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Due to its excellent chemical and mechanical properties, titanium has become the material of choice for orthopedic and dental implants to promote rehabilitation via bone anchorage and osseointegration. Titanium osseointegration is partially related to its capability to form a TiO2 surface layer and its ability to interact with key endogenous proteins immediately upon implantation, establishing the first bone-biomaterial interface. Surgical trauma caused by implantation results in the release of High Mobility Group Box 1 (HMGB1) protein, which is a prototypic DAMP (Damage Associated Molecular Pattern) with multiple roles in inflammation and tissue healing. To develop different surface strategies that improve the clinical outcome of titanium-based implants by controlling their biological activity, a molecular-scale understanding of HMGB1-surface interactions is desired. Here, we use molecular dynamics (MD) computer simulations to provide direct insight into the HMGB1 interactions and the possible molecular arrangements of HMGB1 on fully hydroxylated and non-hydroxylated rutile (110) TiO2 surfaces. The results establish that HMGB1 is most likely to be adsorbed directly onto the surface regardless of surface hydroxylation, which is undesirable because it could affect its biological activity by causing structural changes to the protein. The hydroxylated TiO2 surface shows a greater affinity for HMGB1 than the non-hydroxylated surface. The water layer on the non-hydroxylated TiO2 surface prevents ions and the protein from directly contacting the surface. However, it was observed that if the ionic strength increases, the total number of ions adsorbed on the two surfaces increases, and the protein’s direct adsorption ability decreases. These findings will help to understand the HMGB1-TiO2 interactions upon implantation, as well as the development of different surface strategies by introducing ions or ionic materials to the titanium implant surface to modulate its interactions with HMGB1 to preserve biological function.

Curcumin, a potent phytochemical derived from the spice element turmeric, has been identified as a herbal remedy decades ago and has displayed promise in the field of medicinal chemistry. However, multiple traits associated with curcumin, such as poor bioavailability and instability, limit its effectiveness to be accepted as a lead drug-like entity. Different reactive sites in its chemical structure have been identified to incorporate modifications as attempts to improving its efficacy. The diketo group present in the center of the structural scaffold has been touted as the group responsible for the instability of curcumin, and substituting it with a heterocyclic ring contributes to improved stability. In this study, four heterocyclic curcumin analogues, representing some broad groups of heterocyclic curcuminoids (isoxazole-, pyrazole-, N-phenyl pyrazole- and N-amido-pyrazole-based), have been synthesized by a simple one-pot synthesis and have been characterized by FTIR, 1H-NMR, 13C-NMR, DSC and LC–MS. To predict its potential anticancer efficacy, the compounds have been analyzed by computational studies via molecular docking for their regulatory role against three key proteins, namely GSK-3β—of which abnormal regulation and expression is associated with cancer; Bcl-2—an apoptosis regulator; and PR which is a key nuclear receptor involved in breast cancer development. One of the compounds, isoxazole-curcumin, has consistently indicated a better docking score than the other tested compounds as well as curcumin. Apart from docking, the compounds have also been profiled for their ADME properties as well as free energy binding calculations. Further, the in vitro cytotoxic evaluation of the analogues was carried out by SRB assay in breast cancer cell line (MCF7), out of which isoxazole-curcumin (IC50–3.97 µM) has displayed a sevenfold superior activity than curcumin (IC50–21.89 µM). In the collation of results, it can be suggested that isoxazole-curcumin behaves as a potential lead owing to its ability to be involved in a regulatory role with multiple significant cancer proteins and hence deserves further investigations in the development of small molecule-based anti-breast cancer agents. Graphic abstract

Background: Consumers’ lifestyles demand high-quality products, requesting adequate fruit storage. Management of ethylene production is of paramount importance when planning postharvest storage, since this phytohormone is the key molecule behind the ripening and senescence process. Cold storage combined with 1-MCP has been one of the most applied postharvest treatments to extend the shelf-life of several fruit. However, 1-MCP is a potent inhibitor of ethylene action, leading frequently to the blockage of ripening denominated as ‘evergreen’ effect. Scope and approach: Ethylene biosynthesis and perception pathway are described, as well as a critical review on 1-MCP inhibitory mechanisms. Technologies used to induce postharvest ripening after 1-MCP application are described with special attention to the latest and most significant published works. The most relevant 1-MCP reversion strategies are discussed, aiming to develop more innovative and effective approaches for stimulating ripening. Finally, the importance of tailoring treatments to specific cultivars is discussed, using pear as a case study. Key findings and conclusions: Optimizing temperature and applying exogenous ethylene have been the main methods to reverse the effect of 1-MCP. Also, treatment with other phytohormones has shown promising results. However, the strategies effectiveness is dependent on the cultivar, time of application, and concentration of the applied compound. Also, since 1-MCP binds irreversibly to the ethylene receptor, the biosynthesis of new receptors may reverse the ‘evergreen’ behaviour. Therefore, attempts should be made to develop strategies according to each cultivar and their capacity to stimulate the expression of ethylene genes both related to its biosynthesis and perception. info:eu-repo/semantics/publishedVersion

Extracellular vesicles (EV) are a promising therapeutic tool in regenerative medicine. These particles were shown to accelerate wound healing, through delivery of regenerative mediators, such as microRNAs. Herein we describe an optimized and upscalable process for the isolation of EV smaller than 200 nm (sEV), secreted by umbilical cord blood mononuclear cells (UCB‐MNC) under ischemic conditions and propose quality control thresholds for the isolated vesicles, based on the thorough characterization of their protein, lipid and RNA content. Ultrafiltration and size exclusion chromatography (UF/SEC) optimized methodology proved superior to traditional ultracentrifugation (UC), regarding production time, standardization, scalability, and vesicle yield. Using UF/SEC, we were able to recover approximately 400 times more sEV per mL of media than with UC, and upscaling this process further increases EV yield by about 3‐fold. UF/SEC‐isolated sEV display many of the sEV/exosomes classical markers and are enriched in molecules with anti‐inflammatory and regenerative capacity, such as hemopexin and miR‐150. Accordingly, treatment with sEV promotes angiogenesis and extracellular matrix remodeling, in vitro. In vivo, UCB‐MNC‐sEV significantly accelerate skin regeneration in a mouse model of delayed wound healing. The proposed isolation protocol constitutes a significant improvement compared to UC, the gold‐standard in the field. Isolated sEV maintain their regenerative properties, whereas downstream contaminants are minimized. The use of UF/SEC allows for the standardization and upscalability required for mass production of sEV to be used in a clinical setting., Small extracellular vesicles (sEV) produced by umbilical cord blood mononuclear cells (UCB‐MNC) are rich sources of bioactive molecules likely involved in regenerative processes, such as wound healing. Here, we isolated UCB‐MNC‐sEV with an optimized methodology which can be easily upscaled and reproduced under stringent quality control. Herein, we confirm the regenerative potential of UCB‐MNC‐sEV, bringing them closer to the clinics.

The excess of salts can affect several processes in the crops, and nitrogen (N) can attenuate the depressive effect of salinity. The objective was to evaluate the influence of nitrogen doses on the growth and gas exchange of corn crop irrigated with saline water. The experiment was conducted from June to September 2019 at the University of International Integration of Afro-Brazilian Lusophony, Redenção, CE, Brazil. The experimental design was completely randomized, in a 2 x 3 factorial scheme (supply water of 0.3 dS m-1 and saline solution of 3.0 dS m-1) and three nitrogen doses, 0, 80, and 160 kg ha-1, corresponding to 0, 50, and 100% of the recommended dose respectively, with six repetitions. At 30 and 45 days after sowing (DAS), plant height, leaf area, number of leaves, photosynthesis, transpiration, and stomatal conductance were evaluated. Saline stress affects plant height, leaf area, photosynthesis, transpiration, and conductance at 30 DAS. The doses of 80 and 160 kg ha-1 provide greater performance in plant height, leaf area, photosynthesis, transpiration, and conductance at 30 DAS. The use of low salinity water and doses of 80 and 160 kg ha-1 were more efficient in terms of plant height, leaf area, photosynthesis, transpiration, and conductance at 45 DAS. The dose of 160 kg ha-1 of N attenuates the harmful effects of salts in AG 1051 hybrid maize plants, providing higher values of photosynthesis, transpiration, and stomatal conductance at 45 DAS when irrigated with water of 3.0 dS m-1.

In this study, a commercial enzyme cocktail designed for fruit juice clarification was immobilized on chitosan beads activated with glutaraldehyde and used for setting-up continuous packed-bed and fluidized-bed reactors. Firstly, the enzyme cocktail concentration in the immobilization process was tested to get maximum biocatalyst activity in the reaction. Then, the effect of pH and temperature on the free and immobilized enzyme cocktail stability and activity were studied. Despite the low enzyme cocktail activity recovery after immobilization (1 %), the stability of immobilized enzyme was greater compared to free enzyme, even under extreme reaction conditions. For example, when activity was measured at 90 °C and pH 4.8, the immobilized enzyme cocktail retained 80 % of its initial activity while the free enzyme retained only 35 %. Finally, the clarification capacity of the biocatalysts using orange juice was tested, providing clearer juices when performed in the fluidized-bed reactor, showing 60 % of its initial clarification capacity after 72 h of continuous use. Otherwise, the clarification rate in the packed-bed reactor decreased linearly during 54 h, probably due to the formation of dead zones and preferential paths along the bed. Pectinase immobilized on chitosan particles and used in fluidized-bed reactor seems to be a good alternative for large scale application on juice clarification.

The aim of this study was to evaluate growth, biomass production and mineral composition of forage grasses subjected to different times of potassium (K) application. The experiment was carried out ...

This study investigated the anti-inflammatory and antioxidant effects of hydroalcoholic extracts of mango peel and pulp on oxidative damage in a naproxen-induced gastric injury rat model. The extracts were assessed for antioxidant activity (ABTS and FRAP methods), and the phenolic profile was investigated with UPLC-QToF-MSE . Gastric damage was evaluated in vivo by assessing the membrane lipid peroxidation (malondialdehyde (MDA) content), myeloperoxidase (MPO) enzyme activity, and glutathione (GSH) content. Mango peel and pulp contained high contents of bioactive compounds, particularly phenolics (69.50-5.287.70 mg gallic acid equivalents/100 g), carotenoids (651.30-665.50 μg/100 g), and vitamin C (21.59-108.19 mg/100 g). UPLC-QToF-MSE analysis identified 17 phenol compounds, including gallotannins, glycosylated flavonoids, and xanthone. The hydroalcoholic extracts of mango peel and pulp (LPe and LPu, respectively) significantly reduced the MPO activity and MDA content. In addition to preventing naproxen-induced GSH decline, LPe (30 mg/kg) and LPu (10 mg/kg) restored its content to normal levels. LPe and LPu neutralized the oxidizing agents triggered by naproxen and reduced the severity of gastric lesions owing to their antioxidant properties.

OBJECTIVE: Multiple implantations of the implant healing abutment (IHA) could adversely impact its surface properties in vivo. Furthermore, the effect of sterilization and reuse of the IHA on soft tissue viability and bacterial contamination has not been extensively studied. The goal of this study was to perform an in vitro analysis of mammalian cell viability and bacterial adhesion on the surfaces of retrieved IHA after single & multiple implantations and repetitive cycles of sterilization. MATERIALS AND METHODS: IHA surface morphology was studied using optical microscopy. Cell viability of gingival fibroblasts (HGF-1) and oral keratinocytes (HOKg) in indirect contact with IHAs was assessed for 3 and 7 days. Immersion in bacterial culture was performed with a polyculture of Streptococcus species for 3 days and Streptococcus species with Fusobacterium nucleatum for 7 days. RESULTS: IHAs exhibited signs of surface damage even after a single exposure to the oral cavity. Fibroblasts did not show a significant preference towards control IHAs over used IHAs, whereas keratinocytes exhibited a significant decrease in viability when exposed to IHAs after multiple implantation cycles as compared to controls. Adherent bacterial count increased with increasing number of IHA implantations for both polycultures. CONCLUSIONS: Reusing of IHAs in vivo promoted surface degradation in addition to adversely impacting host cell viability and oral bacterial attachment in vitro. These findings show IHA reuse might potentially affect its clinical performance. CLINICAL RELEVANCE: Careful consideration should be taken when reusing IHAs in patients because this practice can result in permanent surface changes that might affect soft tissue integration during the healing period and promote bacterial colonization.

Objective Very few studies have investigated dental implant components involved in the early stage of healing, especially the implant healing abutment (IHA), despite its vital role in soft tissue contouring and shaping after implant placement. Although these components are labelled by the manufacturer for “single-use only,” it is a common clinical practice to clean, sterilize, and reuse them. Methods In the present study, IHAs after single and multiple implantations were retrieved as per standard procedures, and biological material isolated from the surface was subjected to 16S rRNA sequence analysis. The microbiome analysis was followed by cleaning and sterilization in order to replicate clinical sterilization techniques. Following sterilization, retrievals were subjected to surface characterization with optical and scanning electron microscopy to investigate surface features, and electrochemical testing was performed to evaluate corrosion behavior. Results The microbiota was comprised of early colonizers including Streptococcus species and secondary anaerobic colonizers such as Fusobacterium, Capnocytophaga, and Prevotella species. The surface analysis revealed that irrespective of the cleaning and sterilization techniques, the pristine, homogeneous surface of the new, unused IHAs could not be restored. Both single and multiple-use IHAs had severe surface changes including discoloration, major abrasions, biological contamination, and the IHA retrievals exhibited higher corrosion rate as compared to control specimens. Significance Reusing IHAs multiple times may not be a prudent practice as the microbial colonization and surface changes caused by using this component multiple times may affect the performance of IHAs in soft tissue healing.

Cellular proteostasis is maintained by a system consisting of molecular chaperones, heat shock proteins (Hsps) and proteins involved with degradation. Among the proteins that play important roles in the function of this system is Hsp90, which acts as a node of this network, interacting with at least 10% of the proteome. Hsp90 is ATP-dependent, participates in critical cell events and protein maturation and interacts with large numbers of co-chaperones. The study of Hsp90 orthologs is justified by their differences in ATPase activity levels and conformational changes caused by Hsp90 interaction with nucleotides. This study reports the characterization of Hsp90 from Aedes aegypti, a vector of several diseases in many regions of the planet. Aedes aegypti Hsp90, AaHsp90, was cloned, purified and characterized for its ATPase and chaperone activities and structural conformation. These parameters indicate that it has the characteristics of eukaryotic Hsp90s and resembles orthologs from yeast rather than from human. Finally, constitutive and increased stress expression in Aedes cells was confirmed. Taken together, the results presented here help to understand the relationship between structure and function in the Hsp90 family and have strong potential to form the basis for studies on the network of chaperone and Hsps in Aedes.

Glucosamine is a component of many cellular glycoproteins that constitutes the cartilage, and it has several biological activities, such as anti-inflammatory, antioxidant, antifibrotic, and anticancer, and has been used in arthritis and dermatological treatments. Considering that the biological activities of glucosamine occur mainly in an aqueous environment, it is essential to understand the effects of an aqueous solvent on its geometric and electronic parameters using ab initio molecular dynamics. The Car-Parrinello molecular dynamics results show that the hydroxyl groups form stable hydrogen bonds with the water molecules with intensities ranging from weak (closed-shell interaction) to intermediate (partially covalent interactions). The H bonds formed between the amino group and the water molecule range from weak (closed-shell) to strong (covalent), and it shows an infinity residence time. The natural bonding orbital (NBO) approach was applied to analyze the effects of charge-transfer interactions on the behavior of the hydrogen bonds. The main contribution to stabilizing energies comes from n → σ* hyperconjugation and explains the stability of the H bonds. The energy barrier for the proton transfer from water to the amino group is 0.88 kcal/mol, and the van der Waals complex energy is 0.3 kcal/mol. The low protonation energy barrier shows that glucosamine can be protonated in an aqueous environment at room temperature, which helps to explain many of its biological activities.

The objective of this paper was to optimize, by composite central design coupled to response surface methodology, the enzymatic biodiesel production from oil coming from fish waste, and to characterize the obtained product. The lipase from Thermomyces lanuginosus immobilized on octadecyl metacrylate beads was used as biocatalyst. Optimal conditions were temperature of 35 °C, 10% w/w of biocatalyst content and 216 rpm of agitation rate. Under optimal conditions, an experimental biodiesel yield of 75.3% was obtained after 24 h of reaction time. The biodiesel presented an acid value (0.9 ± 0.28 mg KOH/g) that was higher than the established limits, while other parameters like density (0.89 ± 0.01 g/mL), viscosity (5.3 ± 0.004 mm2/s), calorific value (38.1 ± 0.21 MJ/kg) and cloud point (10.5 ± 0.47 °C), complied with the recommendations of the ASTM D6751 standard.

Gene regulation and metabolism are two fundamental processes that coordinate the self-renewal and differentiation of neural precursor cells (NPCs) in the developing mammalian brain. However, little is known about how metabolic signals instruct gene expression to control NPC homeostasis. Here, we show that methylglyoxal, a glycolytic intermediate metabolite, modulates Notch signalling to regulate NPC fate decision. We find that increased methylglyoxal suppresses the translation of Notch1 receptor mRNA in mouse and human NPCs, which is mediated by binding of the glycolytic enzyme GAPDH to an AU-rich region within Notch1 3ʹUTR. Interestingly, methylglyoxal inhibits the enzymatic activity of GAPDH and engages it as an RNA-binding protein to suppress Notch1 translation. Reducing GAPDH levels or restoring Notch signalling rescues methylglyoxal-induced NPC depletion and premature differentiation in the developing mouse cortex. Taken together, our data indicates that methylglyoxal couples the metabolic and translational control of Notch signalling to control NPC homeostasis., Gene regulation and metabolism co-ordinate self-renewal and differentiation of neural precursors (NPCs) in the developing brain. Here the authors show that methylglyoxal, a glycolytic intermediate metabolite, promotes GADPH-dependent translational repression of Notch1, thereby promoting NPC differentiation.

This study aimed to evaluate the quality traits and fatty acid profile of beef from Nellore and Angus bulls fed whole shelled corn (WSC) and ground corn plus maize silage (GC) diets. Eighteen Nellore and 18 Angus young bulls [381 ± 12 kg initial body weight (BW) and an average age of 20 ± 1.9 months] were used in a completely randomized design using a 2 × 2 factorial arrangement and were slaughtered at a final BW of 451.5 kg and 545.5 kg, respectively. Twenty–four hours after slaughter, samples of longissimus thoracis muscle were collected for the analysis of lipid oxidation, color, fatty acid profile, shear force, and cooking loss. There was no effect of diet × breed interaction on meat color, lipid oxidation, shear force, and cooking loss. Angus beef had lower shear force (p < 0.05) than Nellore beef and had a greater concentration of linoleic acid and polyunsaturated fatty acids (PUFA) (p < 0.01). Beef of bulls fed WSC tended to have greater concentration of CLA C18:2c9t11 (p = 0.09), greater concentration of CLA C18:2t10c12 (p = 0.01), and PUFA (p = 0.05), and consequently, higher oxidation levels. Angus bulls produced beef with greater tenderness and PUFA concentration. The results of fatty acid show a possible change in biohydrogenation when animals are fed the WSC diet, reducing lipogenesis, as this diet increases the C18:2t10c12 content.

The human Abl kinases comprise a family of proteins that are known to be key stimulus drivers in the signaling pathways modulating cell growth, cell survival, cell adhesion, and apoptosis. Recent collative studies have indicated the role of activation of Abl and Abl-related genes in solid tumors; further terming the Abl kinases as molecular switches which promote proliferation, tumorigenesis, and metastasis. The up-regulated Abl-kinase expression in colorectal cancer (CRC) and the role of Abl tyrosine kinase activity in the Matrigel invasion of CRC cells have cemented its significance in CRC advancement. Therefore, the requisite of identifying small molecules which serve as Abl selective inhibitors and designing anti-Abl therapies, particularly for CRC tumors, has driven this study. Curcumin has been touted as an effective inhibitor of cancer cells; however, it is limited by its physicochemical inadequacies. Hence, we have studied the behavior of heterocyclic derivatives of curcumin via computational tools such as pharmacophore-based virtual screening, molecular docking, free-energy binding, and ADME profiling. The most actively docked molecule, 3,5-bis(4-hydroxy-3-methylstyryl)-1H-pyrazole-1-carboxamide, was comparatively evaluated against Curcumin via molecular dynamics simulation using Desmond, Schrödinger. The study exhibited the improved stability of the derivative as compared to Curcumin in the tested protein pocket and displayed the interaction bonds with the contacted key amino acids. To further establish the claim, the derivatives were synthesized via the mechanism of cyclization of Curcumin and screened in vitro using SRB assay against human CRC cell line, HCT 116. The active derivative indicated an IC50 value of 5.85 µM, which was sevenfold lower as compared to Curcumin’s IC50 of 35.40 µM. Hence, the results base the potential role of the curcumin derivative in modulating Abl-kinase activity and in turn may have potential therapeutic value as a lead for CRC therapy. Supplementary Information The online version contains supplementary material available at 10.1007/s13205-021-03051-9.

A novel cellulose acetate-based monophasic hybrid skinned amine-functionalized CA-SiO2-(CH2)3NH2 membrane was synthesized using an innovative method which combines the phase inversion and sol-gel techniques. Morphological characterization was performed by scanning electron microscopy (SEM), and the chemical composition was analyzed by Fourier transform infrared spectroscopy in attenuated total reflection mode (ATR-FTIR). The characterization of the monophasic hybrid CA-SiO2-(CH2)3NH2 membrane in terms of permeation properties was carried out in an in-house-built single hemodialysis membrane module (SHDMM) under dynamic conditions. Permeation experiments were performed to determine the hydraulic permeability (Lp), molecular weight cut-off (MWCO) and the rejection coefficients to urea, creatinine, uric acid, and albumin. SEM confirmed the existence of a very thin (&lt, 1 µm) top dense layer and a much thicker bottom porous surface, and ATR-FTIR showed the main bands belonging to the CA-based membranes. Permeation studies revealed that the Lp and MWCO of the CA-SiO2-(CH2)3NH2 membrane were 66.61 kg·h−1·m−2·bar−1 and 24.5 kDa, respectively, and that the Lp was 1.8 times higher compared to a pure CA membrane. Furthermore, the CA-SiO2-(CH2)3NH2 membrane fully permeated urea, creatinine, and uric acid while completely retaining albumin. Long-term filtration studies of albumin solutions indicated that fouling does not occur at the surface of the CA-SiO2-(CH2)3NH2 membrane.

Infections caused by parasitic worms impose a considerable worldwide health burden. One of the most impactful is schistosomiasis, a disease caused by blood-dwelling of the genus Schistosoma that affects more than 230 million people worldwide. Since praziquantel has also been extensively used to treat schistosomiasis and other parasitic flatworm infections, there is an urgent need to identify novel anthelmintic compounds, mainly from natural sources. In this study, the hexane extract from roots of Piper malacophyllum (Piperaceae) showed to be mainly composed for gibbilimbol B by HPLC/ESI-HRMS. Based on this result, this compound was isolated by chromatographic steps and its structure was confirmed by NMR. In vitro bioassays showed that gibbilimbol B was more active than praziquantel against larval stage of S. mansoni, with effective concentrations of 50 % (EC50 ) and 90 % (EC90 ) values of 2.6 and 3.4 μM, respectively. Importantly, gibbilimbol B showed no cytotoxicity to mammalian cells at a concentration 190 times greater than the antiparasitic effect, giving support for the anthelmintic potential of gibbilimbol B as lead compound for novel antischistosomal agents.

To solve different kinds of optimization challenges, meta-heuristic algorithms have been extensively used. Population initialization plays a prominent role in meta-heuristic algorithms for the problem of optimization. These algorithms can affect convergence to identify a robust optimum solution. To investigate the effectiveness of diversity, many scholars have a focus on the reliability and quality of meta-heuristic algorithms for enhancement. To initialize the population in the search space, this dissertation proposes three new low discrepancy sequences for population initialization instead of uniform distribution called the WELL sequence, Knuth sequence, and Torus sequence. This paper also introduces a detailed survey of the different initialization methods of PSO and DE based on quasi-random sequence families such as the Sobol sequence, Halton sequence, and uniform random distribution. For well-known benchmark test problems and learning of artificial neural network, the proposed methods for PSO (TO-PSO, KN-PSO, and WE-PSO), BA (BA-TO, BA-WE, and BA-KN), and DE (DE-TO, DE-WE, and DE-KN) have been evaluated. The synthesis of our strategies demonstrates promising success over uniform random numbers using low discrepancy sequences. The experimental findings indicate that the initialization based on low discrepancy sequences is exceptionally stronger than the uniform random number. Furthermore, our work outlines the profound effects on convergence and heterogeneity of the proposed methodology. It is expected that a comparative simulation survey of the low discrepancy sequence would be beneficial for the investigator to analyze the meta-heuristic algorithms in detail.

The aim of this work is to present the numerical results of the influenza disease nonlinear system using the feed forward artificial neural networks (ANNs) along with the optimization of the combination of global and local search schemes. The genetic algorithm (GA) and active-set method (ASM), i.e., GA-ASM, are implemented as global and local search schemes. The mathematical nonlinear influenza disease system is dependent of four classes, susceptible S(u), infected I(u), recovered R(u) and cross-immune individuals C(u). For the solutions of these classes based on influenza disease system, the design of an objective function is presented using these differential system equations and its corresponding initial conditions. The optimization of this objective function is using the hybrid computing combination of GA-ASM for solving all classes of the influenza disease nonlinear system. The obtained numerical results will be compared by the Adams numerical results to check the authenticity of the designed ANN-GA-ASM. In addition, the designed approach through statistical based operators shows the consistency and stability for solving the influenza disease nonlinear system.

Umbilical cord blood (UCB) has long been seen as a rich source of naïve cells with strong regenerative potential, likely mediated by small extracellular vesicles (sEV). More recently, small extracellular vesicles (sEV), such as exosomes, have been shown to play essential roles in cell-to-cell communication, via the transport of numerous molecules, including small RNAs. Often explored for their potential as biomarkers, sEV are now known to have regenerative and immunomodulating characteristics, particularly if isolated from stem cell-rich tissues. In this study, we aim to characterize the immunomodulating properties of umbilical cord blood mononuclear cell sEV (herein referred as Exo-101), and explore their therapeutic potential for inflammatory skin diseases. Exo-101 was shown to shift macrophages toward an anti-inflammatory phenotype, which in turn exert paracrine effects on fibroblasts, despite previous inflammatory stimuli. Additionally, the incubation of PBMC with Exo-101 resulted in an reduction of total CD4+ and CD8+ T-cell proliferation and cytokine release, while specifically supporting the development of regulatory T-cells (Treg), by influencing FOXP3 expression. In a 3D model of psoriatic skin, Exo-101 reduced the expression of inflammatory and psoriatic markers IL-6, IL-8, CXCL10, COX-2, S100A7 and DEFB4. In vivo, Exo-101 significantly prevented or reversed acanthosis in imiquimod-induced psoriasis, and tendentially increased the number of Treg in skin, without having an overall impact on disease burden. This work provides evidence for the anti-inflammatory and tolerogenic effect of Exo-101, which may be harnessed for the treatment of Th17-driven inflammatory skin diseases, such as psoriasis.

Metaheuristic algorithms have been widely used to solve diverse kinds of optimization problems. For an optimization problem, population initialization plays a significant role in metaheuristic algorithms. These algorithms can influence the convergence to find an efficient optimal solution. Mainly, for recognizing the importance of diversity, several researchers have worked on the performance for the improvement of metaheuristic algorithms. Population initialization is a vital factor in metaheuristic algorithms such as PSO and DE. Instead of applying the random distribution for the initialization of the population, quasirandom sequences are more useful for the improvement the diversity and convergence factors. This study presents three new low-discrepancy sequences named WELL sequence, Knuth sequence, and Torus sequence to initialize the population in the search space. This paper also gives a comprehensive survey of the various PSO and DE initialization approaches based on the family of quasirandom sequences such as Sobol sequence, Halton sequence, and uniform random distribution. The proposed methods for PSO (TO-PSO, KN-PSO, and WE-PSO) and DE (DE-TO, DE-WE, and DE-KN) have been examined for well-known benchmark test problems and training of the artificial neural network. The finding of our techniques shows promising performance using the family of low-discrepancy sequences over uniform random numbers. For a fair comparison, the approaches using low-discrepancy sequences for PSO and DE are compared with the other family of low-discrepancy sequences and uniform random number and depict the superior results. The experimental results show that the low-discrepancy sequences-based initialization performed exceptionally better than a uniform random number. Moreover, the outcome of our work presents a foresight on how the proposed technique profoundly impacts convergence and diversity. It is anticipated that this low-discrepancy sequence comparative simulation survey would be helpful for studying the metaheuristic algorithm in detail for the researcher.

Previously unreported anthraquinone, acetylpenipurdin A (4), biphenyl ether, neospinosic acid (6), dibenzodioxepinone, and spinolactone (7) were isolated, together with (R)-6-hydroxymellein (1), penipurdin A (2), acetylquestinol (3), tenellic acid C (5), and vermixocin A (8) from the culture of a marine sponge-associated fungus Neosartorya spinosa KUFA1047. The structures of the previously unreported compounds were established based on an extensive analysis of 1D and 2D NMR spectra as well as HRMS data. The absolute configurations of the stereogenic centers of 5 and 7 were established unambiguously by comparing their calculated and experimental electronic circular dichroism (ECD) spectra. Compounds 2 and 5–8 were tested for their in vitro acetylcholinesterase and tyrosinase inhibitory activities as well as their antibacterial activity against Gram-positive and Gram-negative reference, and multidrug-resistant strains isolated from the environment. The tested compounds were also evaluated for their capacity to inhibit biofilm formation in the reference strains.

The role of microRNAs in metabolic diseases has been recognized and modulation of them could be a promising strategy to treat obesity and obesity-related diseases. The major purpose of this study was to test the hypothesis that intramuscular miR-1 precursor replacement therapy could improve metabolic parameters of mice fed a high-fat diet. To this end, we first injected miR-1 precursor intramuscularly in high-fat diet-fed mice and evaluated glucose tolerance, insulin sensitivity, and adiposity. miR-1-treated mice did not lose weight but had improved insulin sensitivity measured by insulin tolerance test. Next, using an in vitro model of insulin resistance by treating C2C12 cells with palmitic acid (PA), we overexpressed miR-1 and measured p-Akt content and the transcription levels of a protein related to fatty acid oxidation. We found that miR-1 could not restore insulin sensitivity in C2C12 cells, as indicated by p-Akt levels and that miR-1 increased expression of Pgc1a and Cpt1b in PA-treated cells, suggesting a possible role of miR-1 in mitochondrial respiration. Finally, we analyzed mitochondrial oxygen consumption in primary skeletal muscle cells treated with PA and transfected with or without miR-1 mimic. PA-treated cells showed reduced basal respiration, oxygen consumption rate-linked ATP production, maximal and spare capacity, and miR-1 overexpression could prevent impairments in mitochondrial respiration. Our data suggest a role of miR-1 in systemic insulin sensitivity and a new function of miR-1 in regulating mitochondrial respiration in skeletal muscle.

The revolutionary idea of the internet of things (IoT) architecture has gained enormous popularity over the last decade, resulting in an exponential growth in the IoT networks, connected devices, and the data processed therein. Since IoT devices generate and exchange sensitive data over the traditional internet, security has become a prime concern due to the generation of zero-day cyberattacks. A network-based intrusion detection system (NIDS) can provide the much-needed efficient security solution to the IoT network by protecting the network entry points through constant network traffic monitoring. Recent NIDS have a high false alarm rate (FAR) in detecting the anomalies, including the novel and zero-day anomalies. This paper proposes an efficient anomaly detection mechanism using mutual information (MI), considering a deep neural network (DNN) for an IoT network. A comparative analysis of different deep-learning models such as DNN, Convolutional Neural Network, Recurrent Neural Network, and its different variants, such as Gated Recurrent Unit and Long Short-term Memory is performed considering the IoT-Botnet 2020 dataset. Experimental results show the improvement of 0.57–2.6% in terms of the model’s accuracy, while at the same time reducing the FAR by 0.23–7.98% to show the effectiveness of the DNN-based NIDS model compared to the well-known deep learning models. It was also observed that using only the 16–35 best numerical features selected using MI instead of 80 features of the dataset result in almost negligible degradation in the model’s performance but helped in decreasing the overall model’s complexity. In addition, the overall accuracy of the DL-based models is further improved by almost 0.99–3.45% in terms of the detection accuracy considering only the top five categorical and numerical features.

The aim of this study was to investigate the effect of altering design variables like cross-linking and freezing temperature (at a time) on morphology of freeze-dried chitosan scaffolds and modulation of release of Diclofenac sodium (model drug). Freeze-dried chitosan scaffolds produced at − 80 °C, cross-linked with genipin, showed swelling of 163.52 ± 9.95% with sustained drug release of 26.37 ± 10.47% over 24 h (P

A dihydropyrimidine (DHPM) derivative was synthesized, characterized by X-ray diffraction and searched in silico for its inhibitory activities against AccD5 enzyme, the CT domain of a Mycobacterium tuberculosis ACCase. Its molecular structure was compared to another DHPM derivative (DHPM II). The results have shown that the (±)2,6-methano-4-thioxo-3,4,5,6-tetrahydro-2H-[1,3,5] benzoxadiazocines (DHPM I) and (±)2,6-methano-4-oxo-3,4,5,6-tetrahydro-2H-[1,3,5] benzoxadiazocines (DHPM II) belong to the monoclinic and triclinic systems, respectively, and their crystal structures are stabilized by N–H⋯O, O–H⋯O and N–H⋯S interactions. The DHPM derivatives established hydrogen bond interactions with the oxyanion-stabilizing residues (Gly-434/Ala-435) beyond the Thr-217, Phe-394 and Ile-216 in the biotin pocket. The predicted MoB of the DHPM derivatives (21R, 24S, 22R) configuration showed that its phenyl moiety was positioned on the interface between the biotin and propionyl-CoA pockets, suggesting a possible blockade of both subsites. Additionally, the hydrogen bonds involving the O-bridged phenyl ring of the DHPM derivatives (21S, 24R, 22S) configuration with Gly434 in the oxyanion-stabilizing region placed its phenyl moiety in the bottom of the biotin pocket establishing hydrophobic interactions with Leu164, Tyr167, Val459 and Ala155. These results indicate the DHPM derivatives as potential AccD5 inhibitors and promising starting points for future optimizations. Although the overlap of DHPM I and DHPM II did not present significant differences, the exchange of a sulfur atom for an oxygen atom increased the predicted biological potential.

Cement-retained restorations on dental implants are a well-established method to replace missing teeth. However, undetected residual cement left during crown cementation procedures encourages microorganism growth, and it has been identified as a risk factor for peri-implant disease. Currently, there is no official guidance for dental cement selection, and the increasing variety of available compositions intensifies the complexity of the clinicians' decision process. The present study aimed to evaluate the in vitro host and bacterial cellular response to four different commercial dental cements as well as their effects on cement surface morphology. Disk specimens (n = 3) of bioceramic, zinc phosphate, resin-modified glass ionomer, and resin cements were exposed to host (murine pre-osteoblasts, human gingival fibroblasts, and undifferentiated human macrophages) and oral bacterial (Streptococcus mutans, Streptococcus salivarius, Streptococcus sanguinis, and Aggregatibacter actinomycetemcomitans) cells. Results indicated that oral bacteria degraded the cement surface, but bacterial viability was not significantly affected by the presence of dental cement. Conversely, the biocompatibility and morphology of host cells were severely impacted by the cement composition. Only the bioceramic cement achieved >70% viability for all cell lines investigated. Within the limitations of this study, the results indicated the importance of considering the biological interactions of a dental cement composition during selection as it played a significant role in the host cellular response and the degree of surface degradation due to bacterial attack.

Curcumin is a pharmacologically active polyphenol derived from the popular spice element-Turmeric. The therapeutic activity of curcumin has been extensively investigated over the last few decades and reports suggest the role of curcumin in a large number of biological activities, particularly its prominent anticancer activity. Curcumin, being a pleiotropic molecule, is a regulator of multiple molecular targets which play crucial roles in various cell signaling pathways. It is known to suppress transformation, inhibit proliferation as well as induce apoptosis. However, despite all these benefits, the efficacy of curcumin remains limited due to its poor bioavailability, poor absorption within the systemic circulation and rapid elimination from the body. To overcome these limiting factors, researchers all around the world are working towards designing a synthetic and superior curcuminoid by making suitable structural modifications to the parent skeleton. These curcuminoids, mainly analogues and derivatives, will not only improve the physicochemical properties but also enhance the efficacy simultaneously. The present review will provide a comprehensive account of the analogues and derivatives of curcumin that have been reported since 2014 which have indicated a better anticancer activity than curcumin.

In this work, we studied the effect of some variables in the reaction between genipin and chitosan, to prepare a support for enzyme immobilization. Reaction temperature, pH, time and genipin concentration were evaluated for support activation and β-galactosidase from Aspergillus oryzae was used as the enzyme model. The immobilized enzyme was characterized by immobilization properties and kinetic parameters and by thermal and operational stability. It was found that support activation at alkaline pH (9.0), at 60 °C for 1 h, resulted in an activity recovery of 37.5%. The immobilized enzyme had a stabilization factor of 2.0 at 50 °C compared with the free enzyme. In batch process, the immobilized preparation kept 100% of its relative initial activity during 40 batches. This research shows, for the first time, a complete study about the parameters that affect the support activation process and the possible structure formed between genipin and chitosan.

The incomplete anthocyanin extraction during the industrial processes turns grape pomace into an inexpensive source of phenolic compounds. The effects of temperature and enzyme preparation percentage (% E/S) on the anthocyanin recovery from grape pomaces of eight grape varieties were evaluated by their physicochemical characteristics and phenolic composition. A factorial 22 design with center point was used to select the preferred conditions for extraction, and the variables of temperature, enzyme preparation, and their interaction were assessed. The grape skin characteristics affected the anthocyanins’ content and their recovery yield, and different improvement conditions were found for each variety of grape. Anthocyanin extraction from Cabernet Sauvignon—the variety which showed the highest percentage of anthocyanin recovery (over 50%)—was improved. The lowest tested temperature (40 °C) and percentage of preparation enzymatic (0.25% E/S) promoted higher anthocyanin extraction, resulting in a natural food colorant with 2.67 g anthocyanins/100 g grape skin dry basis (db). The extraction improvement allowed for a non-toxic natural extract rich in anthocyanins to be obtained; a natural additive which can be considered for potential food industry use in place of synthetic dyes, especially into acidic matrices.

The graft polymerization of methyl methacrylate (MMA) from pre-irradiated polypropylene (PP) films mediated by two different addition-fragmentation chain transfer (RAFT) polymerization mechanisms—surface-initiated RAFT polymerization and interface-mediated RAFT polymerization was studied. In the first mechanism, electron beam irradiation technique was applied to produce the initial radical active sites and peroxides on PP films. 4-cyanopentanoic acid dithiobenzoate (CPADB) was added in the solution to mediate the graft polymerization. In the second mechanism, a new technique utilizing the decomposition and recombination of peroxides produced by electron beam and di(thiobenzoyl) disulfide (DBDS) to anchor CTA on PP films was applied. GPC, ATR-FTIR, XPS, SEM and water contact angle were used to characterize graft layer. Surface-initiated RAFT polymerization was found to be fast and facile with high degree of grafting (Dg) and large number-average molecular weight. But the samples after reaction were swelling and out of shape. Interface-mediated RAFT polymerization led to rather low Dg and low molecular weight. But the samples kept their pristine shapes and had better surface properties.

Even in specialized centers, suboptimal aneurysm clipping can be as high as 12%. Intraoperative fluorescence angiography with indocyanine green and, more recently, fluorescein sodium have been shown to be a good method for intraoperative flow assessment. However, the cost with the apparatus it entails limits its widespread use. We have developed a low-cost universal fluorescence module (FM) designed to visualize fluorescein and perform intraoperative angiography. The purpose of this paper is to describe this device as well as to present our early experience with its use in the treatment of cerebral aneurysms. A FM was designed and built using a cyan-blue narrow bandpass (460 to 490 nm) excitation filter and a yellow-orange longpass (blocking wavelengths under 520 nm) barrier filter mounted on a 3D-printed holding tray in a specific disposition to perfectly match the light source and the objective lens of the surgical microscope. It allowed switching from white light to fluorescence mode in a simple and sterile fashion. Its perfect attachment to the microscope was possible by reusing the lens fittings extracted from used original drape sets that would otherwise be discarded. Four patients underwent aneurysm clipping using the FM at two institutions from April to September 2018. A bright green fluorescence against a dark background was observed after intravenous bolus of fluorescein. Blood vessels became obviously distinct from non-contrast-filled structures such as clipped aneurysms and the brain. Vascular anatomy could be appreciated without any distortion, including perforating arteries. Intraoperative fluorescence angiography was successfully performed with the use of this universal FM after intravenous injection of fluorescein sodium. This simple and low-cost device may be useful in resource-limited centers, where other sorts of intraoperative angiography are not available.

This paper shows the direct comparison of 4 different catalysts (homogenous alkaline (KOH), heterogeneous alkaline (CaO), homogenous acid (H2SO4) and a new biocatalyst (lipase from Thermomyces lanuginosus (TLL) immobilized on octadecyl methacylate)) in the production of biodiesel from cooking oils. The reactions for each catalyst were optimized using response surface statistical methodology, considering as main parameters: substrates molar ratio, percentage of catalyst and reaction time, whereas for enzymatic catalysis instead reaction time, we studied water concentration. Alkaline homogenous catalysis was found to be the most effective, as expected from literature. However, for first time, the new biocatalyst from TLL is just around one order of magnitude under the homogenous catalysis in reaction rate and surpassed the heterogeneous catalysis or the acid catalysis (similar yields in 2 h versus the 1 h of the alkaline catalyst). Moreover, the reaction product using the biocatalytic approach was much cleaner and less energy demanding than the other catalytic approaches. From our view, this is the first report where biocatalysis is close to conventional catalysis in the production of biodiesel.

Three β-glucosidases (Pectinex Ultra SP-L, Pectinex Ultra Clear and homemade preparation from Aspergillus niger) were immobilized using different strategies: ionic adsorption on aminated (MANAE)-agarose beads at pH 5, 7, and 9, followed by biocatalysts modification with glutaraldehyde, or on glutaraldehyde pre-activated supports. The pH of the immobilization was altered to allow different enzyme molecule orientations on the support surface. The biocatalysts from Pectinex Ultra SP-L showed the highest thermal and operational stabilities when immobilized on MANAE-agarose-glutaraldehyde at pH 7. The β-glucosidase from Pectinex Ultra Clear and from A. niger produced best results when immobilized on MANAE-agarose beads at pH 5 and 7, respectively, which was later treated with glutaraldehyde. The best immobilization results using pre-activated supports were observed for the enzyme present in Pectinex Ultra SP-L, to which the highest thermal stabilities were obtained. Remarkably, the enzyme from A. niger, immobilized on MANAE-agarose at pH 9 and subsequently treated with glutaraldehyde, produced the highest stabilization (approximately 560 times more stable than soluble enzyme at 60 °C). Results showed that optimal protocol for β-glucosidases immobilizations using the glutaraldehyde chemistry must be individually tested and tailored to each type of enzyme.

Currently many assume that bacteria are the primary etiological factor associated with failure of titanium dental implants. However, emerging data indicates a possible role for mechanical forces in implant failure. This study is based on the hypothesis that the synergistic effect of mechanical forces and bacterial biofilm can lead to surface damage resulting in in vivo release of metallic particles. The primary aim of the study was to develop a dynamic fatigue test method for dental implants immersed in wet environments such as; (i) 0.01 M phosphate buffer saline (PBS); (ii) lactic acid (pH = 5); (iii) bacterial polyculture. Four dental implants each were subjected to fatigue loading from 45 N to 450 N at 4 Hz for 2 million cycles while immersed in (i) PBS (negative control); (ii) bacterial culture (test); and (iii) lactic acid (positive control). Post-testing, optical microscopy, x-ray photoelectron spectroscopy, and electrochemical corrosion tests were performed to evaluate the surface morphology, chemistry, and potential, respectively, of titanium implants. Post-testing, surface discoloration was evident in all three groups. However, the surface damage was further established in XPS analyses of test specimens, which showed that the interplay of bacterial biofilm and mechanical forces resulted in thinning of the TiO2. Lower corrosion potential (Ecorr) of the test specimens compared to positive and negative controls also illustrated damage to the oxide layer. However, other electrochemical parameters such as linear polarization resistance (LPR) and corrosion rate (CR) were comparable among the groups indicating the corrosion resistance post-testing. The synergistic effect of cyclic occlusal loading and bacteria biofilm could negatively affect the surface of titanium dental implants.

The β-glucosidase activities of nine commercial enzymatic preparations were compared by evaluating the effects of pH, thermal stability, kinetic parameters, and glucose tolerance. The pH value of the reaction medium strongly influenced the activities, stabilities, and glucose inhibition of the assayed β-glucosidases. Celluclast® 1.5 L showed the highest activity on pNPG hydrolysis (70.55 U mL−1 and 0.69 U mg−1), whereas Lallzyme Beta produced the highest yields on cellobiose hydrolysis (93.4%). Regarding the glucose tolerance and the pH, Pectinex Ultra SP-L presented the maximum glucose tolerance at pH 3.0, keeping 54% of its initial activity in the presence of 167 mmol L−1 of glucose, whereas at pH 7.0, Pectinex Smash XXL presented 44% of activity at 222 mmol L−1 of glucose. Pectinex Smash XXL showed the highest KI (19.75 mol L−1), whereas Celluclast® 1.5 L presented the highest KI/KM (19). Our results suggest that these commercial preparations are promising sources of β-glucosidases, being Pectinex Smash XXL indicated for applications at neutral pH because of its glucose tolerance and thermal stability at this pH value, whereas Celluclast® 1.5 L, Lallzyme Beta, and Pectinex Ultra SP-L are more recommended for applications at acid pH, such as in fruit juices and wine productions.