transfer under conditions of different supply voltages, as this expands the possibilities of such materials' application. Elastomers based on silicon-organic compounds and polyurethane modified with multi-walled carbon nanotubes (MWCNTs) were studied at various concentrations of Ni/MgO or Co-Mo/MgO and voltages (220, 250, and 300 V). It was found that an increase in voltage from 220 to 300 V leads to an initial increase in specific power on one-third followed by a subsequent decrease in a specific power when switched on again to 220 V (for -40 °C) of up to ~44%. In turn, for a polyurethane matrix, an increase in voltage to 300 V leads to an initial peak power value of ~15% and a decrease in power when switched on again by 220 V (for -40 °C) to ~36% (Ni/MgO -MWCNT). The conducted studies have shown that the use of a polyurethane matrix reduces power degradation (associated with voltage surges above 220 V) by 2.59% for Ni/MgO-based MWCNT and by 10.42% for Co-Mo/MgO. This is due to the better heat resistance of polyurethane and the structural features of the polymer and the MWCNT. The current studies allow us to take the next step in the development of functional materials for electric heating and demonstrate the safety of using heaters at a higher voltage of up to 300 V, which does not lead to their ignition, but only causes changes in electrophysical parameters.
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Due to the current environmental situation, biopolymers are replacing the usual synthetic polymers, and special attention is being paid to poly-3-hydroxybutyrate (PHB), which is a biodegradable polymer of natural origin. In this paper, the rate of biodegradation of films and fibers based on PHB was compared. The influence of exposure to soil on the structure and properties of materials was evaluated using methods of mechanical analysis, the DSC method and FTIR spectroscopy. The results showed rapid decomposition of the fibrous material and also showed how the surface of the material affects the rate of biodegradation and the mechanical properties of the material. It was found that maximum strength decreased by 91% in the fibrous material and by 49% in the film. Additionally, the DSC method showed that the crystallinity of the fiber after exposure to the soil decreased. It was established that the rate of degradation is influenced by different factors, including the surface area of the material and its susceptibility to soil microorganisms. The results obtained are of great importance for planning the structure of features in the manufacture of biopolymer consumer products in areas such as medicine, packaging, filters, protective layers and coatings, etc. Therefore, an understanding of the biodegradation mechanisms of PHB could lead to the development of effective medical devices, packaging materials and different objects with a short working lifespan.
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We recently reported that the restoration of cervical vertebral arterial blood flow access (measured as systolic peak (PS)) to the rhomboid fossa leads to the recovery of the HbA1c level in the case of patients with a pre-Diabetes Mellitus (pre-DM) condition. The theory of centralized aerobic-anaerobic energy balance compensation (TCAAEBC) provides a successful theoretical explanation for this observation. It considers the human body as a dissipative structure. Reported connections between arterial hypertension (AHT) and the level of HbA1c are linked through OABFRH. According to the TCAAEBC, this delivers incorrect information about blood oxygen availability to the cerebellum. The restoration of PS normalizes AHT in 5-6 weeks and HbA1c in 12-13 weeks. In the current study, we demonstrate the model which fits the obtained experimental data. According to the model, pathways of onset and recovery from pre-DM are different. The consequence of these differences is discussed. The great significance of the TCAAEBC for medical practice forces the creation of an appropriate mathematical model, but the required adjustment of the model needs experimental data which can only be obtained from an animal model(s). The essential part of this study is devoted to the analysis of the advantages and disadvantages of widely available common mammalian models for TCAAEBC cases.
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N-butyl-N-methyl-1-phenylpyrrole[1,2-a] pyrazine-3-carboxamide (GML-3) is a potential candidate for combination drug therapy due to its anxiolytic and antidepressant activity. The anxiolytic activity of GML-3 is comparable to diazepam. The antidepressant activity of GML-3 is comparable to amitriptyline. GML-3 is an 18 kDa mitochondrial translocator protein (TSPO) ligand and is devoid of most of the side effects of diazepam, which makes the research on the creation of drugs based on it promising. However, its low water solubility and tendency to agglomerate prevented its release. This research aimed to study the effect of dry grinding, the rapid expansion of a supercritical solution (RESS), and the eutectic mixture (composite) of GML-3 with polyvinylpyrrolidone (PVP) on the particle size, dissolution rate, and lattice retention of GML-3. The use of supercritical CO2 in the RESS method was promising in terms of particle size reduction, resulting in a reduction in the particle size of GML-3 to 20-40 nm with a 430-fold increase in dissolution rate. However, in addition to particle size reduction after RESS, GML-3 began to show signs of a polymorphism phenomenon, which was also studied in this article. It was found that coarse grinding reduced particle size by a factor of 2 but did not significantly affect solubility or crystal structure. Co-milling with the polymer made it possible to level the effect of the appearance of a residual electrostatic charge on the particles, as in the case of grinding, and the increased solubility in the resulting mechanical mixtures of GML-3 with the polymer may also indicate the dissolving properties of polymers (an increase in 400-800 times). The best result in terms of GML-3 solubility was demonstrated by the resulting GML-3:PVP composite at a ratio of 1:4, which made it possible to achieve a solubility of about 80% active pharmaceutical ingredient (API) within an hour with an increase in the dissolution rate by 1600 times. Thus, the creation of composites is the most effective method for improving the solubility of GML-3, superior to micronization.