Polymeric nanofibers are attractive nanomaterials owing to their high surface-area-to-volume ratio and superior flexibility. However, a difficult choice between durability and recyclability continues to hamper efforts to design new polymeric nanofibers. Herein, we integrate the concept of covalent adaptable networks (CANs) to produce a class of nanofibers ⎯ referred to dynamic covalently crosslinked nanofibers (DCCNFs) via electrospinning systems with viscosity modulation and in-situ crosslinking. The developed DCCNFs possess homogeneous morphology, flexibility, mechanical robustness, and creep resistance, as well as good thermal and solvent stability. Moreover, to solve the inevitable issues of performance degradation and crack of nanofibrous membranes, DCCNF membranes can be one-pot closed-loop recycled or welded through thermal-reversible Diels-Alder reaction. This study may unlock strategies to fabricate the next generation nanofibers with recyclable features and consistently high performance via dynamic covalent chemistry for intelligent and sustainable applications. Polymeric nanofibers are attractive nanomaterials owing to their high surfacearea- to-volume ratio and superior flexibility but designing durable and recyclable polymer nanofibers is challenging. Here, the authors integrate the concept of covalent adaptable networks to produce dynamic covalently crosslinked nanofibers via electrospinning. To date, natural/synthetic polymers, carbon-based/semiconducting/composite nanomaterials, and ceramics have been employed to fabricate nanofibers6. Among them, polymers are the most commonly used raw materials for nanofibers due to their wide range of sources and low cost8. Most thermoplastics with suitable molecular weight can be transformed into nanofibers by electrospinning as long as they can be dissolved in appropriate solvents with suitable viscosity or melted without degradation. However, compared to thermosets, thermoplastics have poor mechanical properties, dimensional solvent, and thermal stability10, limiting the applications of thermoplastics-based nanofibers. In contrast, thermosets-based nanofibers obtained by in-situ formation provide a powerful solution to these problems15, while thermosets are difficult to be recycled due to their highly crosslinked three-dimensional networks, resulting in a waste of resources and a huge burden on the environment18. Therefore, it is of urgent necessity to solve those issues and simultaneously endow the nanofibers with emerging functionalities and features.Nanofiber is a class of nanomaterials with diameters ranging from tens to hundreds of nanometers with high surface-area-to-volume ratio and good flexibility, which makes them uniquely suitable for various applications, including energy harvesting/conversion/storage components, electronic/photonic devices, biomedical scaffolds, catalytic supports, “smart” mats as well as filtration membranes22. In the conditions of use, CANs can remain stable, while rearrangement of the topological network or polymer chain depolymerization could occur when the dynamic bond exchange is activated by external stimuli24. Due to this unique feature, CANs have been extensively explored in the last decade, in synthetic and dynamic chemistry and materials science31. Moreover, when it comes to nanofibers, CANs are promising candidates for nanofibers considering the following advantages: (i) In the dynamic crosslinking system, the viscosity can be easily regulated by the pre-reaction between the crosslinking points34. It is promising to obtain nanofibers from low molecular weight polymers or low viscosity solution systems through the in-situ forming of dynamic crosslinks during electrospinning; (ii) The integration of crosslinking points can give nanofibers with excellent mechanical properties, dimensional, thermal, and solvent stability. (iii) The dynamic nature of CANs can endow the nanofibers with closed-loop recyclability, repairability and stimulus responsiveness, which are promising to solve the issue of limited lifecycle of nanofibers and expand the functions and applications of nanofibers. (iv) CANs based on various polymers and dynamic bonds/reactions have been developed35 and the diverse CANs can greatly enrich the family of nanofibers. Therefore, by integrating the dynamic covalent chemistry, nanofibers are able to be developed with new dimensions of simplicity, practicality, smart and sustainability.Covalent adaptable networks (CANs) refer to a kind of crosslinked polymers with dynamic covalent bonds, which ideally combine the excellent properties of thermosets with the processability of thermoplastics36 between furan and maleimide. The obtained DCCNFs exhibited homogeneous morphology, good flexibility, excellent mechanical properties, as well as dimensional, thermal and solvent stability. In addition, by means of the dynamic properties of the thermal response DA reaction in DCCNFs, the closed-loop recycling and welding of nanofibrous membranes could be readily achieved. We believe this strategy can be applied to other CANs to greatly enrich the family of nanofibers, and the developed DCCNFs can be further utilized in the fields of smart and sustainable materials.Herein, we demonstrate the concept of dynamic covalently crosslinked nanofibers (DCCNFs) by integrating the dynamic covalent crosslinking chemistry and nanofibers, aiming at high performance and closed-loop lifecycle of nanofibers. Figure n and Mw of FMA-co-BMA are around 40.1 K and 81.8 K, respectively  in DMF (25 wt.% of polymer in DMF), the viscosity of the mixed solution at room temperature can be easily regulated between 30-288 cps by heating at 60 °C within 55 minutes via Diels-Alder (DA) cycloaddition reaction  spectra  in DCCNFs decreases with the increasing BMI loading. The stretching vibration peaks of C = O in DA adduct around 1778 cm−1 appear, and their intensities also increase with the increase of BMI content, indicating the successful reaction between furan and BMI42. Besides, for sample DCCNF-30C, the characteristic peak of =C − H bending in maleimide around 685 cm−1 fully disappears, indicating the complete reaction between FMA-co-BMA and BMI. While for samples with high crosslinker loadings (DCCNF-60C and DCCNF-100C), the residues of the maleimide group are observed. This is due to the fact that the rigidity and steric hindrance of the polymer increases with the increase of BMI content, resulting in a decrease in the chance of active group contact. Nevertheless, this does not affect the formation of crosslinking networks. As shown in Fig. 43. Hypothetically, the gel content of DCCNF-100C with the largest crosslinker loading should be the highest, but it is lower than that of DCCNF-60C in the selected solvents and temperatures. This may be due to the increase in steric hindrance between the furan ring and the maleimide, as mentioned previously -co-(butyl methacrylate)]  with pendant furan groups was prepared by free radical polymerization  of the DCCNFs can be obtained, which are between 339 and 419 nm  of the nanofibrous membranes  was used to characterize the micromorphology of the nanofibers and illustrate the formation of nanostructures. As shown in Fig. nes Fig. . The nan46. Figure Tg of FMA-co-BMA is around 35 °C. However, after crosslinking, Tg cannot be observed in the DSC thermograph of DCCNFs, and only the retro DA reaction starting from around 90 to 95 °C for different samples is indicated20. In view of the undetected Tg of DCCNFs in DSC thermograph, a reasonable explanation is that the Tg of DCCNFs is higher than the temperature of retro DA. The retro DA reaction occurs earlier than Tg, resulting in a change in the polymer structure and invisible Tg in DSC thermograph. This is further evidenced by the DMA curves, as the storage modulus of DCCNFs does not decrease significantly before 90 °C  are both lower than their Tg (> 94 °C), and the higher rigid BMI loading leads to the lower reaction probability between furan and maleimide of DCCNP-100C. As a result, DCCNP-100C has high internal stress and comparatively low tensile strength. Moreover, we summarized the material properties of several electrospun nanofibrous membranes made from commercial polymers in literature and compared these with the developed DCCNF membranes. As show in Supplementary Table In situ crosslinking not only endows polymers with processability but also offers them excellent properties. Thermal and mechanical properties of DCCNFs were characterized, which are also important parameters for nanofibers °C Fig. . These r49. DCCNF−100C with a more rigid structure presents better creep resistance with little creep below 60 °C, and only 7.2% and 14.2 % creep ratio at 70 °C and 80 °C, respectively. The thermal stability can be evaluated from the thermal stability of polymers and nanofibers. As shown in Supplementary Fig. Td5%) and char yield at 700 °C (R700) than uncross-linked FMA-co-BMA due to the introduction of aromatic rings in BMI. The DCCNF-100C with more aromatic rings loading presents higher Td5% and R700 than other samples. For the thermal stability of nanofiber, DCCNF-60C was treated at different temperatures for 24 h, and their morphologies were imaged by FESEM , indicating that DCCNF can be completely degraded into the original mixture in DMF. The above three pieces of evidence strongly prove the thermal reversibility of the developed nanofibers.The above results demonstrate the excellent performance of DCCNFs. However, not just nanofibers but all polymers, their life is limited due to inevitable performance degradation or macroscopic and microscopic fractures during usage, leading to a waste of resources and a heavy burden on the environments52 Fig. . In the s52 Fig. . ii) bons52 Fig. , the chatly Fig. . iii) mo−1, furan ring breathing at 1016 cm−1, and C = O stretching vibration in DA adduct at 1778 cm−1. In addition, the recycled DCCNF-60C also preserves the original morphology with homogeneously distributed nanofibers , and after heating at 140 °C for 20 min, DCCNF-60C was fully degraded in DMF due to the retro-DA reaction Fig. . After hers Fig. . There iers Fig. . In termSubsequently, we explored the weldability of DCCNF, which could also be achieved by the dissociation and association of dynamic DA reaction Fig. . In the In summary, we propose the concept of dynamic covalently crosslinked nanofibers (DCCNFs) through the successful unification of covalent adaptable networks chemistry and nanofiber technology, which yields an excellent combination of high performance and sustainability for nanofibers. The DCCNFs can be readily fabricated by viscosity modulation and in-situ crosslinking based on the catalyst-free DA reaction between a furan-suspended linear copolymer and bismaleimide via the electrospinning process. The produced DCCNF membranes present homogeneous macro and micro morphologies, high porosity, hydrophobicity, and good flexibility. Besides, FTIR spectra and gel content prove the successful formation of DA adduct and highly crosslinked networks, which endows DCCNF membranes with excellent thermal and mechanical properties as well as dimensional, thermal, and solvent stabilities. Moreover, the wear-and-tear problems, such as performance degradation, macroscopic and microscopic fractures, can be solved due to the dynamic dissociation and association of the thermal-reversible Diels-Alder reaction. DCCNFs exhibit excellent one-pot closed-loop recycling and post-fracture welding capabilities with negligible change in morphology and performance after recycling and welding. The robust and flexible DCCNFs with one-pot closed-loop recyclability and weldability may have great potential for electronics, energy and environmental applications.55. FMA , BMA , and free radical initiator AIBN  were dissolved in 50 mL toluene using a 250 mL flask. The solution was stirred and purged with argon for 40 minutes at room temperature to ensure that all air was expelled. Subsequently, the solution was heated to 70 °C and reacted for 24 h. After the reaction, FMA-co-BMA was obtained by precipitation in methanol for four times and then dried in a vacuum oven.FMA-co-BMA was synthesized by free radical polymerization1. 0.8 g FMA-co-BMA was dissolved in 2.4 g DMF (25 wt.% of polymer) in a 20 ml sample bottle. Then BMI with a different molar ratio to furan in FMA-co-BMA  with a gap of 20 cm, followed by drying and post-curing at 60 °C for 24 h before use.DCCNFs were prepared by electrospinning1/m0, where m0 is the original mass before the test, and m1 is the final mass after drying.Different samples (around 200 mg) were separately placed in various solvents at RT or 60 °C for 72 h and then washed with the same solvents and dried in a vacuum oven for 24 h. The gel content (%) is calculated by the following formula: 100 × mh-7th and 8th-10th recycling cycles, polymer concentration was adjusted to 20% and 15%, respectively, and other parameters were the same for each recycling cycle.0.8 g DCCNF-60C was put into 2.4 ml DMF (25 wt.% of polymer content), followed by heating at 140 °C for 20 min. DCCNF-60C was fully degraded in DMF by retro-DA reaction. After the solution was rapidly cooled to room temperature in water, it was heated at 60 °C until the viscosity reached around 80 cps at room temperature. Then the solution was sucked into a 5 mL syringe with a blunt 22-gauge needle and fabricated using electrospinning as in the original process to obtain the recycled DCCNF-60C. For 4Two fragments of the cut DCCNF-60C were placed closely and sandwiched by two glasses to ensure good contact. Then, the samples were heated at 100 °C in an oven for different times to study morphology and mechanical properties under different bonding times. After that, the welded samples were heated at 60 °C for 24 h to ensure the association of partially dissociated DA adduct.Supplementary Information


Staphylococcus aureus and Escherichia coli. Results showed that the release profiles of TCL and therefore the antibacterial activity were directly related to the type of nanofibers. In the case of monolithic nanofibers, the NFs matrix was composed of polyelectrolyte complex (PEC formed between CHT and PCD) and resulted in a prolonged release of TCL and a sustained antibacterial effect. In the case of core-sheath NFs, the PEC was formed only at the core-sheath interface, leading to less stable NFs and therefore to a faster release of TCL, and to a less extended antibacterial activity compared to monolithic ones.This work focuses on the manufacture of core-sheath nanofibers (NFs) based on chitosan (CHT) as sheath and cyclodextrin polymer (PCD) as core and loaded with triclosan (TCL). In parallel, monolithic NFs consisting of blended CHT-PCD and TCL were prepared. Nanofibers were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), and Fourier Transform Infrared spectroscopy (FTIR). SEM displayed the morphology of NFs and the structure of the nanowebs, while TEM evidenced the core-sheath structure of NFs prepared by coaxial electrospinning. The core diameters and sheath thicknesses were found dependent on respective flow rates of both precursor solutions. Nanofibers stability and TCL release in aqueous medium were studied and correlated with the antibacterial activity against  Over the past decade, nanofibrous electrospun materials have proven their interest in the biomedical field, especially for drug delivery purposes ,2,3. IndAmong the natural polymers used for the design of nanofibrous drug delivery carriers, polysaccharides have been widely studied thanks to their biocompatibility and biodegradability ,5,6,7. DDrug release from NFs systems present profiles that depend on extrinsic  and intrinsic parameters, with the latter concerning their strategy of incorporation in the nanofibrous mats (on the surface or in the NFs matrix), the hydrophobicity of the drug and its crystalline or amorphous state, the type of interactions of the active principle with the NFs surface, the nature of the polymer matrix, the swelling of NFs, and also the nanofibers structure and morphology. Indeed, the electrospinning of a polymer/drug mixture offers the possibility to vary the method of drug embedding within the nanofibers ,27. The Staphylococcus aureus and Escherichia coli evidenced by Kirby Bauer method. Results are discussed accordingly with the cyclodextrin polymer and chitosan distribution in the nanofibers, i.e., blended (bulk PEC) or forming core and sheath (PEC at the core-sheath interface).The goal of this study was to develop core-sheath nanofibers with anionic cyclodextrin polymer complexing triclosan as core and chitosan as sheath by coaxial electrospinning. The effect of inner and outer solutions flow rates on the nanofibrous structure and size was investigated by SEM and TEM to assess the obtained morphologies. Core-sheath nanofibers obtained from coaxial needle were compared to classical monolithic ones, in terms of stability and drug release in aqueous medium at pH 7.4 and antibacterial effect against v 95,000 g·mol−1, 94.3% deacetylated, Sigma Aldrich, Saint-Quentin Fallavier, France, batch number MKBL7900 V), Polyethylene oxide , glacial acetic acid (AA), citric acid (CTR), sodium hypophosphite monohydrate (NaH2PO2·H2O), phosphate buffered saline (PBS), and triclosan  phenol, TCL) were purchased from Sigma Aldrich . (2-hydroxypropyl)-β-cyclodextrin (HPβCD) Kleptose® HP MS = 0.62 was provided by Roquette .Chitosan .1H NMR) and its average molecular masses in weight and number (Mw and Mn) were 64,650 g·mol−1 and 13,500 g·mol−1, respectively (measured by size exclusion chromatography in water). The number of residual carboxylic acid groups was estimated to 4.00 ± 0.10 mmol of COOH functions per gram of PCD (determined by acid-base titration method).The anionic polymer (PCD) of HPβCD crosslinked by CTR was synthesized according to a method previously described by Martel et al. ,25. AccoDifferent polymer compositions were prepared in order to produce monolithic and core-sheath nanofibers. PEO was systematically added in electrospun solutions in order to enhance the chain entanglements and hydrogen bonds to promote the formation of a continuous jet and nanofibers deposition on the collector .w/v was first dissolved in water. A total of 5 wt% of TCL according to total polymers concentrations  was added to PCD solution. The mixture was kept under stirring for 72 h at 37 °C. CHT and PEO powders mixture (9:1) (w/w) was then added to PCD/TCL solution. Finally, glacial acetic acid was added in order to obtain a final concentration of acid of 90% (v/v), and the clear solution was stirred overnight at room temperature. As control to evidence the role of PCD on the release and antibacterial effect of TCL, a solution based on a mixture of CHT, PEO, and 5 wt% of TCL was also prepared. The obtained solutions were then loaded into a 5 mL plastic syringe connected to a 21-gauge needle  by the intermediate of a polyethylene catheter  and placed onto a syringe pump . A high voltage was then applied, and the nanofibers were collected on a roll collector . The optimal electrospinning parameters were determined in a previous study as follows: a flow rate of 0.5 mL/h, an applied voltage of 13 kV, and a tip-to-collector distance of 200 mm [Monolithic nanofibers (M0 and M1) were generated from classical needle . PolyHPβf 200 mm . Relativw/v)/TCL  and PEO (2 wt% (w/v)) were dissolved in glacial acetic acid/water at a concentration of 50% (v/v). The outer solution was prepared by dissolving a mixture of 3.5 wt% of CHT and PEO (9:1) in glacial acetic acid/water at a concentration of 90% (v/v). The electrospinning apparatus was equipped with a coaxial system . The two solutions were loaded into two separate 5 mL syringes placed onto syringe pumps  connected to the coaxial system through polyethylene catheters . The tip-to-collector distance was set to 200 mm and the applied voltage was adjusted to 15–20 kV. The flow rate was varied for both inner and outer solutions in order to study its effect on core-sheath structure. Relative humidity and temperature were fixed at 35% ± 2% and 20 ± 2 °C, respectively. Finally, the nanofibers were submitted to a heat treatment at 90 °C in order to improve their stability in aqueous medium and stored in desiccators containing silica gel at room temperature.Core-sheath nanofibers (CS1 to CS4) were prepared by coaxial electrospinning . The innThe solution compositions and experimental conditions are given in The morphology and diameter size of the nanofibers were analyzed using SEM (Hitachi S-4700 SEM field emission GU) operating at an accelerating voltage of 5 kV and an emission current of 10 µA. Samples were sputtered beforehand with a thin layer of chrome. Diameter sizes were calculated using the software ImageJ as an average of 50 nanofibers diameter measurements.The core-sheath structure was investigated using TEM (Tecnai FEI TEM G2-20 twin equipped with a LaB6 filament) operating at an accelerating voltage of 200 kV.−1 to 650 cm−1 (scan number = 8) with a resolution of 4 cm−1.The chemical structure of nanofibers was studied by Attenuated Total Reflectance—Fourier Transformed InfraRed (ATR-FTIR) spectroscopy using a PerkinElmer spectrometer (Spectrum One) equipped with Spectrum software. Spectra were recorded from 4000 cmNanofibrous samples weighing approximately 20 mg were cut and placed in PBS at pH 7.4. At different time intervals, the sample was removed, rinsed with distilled water, dried at 37 °C, and finally weighed with a precision balance . Measures were conducted in triplicates.0 = initial dry weight and Wt = dry weight at specific time (t).The weight loss of the membranes (WL) was calculated according to the following Equation (1):The release of TCL in PBS at pH 7.4 was carried out in batch. A total of 20 mg of nanofibrous membranes loaded with TCL were placed into 150 mL of PBS under agitation (100 rpm) in a thermostatically controlled oscillating oven at 37 °C . At each predefined time, aliquots (3 mL) of the soaking solution were transferred into quartz cells (1 cm). The absorbance was measured at a wavelength of 282 nm using a UV spectrometer (Shimadzu UV-1800). Withdrawn aliquots were then returned into the batch solutions in order to keep the volume of the supernatant unchanged. Analyses were carried out in triplicates.t/M∞ is the percentage of accumulated drug for a specific time (t), n is the release exponent, and k is the release constant. This equation is only applicable for low release times and the part of the release profile where Mt/M∞ is inferior to 0.6. This model classifies the release kinetics mechanisms depending on the value of the exponent n. In the case of cylindrical matrices, if 0.45 ≤ n, the release mechanism is considered as Fickian (drug diffusion); if 0.45 < n < 0.89 or n = 0.89 or n > 0.89, the mechanism is considered as non Fickian, which indicates that drug diffusion is combined with another mass transfer mechanism .The release mechanism was studied according to the mathematic model of Korsmeyer-Peppas  applied S. aureus (strain CIP 224) and E. coli (strain K12) were suspended in Ringer’s cysteinated diluent in order to obtain a stock suspension with a density of 1.0 × 104 CFU/mL. A total of 18 mL of Mueller-Hinton agar (MHA) were poured in Petri dishes (Ø9 cm) and then, 0.1 mL of the S. aureus or E. coli stock suspension were thereafter seeded on the agar. Three holes of 6 mm in diameter were punched per Petri dish and 50 µL of the release medium were added into the holes. After 24 h incubation at 37 °C, the diameter of the inhibition zone was measured and plotted as a function of contact time in PBS. Inhibition tests were performed in triplicate for each time point.The antibacterial activity of released medium from TCL loaded nanofibers was evaluated by the diffusion Kirby-Bauer test after sterilization by UV irradiation during 1 h for each face. TCL loaded nanofibers (Ø15 mm) were immersed in 5 mL of sterile PBS at 37 °C under agitation (80 rpm) with 100% renewal of the medium at different time intervals: 15 min, 30 min, then every hour up to 6 h, and finally every day up to 9 days. SEM pictures of monolithic and core-sheath NFs are shown in v/v) for core solution, 90% (v/v) for sheath solution) were chosen to prevent the formation of a polyelectrolyte complex between cationic CHT and anionic PCD at the needle output, which would induce the formation of aggregates and therefore would hinder the jet stretching. As a matter of fact, in concentrated organic acids, it can be considered that the carboxylic groups of PCD are protonated and consequently do not interact with CHT ammonium groups. Indeed, defect-free nanofibers were obtained by coaxial electrospinning for each flow rates settings. Average diameters of core-sheath nanofibers are also given in For core-sheath nanofibers c–f, acetSEM micrographs show that two classes of diameter ranges are obtained. For instance, in CS1 c, nanofiIn order to evidence the core-sheath structure of nanofibers produced by coaxial electrospinning, samples were observed by TEM and micrographs are shown on For constant inner solution flow (samples CS1 to CS3), the sheath thickness increases with the outer solution flow. Indeed, by increasing the outer solution flow, a higher amount of CHT would wrap PCD/TCL leading to a higher sheath thickness. For constant outer solution flow (samples CS2 and CS4), the core diameter increases with the inner solution flow while the sheath thickness remains constant.Moreover, FTIR-ATR spectra of core-sheath nanofibers  present The weight loss of both monolithic and core-sheath NFs within time in PBS buffer at pH 7.4 is presented in The release profiles of TCL from both monolithic and core-sheath NFs in PBS are compared in On the other hand, the monolithic nanofibers based on cyclodextrin polymer (M1) exhibit a lower burst effect and a prolonged release up to 6 days. In monolithic nanofibers, interactions between CHT and PCD are dense. This is due to their intimate blending and to the formation of a polyelectrolyte complex leading to the homogeneous matrix of nanofibers, whereas this polyelectrolyte complex is formed only at the core-sheath interface. Therefore, core-sheath nanofibers are less water-resistant than monolithic ones and display a faster release of TCL, as revealed from degradation study and release tests.After that burst effect, the drug is gradually released until a plateau raised after 7 days at 93%, 100%, 96.5%, and 90% for CS1, CS2, CS3, and CS4, respectively, and after 6 days at 68% for M1, confirming the role of the polyelectrolyte complex to retain the drug within the polymer network.In order to determine the release mechanisms of TCL from the electrospun nanofibers, the Korsmeyer-Peppas model has been applied to the release kinetics and the results are shown in 2 values confirm the good adequacy of the model with the experimental data. In all cases, except for CS4 nanofibers, the n value is lower than 0.45, indicating that the TCL release mechanism is governed by Fick’s law of diffusion. In the case of CS4 nanofibers, the n value higher than 0.45 implies that diffusion is not the only mechanism, but that swelling and/or degradation also play a role in the release of TCL.The correlation ratio RS. aureus and E. coli was assessed to compare the two types of nanofibers and is presented in The antibacterial activity of the released medium from TCL loaded monolithic (M0 and M1) and core-sheath (CS1) nanofibers against S. aureus or E. coli for monolithic nanofibers, with a higher efficacy towards S. aureus. The antibacterial activity of monolithic nanofibers without PCD (M0) is observed up to 4 days for S. aureus and 3 days for E. coli. Monolithic nanofibers with PCD (M1) exhibit a significant antibacterial effect up to 9 days, correlated with the prolonged release of TCL within this period (s period a.In contrast, core-sheath nanofibers present a reduced antibacterial effect in terms of intensity and time compared to monolithic M1 nanofibers. The initial content of TCL is different in the two series . Indeed,This study aimed at evaluating the potential of core-sheath nanofibers based on chitosan and cyclodextrin polymer for the release of an active principle. Characterization techniques confirmed the formation of the core-sheath structure with chitosan as sheath and cyclodextrin polymer as core, which sizes and degradation rates were controlled by tuning the electrospinning solution flow rates. The drug release and antibacterial assays consolidated the potential of the cyclodextrin polymer for the design of prolonged drug delivery nanofibrous systems. The comparison of monolithic and core-sheath nanofibers highlighted the improvement of anionic cyclodextrin polymer properties through the formation of a strong polyelectrolyte complex with cationic chitosan, especially when it is formed within the whole nanofibers instead of at the interface of both polymers. However, the choice of a core-sheath structure could be considered in the case of the incorporation of two non-miscible drugs, which would be compatible with the core and sheath solutions, respectively.


Background and Objectives: Warfarin and a skeletal muscle relaxant are co-treatments in nearly a quarter-million annual United States (US) office visits. Despite international calls to minimize patient harm arising from anticoagulant drug interactions, scant data exist on clinical outcomes in real-world populations. We examined effects of concomitant use of warfarin and individual muscle relaxants on rates of hospitalization for thromboembolism among economically disadvantaged persons. Materials and Methods: Using 1999–2012 administrative data of four US state Medicaid programs, we conducted 16 retrospective self-controlled case series studies: half included concomitant users of warfarin + one of eight muscle relaxants; half included concomitant users of an inhaled corticosteroid (ICS) + one of eight muscle relaxants. The ICS analyses served as negative control comparisons. In each study, we calculated incidence rate ratios (IRRs) comparing thromboembolism rates in the co-exposed versus warfarin/ICS-only exposed person-time, adjusting for time-varying confounders. Results: Among ~70 million persons, we identified 8693 warfarin-treated subjects who concomitantly used a muscle relaxant, were hospitalized for thromboembolism, and met all other inclusion criteria. Time-varying confounder-adjusted IRRs ranged from 0.31  for metaxalone to 3.44  for tizanidine. The tizanidine finding was robust after quantitatively adjusting for negative control ICS findings, and in numerous prespecified secondary analyses. Conclusions: We identified a potential >3-fold increase in the rate of hospitalized thromboembolism in concomitant users of warfarin + tizanidine vs. warfarin alone. Alternative explanations for this finding include confounding by indication, a native effect of tizanidine, or chance. Minimizing patient harm associated with anticoagulants and their drug interactions is an international patient safety goal. To address knowledge gaps in anticoagulant safety, the United States (US) Department of Health and Human Services issued a call to generate real-world evidence on anticoagulant drug interactions . Yet, thRecent data suggest that warfarin and a skeletal muscle relaxant are co-treatments in 240,000 annual US office visits  as proviWe conducted 16 retrospective self-controlled case series (SCCS) studies: half included concomitant users of warfarin + one of eight muscle relaxants; half included concomitant users of an inhaled corticosteroid (ICS) + one of eight muscle relaxants. The ICS analyses served as negative control comparisons . We defiAmong ~70 million Medicaid beneficiaries in states contributing data, we identified 8693 warfarin-treated subjects who concomitantly used a muscle relaxant, experienced ≥1 thromboembolism event, and met all other inclusion criteria. Subjects were predominantly female (67.4%), white (45.6%), with a median age of 67.4 years, and contributed 1,005,246 observation days. The mean per-subject observation period was 116 days. warfarin + metaxalone to 3.44 (1.53–7.78) for warfarin + tizanidine. Negative control findings ranged from 0.39 (0.10–1.49) for ICS + tizanidine to 1.99 (1.04–3.83) for ICS + carisoprodol. See Confounder-adjusted IRRs for thromboembolism ranged from 0.31  for warfarin + tizanidine use may result in a modest, delayed INR reduction (−0.4 units during the third and fourth months of concomitant use) [warfarin + tizanidine vs. warfarin alone. This finding, if causal, may represent a clinically relevant drug interaction, yet could also be explained by: confounding by indication for tizanidine; a native pharmacodynamic effect of tizanidine; the failure of an assumption underlying the statistical  model; and/or chance. We subsequently discuss the possibilities of causation, systematic error, and chance. Warfarin users are commonly co-treated with a muscle relaxant , and tizant use) . We therR-warfarin and tizanidine are CYP1A2 substrates, we are unaware of evidence that tizanidine induces CYP1A2, which would enhance R-warfarin inactivation. We therefore must consider potential non-causal explanations, such as confounding. As an example, initiation of tizanidine to treat spasticity may portend a multiple sclerosis (MS) flare, and MS is associated with thromboembolism [R-warfarin inactivation. This explanation is unlikely since: within-subject smoking status is unlikely to change over the relatively short observation time; and our finding for cyclobenzaprine, also a CYP1A2 substrate, was null . Another potential non-causal explanation is a native pharmacodynamic effect of tizanidine. This is unlikely since: tizanidine’s alpha-2 agonist effects do not affect stroke [ICS + tizanidine was inconsistent with a large positive association (upper 95% confidence limit: 1.49). It is additionally important to note that prior screening findings [A plausible pharmacokinetic mechanism would help support a case for causality. While embolism ,13. Howeembolism , and immembolism . Anotherembolism . Smokingt stroke ; and ourFirst, recurrent outcomes must be independent. This assumption may be violated if different within-patient factors cause a subsequent vs. initial thromboembolic event. Yet, our tizanidine finding held in a secondary analysis limited to persons with one thromboembolic event . Second, outcomes must not affect observation time or subsequent exposure. The former may be violated given thromboembolism-related mortality; yet, our tizanidine finding held in a secondary analysis limited to persons surviving during observation . The latter may be violated since muscle relaxants may be initiated after a stroke to treat spasticity; yet, this would explain a protective (not elevated) finding, as such stroke events would occur during warfarin-only exposed observation days and thereby artificially inflate the IRR’s denominator. Third, exposures must not affect outcome ascertainment. We cannot think of a mechanism by which tizanidine could influence the diagnosis of or billing for thromboembolism. An additional limitation includes our lack of access to INR results. Finally, we cannot rule out the possibility of chance findings.We must also consider the potential for systematic error introduced by violations of assumptions underlying the SCCS method. warfarin + tizanidine vs. warfarin alone. While this finding may represent a clinically relevant drug interaction, alternative explanations include confounding, bias, and chance. Future work using a different data source  and/or alternative study design should seek to replicate this finding.Using an epidemiologic design that inherently controls for measured and unmeasured static confounders, adjusting for critical time-varying confounders, and using a negative control, we identified a potential >3-fold increase in the rate of thromboembolism in concomitant users of


Stevioside, one of the natural sweeteners extracted from stevia leaves, and its derivatives are considered to have numerous beneficial pharmacological properties, including the inhibition of activated coagulation factor X (FXa). FXa-PAR signaling is a possible therapeutic target to enhance impaired metabolism and insulin resistance in obesity. Thus, the goal of the investigation was a QSAR analysis using multivariate adaptive regression splines (MARSplines) applied to a data set of 20 isosteviol derivatives bearing thiourea fragments with possible FXa inhibitory action. The best MARS submodel described a strong correlation between FXa inhibitory activity and molecular descriptors, such as: B01[C-Cl], E2m, L3v, Mor06i, RDF070i and HATS7s. Five out of six descriptors included in the model are geometrical descriptors quantifying three-dimensional aspects of molecular structure, which indicates that the molecular three-dimensional conformation is of high significance for the MARSplines modeling procedure and obviously for FXa inhibitory activity. High model performance was confirmed through an extensive validation protocol. The results of the study not only confirmed the enhancement in pharmacological activity by the presence of chlorine in a phenyl ring, but also, and primarily, may provide the basis for searching for new active isosteviol analogues, which may serve as drugs or health-beneficial food additives in patients suffering from obesity and comorbidities. Stevia rebaudiana Bertoni. Steviol glycosides are composed of a diterpene ent-kaurene core (steviol), linked to one or more glucose units. Stevia leaves have been utilized by Paraguayan Indians for centuries to sweeten Mate tea. Both stevia extract and stevioside have been known for their healthy properties by local people in South America and used in traditional medicine for centuries. Numerous studies have confirmed various therapeutic benefits of rebaudioside A (a related compound) and stevioside and its metabolic components, such as steviol and isosteviol anthracene (DMBA)-induced mouse skin was used , is the first to appear in the established QSAR model. This class of substructure descriptors, applicable to any pair of atoms and bond types between them, is founded on a two-dimensional representation of a molecule. Those descriptors frequently are Boolean variables encoding the presence or absence of a particular atom pair in each molecule . The B01Weighted holistic invariant molecular descriptors contain global and directional information and are estimated by a principal component analysis on Cartesian coordinates of the atoms weighted in different ways. They encode relevant molecular 3-dimensional information concerning molecular size, shape, symmetry, and atom distribution with respect to invariant reference frames . There a3D-MoRSE (Molecular Representation of Structures based on Electron diffraction) descriptors were designed for encoding the 3D structure of a molecule by a fixed number of variables. Despite the fact that descriptors from this block comprise information pertaining to the whole molecule, they are defined mainly by short-distance atom pairs . DescripRadial distribution function descriptors with RDF070i, included in the elaborated model, are based on the distance distribution in the geometrical representation of a molecule and constitute a radial distribution function code, which exhibits similar characteristics as the 3D-MoRSE code. In addition to information about interatomic distances of a whole molecule, they contain information on bond distances, ring types, planar and nonplanar systems and atom types. RDF descriptors are unique, concerning the three-dimensional arrangement of the atoms, invariable against the translation and rotation of the entire molecule and independent of the number of atoms ,26. In tThe last variable belongs to GETAWAY descriptors. This block of descriptors has been proposed in order to match 3D-molecular geometry, atom relatedness and chemical information with the use of various atomic weighting schemes. These descriptors are a source of local or/and distributed information on molecular structure . The HATTo summarize, the accomplished model contains one 2D and five 3D descriptors, which suggests that the molecular 3D conformation is very important for the MARSplines modeling process and, as a consequence, for FXa inhibitory activity. In addition, what should be emphasized is the joint use of GETAWAY and WHIM descriptors, with a cumulative share in the model of 50%. This combination of variables provides more predictive models, especially in the case of biological activities, as suggested by Consonni et al. . The elaA set of isosteviol thiourea derivatives was subjected to a molecular modeling study and an approach of MARSplines was employed for predicting FXa inhibitory activity. The developed QSAR model reveals information about the importance of the presence of chlorine atoms (B01[C-Cl]), the uniform distribution of the atomic mass (E2m), the molecular volume (L3v), the 3D molecular distribution of ionization potential (Mor06i and RDF070i) and the intrinsic properties of a molecule (HATS7s). Five out of six descriptors are geometrical descriptors quantifying three-dimensional aspects of molecular structure. Despite a relatively small set of studied compounds, the high application value of the obtained model was confirmed through an extensive validation protocol typical of QSAR models. Consequently, all calculated validation coefficients reflect the predictive power of regression. As FXa-PAR signaling is a possible therapeutic target to enhance impaired metabolism and insulin resistance in obesity, the predictive model may represent a valuable tool in searching for new active isosteviol analogues. Finally, the results of the present study confirmed an enhancement in pharmacological activity of isosteviol analogues by the presence of chlorine in the phenyl ring. Nevertheless, future studies are necessary to investigate the influence of a wider variety of substituents.


The prepared composite nanofibers were characterized with Scanning Electron Microscopy (SEM), and Fourier Transform Infrared analysis (FTIR). The composite nanofiber was evaluated for the removal of indigo carmine dye from aqueous solutions. The effects of contact time, initial dye concentration, solution pH and adsorption equilibrium isotherms were studied. The adsorption of indigo carmine was found to be greatly affected by solution pH. The maximum loading capacity was determined to be 154.5 mg g−1 at pH = 5. The experimental kinetic data were fitted well using a pseudo-first order model. The adsorption isotherm studies showed that the adsorption of indigo carmine fits well with the Langmuir model. The reuse of the composite nanofiber was also investigated in which more than 90% of indigo carmine was recovered in 5 min. The results of stability studies showed that the adsorption efficiency can remain almost constant (90%) after five consecutive adsorption/desorption cycles.Surface coated magnetite nanoparticles (Fe 3O4 NPs) with 3-mercaptopropionic acid were immobilized on amidoximated polyacrilonitrile (APAN) nanofibers using electrospinning followed by crosslinking.Surface coated magnetite nanoparticles (Fe Several techniques have been investigated for the treatment of water streams containing organic dyes, including decolouration, chemical coagulation and precipitation, biodegradation, membrane filtration and active sludge, and adsorption.2–6 Among these techniques, adsorption is one of the most efficient processes, and is widely used since the other techniques require a large quantity of chemicals and/or high energy, and are expensive.7The textile industry is one of the major sources of wastewater containing organic dyes. Indigo carmine (IC), also known as 5,5′-indigodisulfonic acid sodium salt, is one of the important organic dyes because its extensive use in textile and other industries such as paper, plastic, leather, food, cosmetics, and printing. These organic dyes are common water pollutants and may cause damage to health and ecosystems due to their mutagenic and carcinogenic effects.8 natural materials9–12 and synthetic resins.13 Application of some of these materials is limited due to high cost, difficulty of disposal and reuse. In addition, separation of these adsorbents from the aqueous solutions is still problematic.There are several materials that have been investigated for the removal of indigo carmine from solutions, including activated carbon,14,15 Previously, we have investigated the use of composite nanofibers for the adsorption of heavy metals16,17 and photocatalytic degradation of organic pollutants under UV and visible light irradiation.18,19 Furthermore, in our earlier work we have also demonstrated that Fe3O4 nanoparticles have high potential to be used as adsorbents, either in the form of pristine nanoparticles or after modifying the surface with organic reagents.20–22 However, separation of the nanoparticles (adsorbent) from the treated solution limits the process development. One of the plausible strategies is to immobilize the nanoparticles on a flexible substrate such as nanofibers in order to eliminate the nanoparticles separation and their loss to the environment. This will also allow the reuse of the adsorbent material several times on continuous flow system. In this study, composite nanofibers consisting of amidoximated polyacrylonitrile nanofibers (APAN) and surface coated Fe3O4 nanoparticles with 3-mercaptopropionic acid (3-MPA) were used for the removal of indigo carmine from aqueous solutions. The surface modified Fe3O4 nanoparticles were chemically cross-linked to the electrospun APAN nanofibers in order to increase the density of active adsorption binding sites and thus improve the adsorption efficiency of the organic dye.Recently, composite nanofibers attracted great attention in wastewater treatment applications due to their large surface area to weight ratio, high flexibility, high porosity, and ease of surface functionalization.2OH·HCl), sodium carbonate (Na2CO3), were purchased from Sigma Aldrich. N-Hydroxysuccinimide (98%-NHS), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), iron(ii) chloride tetrahydrate (FeCl2·4H2O), iron(iii) chloride hexahydrate (FeCl3·6H2O), diethylene glycol (DEG), dimethylformamide (DMF), sodium hydroxide (NaOH), nitric acid (HNO3), ethanol and 3-mercaptopropionic acid (3-MPA) was purchased from Sigma Aldrich., and deionized water (DI) with resistivity of 15 MΩ cm using Mili-Q water was used in all experiments. Indigo carmine (C16H8N2Na2O8S2) was purchased from Sigma Aldrich and used without further purification. The color index numbers (CI) of indigo carmine dye is 73 015. The chemical structure of indigo carmine is shown in Polyacrylonitrile (PAN) , hydroxylamine hydrochloride  were added to a three-necked flask with nitrogen bubbling through the solution and flask environment. A mixture of 4 mmol of NaOH and 10 g of DEG was then added to the flask. The mixture was heated to 220 °C and kept under constant stirring for 2 h. 1 mmol of capping ligand (3-MPA) was dissolved in a mixture of 400 μL DI water and 5 g DEG. After two hours, this mixture was injected into the flask and then the system was cooled to room temperature while constantly stirring. The product was then washed 5 times with ethanol followed by centrifugation at 8000 rpm for 10 min in order to remove the excess of DEG and other unreacted chemicals. Finally, the nanoparticles were re-dispersed in DI water.APAN nanofibers were prepared as detailed elsewhere.3O4–MPA nanoparticles were then activated using (1-3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC)/N-hydroxysuccinimide (NHS) to be further coupled to the surface of APAN nanofibers containing the primary amine functional sites. An aqueous dispersion (2 mL) of as-synthesized 3-MPA capped Fe3O4 nanoparticles were added to 95.8 mg of EDC and 57.5 mg of NHS dissolved in 100 mL sulphate buffer solution. The solution was shaken for 30 min at room temperature. The surface activated Fe3O4–MPA nanoparticles were then added to APAN nanofibers and kept shaking for 3 h to fulfill the crosslinking reactions. The final composite nanofibers were washed with DI water for 3 times to remove the uncoupled nanoparticles and reaction by-products. The composite nanofibers were dried in air at room temperature. A schematic representation of the aforementioned process based on the fabricated composite nanofibers is briefly sketched  of 611 nm.Morphology of the nanofiber composites was observed using scanning electron microscopy  equipped with energy-dispersive X-ray (EDX) detector. Fourier transform infrared spectroscopy  was used to confirm the presence of thiol groups on the surface of the nanoparticles as well as the covalent attachment of nanoparticles onto the surface of the nanofibers. The concentration of IC in the solution was measured using UV-Vis/NIR spectrophotometer  at the maximum absorption wavelength . Liquid samples were taken at regular time intervals and the concentration of dye in the solution was analyzed using UV-Vis/NIR spectrophotometer. The wavelength used for the analyses was 611 nm.Adsorption kinetics was conducted using the batch method. The experiments were carried out in 250 mL glass flask containing a fixed amount of adsorbent of 10 mg with 100 mL dye solution at initial concentration of 20 mg L−1) at room temperature. The solutions were mixed with the composite nanofibers for 2 hours at pH = 5. After adsorption, the amount of residual dye in the solution was measured through UV-Vis spectrophotometer. The equilibrium adsorption capacity of APAN/Fe3O4–MPA was calculated according to the following equation;qe is the amount adsorbed (mg dye/g adsorbent) at equilibrium, Ci is the initial dye concentration (mg L−1), Ce is the final dye concentration (mg L−1), V is the solution volume (L) and m is the mass of adsorbent used (g).The IC adsorption isotherms for the fabricated composite nanofibers were measured by varying the initial dye concentrations and keeping the other conditions constant. Thus the composites nanofibers were in contact with 10 mL of aqueous solutions with different initial dye concentration , and Cads is the amount of IC adsorbed onto the composite nanofibers (mg L−1).Desorption of IC was carried out by mixing the loaded composite nanofibers with 4 mmol L3O4–MPA are shown in 3O4 nanoparticles are attached to the surface of APAN nanofibers. The surface of APAN/Fe3O4–MPA composite nanofibers did not show any serious cracks or degradation.SEM micrographs of APAN/Fe3O4–MPA composites nanofiber were obtained and the results are presented in −1), carbonyl (1660 cm−1), C–H stretching (2941 cm−1) and CH2 bending (2870 cm−1). It can be observed the characteristic peaks of 969 cm−1 (assigned to N–O), and the bending vibrations of the amine group NH or NH2 (1667 cm−1) confirms the conversion of the nitrile group to amidoxime. The shoulder at 1600 cm−1 is assigned to N–H bond, which is due to presence of amine groups after functionalization.26 Peak at 1653 cm−1 is also attributed to both N–H and N–O groups present at both APAN and APAN/Fe3O4–MPA.27 However, the reason for the shift and higher intensity of the peak for APAN/Fe3O4–MPA is due to the presence of amide groups with strong absorption about 1640 cm−1, produced by chemical reaction between carboxyl groups of nanoparticles and primary amine of the nanofibers. The overlapping between broad band of N–O and N–H with strong band for amide has been observed as a single band at 1649 cm−1.28 The band at 915 cm−1 assigned to N–O, demonstrate that the surface functionalization of the nanofibers has been completed. The presence of CH2 and C PBM data was replaced with SVG by xgml2pxml:<glyph-data id="z.dbd" format="PBM" resolution="300" x-size="8" y-size="10" xml:space="preserve">00000000000000000000000000000000111111110000000011111111000000000000000000000000</glyph-data><svg xmlns="http://www.w3.org/2000/svg" version="1.0" width="13.200000pt" height="16.000000pt" viewBox="0 0 13.200000 16.000000" preserveAspectRatio="xMidYMid meet"><metadata>Created by potrace 1.16, written by Peter Selinger 2001-2019</metadata><g transform="translate scale" fill="currentColor" stroke="none"><path d="M0 440 l0 -40 320 0 320 0 0 40 0 40 -320 0 -320 0 0 -40z M0 280 l0 -40 320 0 320 0 0 40 0 40 -320 0 -320 0 0 -40z"/></g></svg>O peaks, which further prove the presence and successful bonding of iron oxide nanoparticles to the surface of the nanofibers.29 The C–S spectra band, which is between 600 to 700 cm−1 overlaps with the iron oxide vibrational band and it would be hard to distinguish.30,31 The peak at 1700 cm−1, which is assigned for stretching of CO carboxylic group has disappeared from the spectra and instead the peak at 1650 cm−1 has become sharper with high intensity. This suggest that the binding of 3-MPA to Fe3O4 nanoparticles occurs by formation of surface bonds through the COOH group rather than through the SH group. Similar observations were reported for ZnO coated with 3-mercaptopropionic acid32 and iron oxide nanoparticles coated with mercaptosuccinic acid.33FTIR spectra of APAN nanofibers and APAN/Fe3O4–MPA. The effect of the contact time was studied under pH = 5 and IC concentration of 20 mg L−1 at room temperature (23 ± 1 °C). The results obtained  on Fe3O4–MPA, the experimental data was fitted using the non-linear regression of pseudo-first order, pseudo-second order, general-order kinetic, and the Avrami kinetic models. In this study, non-linear method was used to determine the kinetic parameters by minimizing the respective coefficient of determination between experimental data and predicted values. The non-linear expressions of pseudo first-order and pseudo second-order kinetic models are given in 41To pinpoint the rate-controlling mechanism of the adsorption of IC onto APAN/FeThe initial adsorption rate can be expressed by;42k1 (min−1) is the pseudo-first order rate constant of adsorption, and k2 (min−1) is the pseudo-second order rate constant of adsorption, t is the contact time (min), kN is the general order rate constant [min−1 (g mg−1)n−1], n is the order of adsorption; kAV is the Avrami kinetic constant (min−1); and nAV is the fractional adsorption order related to the adsorption mechanism, while qe,cal and qt (mg g−1) are the calculated  adsorption capacity at equilibrium, and adsorption capacity at time t; respectively.The general order kinetic, and the Avrami models can be described by the following equations, respectively;R2), adjusted coefficient of determination (Radj2), and the standard deviation (SD) was used to test the best-fitting of the kinetic model to the experimental data:qi,cal represents the individual theoretical q value predicted by the model; qi,exp represents the individual experimental q value; q̄exp is the average of experimental q values; n represents the number of experiments; and p represents the number of parameters in the model45In this study, the coefficient of determination , adjusted coefficient of determination (Radj2), and the standard deviation (SD) was used to obtain the best model of isotherm explaining the adsorption experimental data.The equilibrium adsorption capacity of APAN/FeKL (L mg−1) is the Langmuir equilibrium constant which is related to the affinity of binding sites with the adsorbate and qm (mg g−1) is the monolayer capacity referred to the amount of IC required to occupy all the available sites per unit mass of sample. Langmuir isotherm determines whether the adsorption is favorable or unfavorable.The Langmuir model assumes the adsorption of IC occurs as a monolayer on a homogeneous surface and is expressed as;Radj2) and the standard deviation (SD) are listed in Radj2 (0.9820) and low value of SD (3.89) indicated that the adsorption data followed Langmuir isotherm model and the adsorption of IC preferably follows monolayer and homogeneous adsorption process. The calculated maximum adsorption capacity for IC (152.35 mg g−1) obtained in this work in comparison with other reported adsorbents was listed in The values of Langmuir parameters obtained from the treatment of the experimental data as well as of the adjusted coefficient of determination (KF (mg g−1) (L mg−1)n1/ is the Freundlich constant related to the adsorption capacity and 1/n is the heterogeneity factor. The obtained values of Freundlich parameters are listed in n was found to be less than unity indicates favorable adsorption process. The values of Radj2 (0.9333) and SD (9.82) indicated that Freundlich model was not appropriate to describe the adsorption experimental data.The Freundlich expression is based on adsorption onto a heterogeneous surface. The isotherm parameters were calculated using the non-linear form of Freundlich equation, which is given by the following equation;38qmT is the Toth maximum adsorption capacity (mg g−1), αT is the Toth model constant (L mg−1) and t is the model exponent, which is related to heterogeneity of the surface. The model suggests when t = 1, the adsorption occurs on a homogeneous surface, and when t < 1, the adsorption occurs on a heterogeneous surface. The values of the isotherm constants with Radj2 and SD are given in Radj2 (0.9769) and low SD value (4.31) indicated that the isotherm model may use to describe the adsorption experimental data. Also, the Toth component t was close to unity, supporting that the adsorption occurred onto a homogeneous surface.Toth isotherm model is used to describe heterogeneous adsorption systems, which satisfies both low and high-end boundary of the concentration. The non-linear equation of Toth model is given as;3O4–MPA was investigated by varying the pH of the solution over the range of 2–9. The amount of adsorption for IC as a function of pH is shown in 3O4–MPA and IC, which exists mainly as anion form at higher pH, and thus reduces the adsorption of IC.43 The thiol functional groups on the surface of the nanoparticles (Fe3O4-MPA) may influenced by the pH changes and as a result the thiol interactions with the IC dye may also affected. In order to fabricate the APAN/Fe3O4–MPA, the surface of APAN nanofibers contains amide (–CONH) and amine (–NH2) was coupled with MPA coated Fe3O4 nanoparticles containing thiol functional groups (–SH). The thiol functional groups on the surface of Fe3O4 nanoparticles are the prominent sites due to their higher concentration. In acidic solutions (pH = 5), the functional groups of the composite nanofibers would be positively charged .The adsorption of IC onto APAN/Fe44,45 Therefore, having the oppositely charged species (positive on the nanofibers and negative in the solution), the adsorption process will take effect through electrostatic attraction. However, the anionic compartment of IC also contains N–H groups which have the ability to form hydrogen bonding with either the amide functional group or unreacted primary amines of the nanofibers, which will also facilitate the adsorption process. In our previous work, the pH for point of zero charge (pHpzc) of Fe3O4–MPA nanoparticles was found to be around 7.4.21 Thus, Fe3O4–MPA nanoparticles have positive charge at pH < pHpzc and negative surface charge at pH > pHpzc. In case of desorption of IC from the loaded composite nanofibers at basic pH, the functional groups, whether on the surface of Fe3O4 nanoparticles or on the surface of APAN nanofibers, will be negatively charged  at pH ∼ 10. Desorption of the IC from the loaded APAN/Fe3O4–MPA was very fast in the basic solution and 5 min was sufficient to reach the maximum desorption efficiency of 95%.The regeneration of the adsorbent is considered as an important parameter and its reuse is considered an economic necessity factor. Therefore, desorption tests were conducted to regenerate the IC dye from loaded APAN/Fe3O4–MPA was reused in subsequent adsorption–desorption experiments. In these experiments the adsorption efficiency of IC onto APAN/Fe3O4–MPA was determined from five consecutive adsorption–desorption cycle. The results obtained  being released into the solution.Furthermore, the APAN/Feobtained  showed t46 autoclaved cellular concrete/Fe2O3,47 coal fly ash and zeolite,48 1,10-phenanthrolinium intercalated benotite,49 Mg–Al–CO3-calcined layered double hydroxides,50 TiO2-coated non-woven fibers,51 MnOx/TiO2 nanoparticles,52 and Mn-supported TiO2.53 However, the reported experiments were either performed in low concentrations of indigo carmine, high amount of adsorbent, high acidity–alkalinity of the dye solution and meanwhile the adsorption capacity for most of the adsorbent materials were relatively low in comparison to our study (54In comparison to the literature, most of the data reported were on the use of photodegradation method for the removal of indigo carmine from solutions. A variety of materials have been tested such as zirconium phosphates,ur study . In the 3O4–MPA composites nanofiber was prepared by electrospinning followed with chemical cross-linking and evaluated for the removal of indigo carmine from aqueous solutions. The results demonstrated that the prepared composite nanofibers showed high adsorption efficiency compared to some other reported adsorbents. Adsorption isotherms reveal that the adsorption mechanism obeys Langmuir model in which monolayer mechanism can be taken in consideration. The adsorption kinetics results showed that the dye adsorption fitted pseudo first order kinetics. The adsorption equilibrium can be reached within 25 min in which it is shorter than other common adsorbents such as activated carbon, charcoal, and chitosan. The strong adsorption ability of the composite nanofibers may attribute to the accessibility for the dye to the active binding sites. The APAN/Fe3O4–MPA composites nanofibers can be generated and reused several cycles without any significant loss of the adsorption efficiency of indigo carmine. Therefore, the APAN/Fe3O4–MPA can be considered as a potential adsorbent for the removal of indigo carmine from contaminated water.In this work, surface modified APAN/FeThe authors declare that they have no conflict of interest.


Kaposi sarcoma (KS) is a neoplasm of endothelial cells that is caused by human herpesvirus-8. There are 4 different classifications of KS, including classic , endemic , iatrogenic (immunosuppression/organ transplant-related), and epidemic (HIV-associated). KS is characterized by violaceus or dark macules, plaques, or nodules on the skin with potential involvement of the mouth, gastrointestinal tract, lungs, or lymph nodes.,+ cells from baseline, as well as clinical symptoms consistent with an inflammatory process but not consistent with an expected course of a previously or newly diagnosed opportunistic infection or drug side effect or toxicity.+ cell count ≥ 50 cells/mm,,8First-line treatment for HIV-associated KS includes antiretroviral therapy (ART).We report a case on IL bleomycin treatment success for HIV-associated KS in the setting of IRIS.A 30-year-old man with a history of HIV (diagnosed in 2016), syphilis, and stroke (in the setting of Moyamoya disease) was previously on ART with Complera (emtricitabine/rilpivirine/tenofovir) in 2016 but stopped his medications and did not reestablish care until roughly 2019. In April 2021, his CD4 count was 184, and his viral load was <20, and in May 2021, he was started on ART, Biktarvy .A), and a biopsy revealed KS . It was recommended to start IL bleomycin in the setting of IRIS KS.B). These unresolved nodules appeared much smaller on the examination and will be monitored with continued follow-up with this patient. If the nodules increase in size or change in morphology, they will be biopsied.The patient received 4 total treatments of IL bleomycin in February and March of 2022. In his first treatment as a test dose, 0.5 cc of bleomycin sulfate 3 unit/mL was injected intradermally in 3 lesions . In the subsequent treatments, 3 weeks apart, there were approximately 10 lesions that required additional injections. Most were resolved after only 1 session and required ≤0.5 units. At the end of his treatment sessions, there were still 3 lesions that have not fully resolved, and it remains unclear if they reflect residual KS or scarring or fibrosis from bleomycin , B. Thes,The efficacy of IL bleomycin for HIV-associated KS has been reported in a few studies but not in the setting of KS-IRIS. One study in 1984 used 0.1 mg of IL bleomycin or IL vincristine and reported 80% complete regression with partial regression of the other 20% of 93 KS nodules, whereas another study in 1995 used IL bleomycin as monotherapy and found 87% of the 134 lesions showed complete or partial regression using a median dose of 1.5 mg per lesion.Although our patient did not have evidence of lung opacities on chest CT, he did have lymphedema on examination. This combined with the abrupt onset of KS lesions after restarting ART is consistent with KS-associated IRIS. Monotherapy of IL bleomycin was used to treat the lesions and substantially decreased the size of the nodules. Because of the effectiveness of this treatment, cryotherapy was not used, although success was reported in a previous case. This knowledge is useful because of the potential side effect of significant posttreatment dyspigmentation seen with cryotherapy, especially in darker-skinned individuals.This case supports prior research that IL bleomycin is an effective treatment for HIV-associated KS and provides further evidence that this treatment can also be used for HIV-associated KS in the setting of IRIS. Notably, it is possible that while IRIS caused paradoxical KS, immune reconstitution could have also been responsible for clearing the disease without the use of any therapeutic intervention. IL bleomycin should be considered in patients desiring treatment or for those who do not spontaneously improve from immune reconstitution.None disclosed.


Kaposi’s sarcoma is a rare disease with four known variants: classic, epidemic, endemic and iatrogenic (transplant-related), all caused by an oncogenic virus named Human Herpes Virus 8. The viral infection in itself, along with the oncogenic properties of HHV8 and with immune system dysfunction, forms the grounds on which Kaposi’s Sarcoma may develop. Infection with HHV8 occurs through saliva via close contacts, blood, blood products, solid organ donation and, rarely, vertical transmission. Chronic inflammation and oncogenesis are promoted by a mix of viral genes that directly promote cell survival and transformation or interfere with the regular cell cycle and cell signaling . The most common development sites for Kaposi’s sarcoma are the skin, mucocutaneous zones, lymph nodes and visceral organs, but it can also rarely appear in the musculoskeletal system, urinary system, endocrine organs, heart or eye. Histopathologically, spindle cell proliferation with slit-like vascular spaces, plasma cell and lymphocyte infiltrate are characteristic. The clinical presentation is heterogenic depending on the variant; some patients have indolent disease and others have aggressive disease. The treatment options include highly active antiretroviral therapy, surgery, radiation therapy, chemotherapy, and immunotherapy. A literature search was carried out using the MEDLINE/PubMed, SCOPUS and Google Scholar databases with a combination of keywords with the aim to provide critical, concise, and comprehensive insights into advances in the pathogenic mechanism of Kaposi’s sarcoma.  Although it is a fairly rare disease, Kaposi’s sarcoma (KS) warrants attention due to its targeting of a vulnerable group, namely immunocompromised patients, through disease (human immunodeficiency virus (HIV)) or medication (iatrogenic). It was first described in 1872 by Moritz Kaposi in an article called Idiopathic multiple pigmented sarcoma of the skin, in which he presented five cases, each pertaining to men of older age and involving painful lesions of the skin, namely plaques and nodules. This would later be known as classic Kaposi’s sarcoma [Later on, during the acquired immunodeficiency syndrome (AIDS) epidemic, a new variant of KS emerged, namely the AIDS-related variant , which dIn Africa, the increased number of cases of KS would later come to define the endemic variant . This vaThe fourth and final variant of KS known is post transplantation and iatrogenic . RecentlAll four variants described involve Kaposi’s sarcoma-associated herpesvirus (KSHV), but by itself the virus is not enough to start the oncogenic process. The second common factor is immunosuppression, or a malfunctioning immune system. Currently KS is defined as a human herpes virus 8 (HHV8) associated angioproliferative disease. Kaposi’s sarcoma is a trifecta of pathogenic mechanisms and develops only when a mix of viral infection, oncogenesis and chronic inflammation occur .In the current review, we summarize recent findings on the cellular and molecular mechanisms involved in development of KS based on a literature search using scientific databases including MEDLINE/PubMed, SCOPUS and Google Scholar. The search process comprised the following word combinations: “Kaposi’s sarcoma” or “Kaposi’s Sarcoma-Associated Herpesvirus” or ” Human Herpes virus 8” AND ”pathogenesis” or ”molecular biology” or ”immune modulation”. Studies between 2010 and April 2022 were selected. Additional references were obtained from the reference lists of the already included studies.Rhadinovirus, the only one of the genus with human tropism. As previously outlined, HHV8 is found in all types of Kaposi’s sarcoma [Around 12% of all cancers worldwide are caused by oncogenic viruses ,8. Among sarcoma , and is  sarcoma . Infection occurs through saliva via close contact, blood, blood products, solid organ donation and, rarely, mother to fetus .In 1994, Chang et al. first identified the KSHV in the lesions of an AIDS-KS patient by comparing affected and normal tissues by polymerase chain reaction (PCR) amplification .Endothelial cells, dendritic cells, monocytes, B cells, epithelial cells and fibroblasts are all susceptible to infection by KSHV according to a study done by Bechtel et al. in 2003  and, morKSHV has an enveloped icosahedral capsid with 162 capsomers and a total diameter of about 150–200 nm. The capsid is surrounded by the tegument and the virus envelope, which is studded with multiple glycoproteins such as gB, gH, gL, gM, gN, ORF4 and gpK8.1A, that are vital for the binding and entry into the host cell . ThroughLike many other viruses, KSHV has a lytic (short period) and latent (dormant—predominant for most of the time) phase . During its latent phase, KSHV does not cause its host to exhibit any obvious signs of pathology . After vThe lytic reactivation represents another critical step in tumorigenesis, as demonstrated by the finding that inhibition of the lytic cycle using Ganciclovir reduced the risk of developing KS by 75% . The lytGenes that are expressed in the lytic cycle are divided into three groups: immediate early (IE), early (E) and late (L) genes. The lytic phase genes of the IE and E groups of most relevance to KS are summarized in As previously mentioned, HHV8 is insufficient by itself to cause KS. A combination of a compromised immune system (whether achieved through medication or through a condition such as AIDS), genetic predisposition and environmental factors is needed for oncogenesis.Most tumors present a single cell as a monoclonal point of origin; however, KS sometimes presents itself as oligoclonal ,85. The LANA-1, the major protein expressed during the latent phase, upregulates vFlip (which has antiapoptotic functions) and vCyclin (overcomes cell cycle arrest of RB through phosphorylation) , and stav-IL6, a protein expressed both during the latent  and lytic viral phase of KSHV, plays an important role in KS genesis through angiogenesis, cell proliferation and invasion via downregulation of caveolin 1 (CAV1) , which hvBCL-2 is encoded by the ORF16 gene and is a functional homologue of the human B-cell lymphoma 2 (BCL-2) gene . vBCL-2 vCyclin forms a complex with CDK6 which phosphorylates BCL-2. vCyclin accelerates cell-cycle progression and also promotes apoptosis in cells with increased levels of CDK6. This complex inactivates BCL-2 through phosphorylation; however, vBCL-2 escapes inactivation from vCyclin and continues to promote cell survival . Another molecule that serves to inhibit apoptosis is the viral inhibitor of apoptosis protein (vIAP) encoded by the ORFK7 gene . In a stK1 plays an important role in lytic replication, cellular survival and immortalization of human endothelial cells . ThroughPhysiologically, angiogenesis represents the formation of new blood vessels from existing ones. The migration, growth and differentiation of endothelial cells are involved in this process. Many tumors require angiogenesis for growth. Tumors often stimulate angiogenesis to supply themselves with nutrients and to sustain themselves . Those tKaposi’s sarcoma development is somewhat different (but not unique). It can promote VEGF-A secretion in normoxic conditions by several methods by way of KSHV proteins. KSHV genes that contribute to the stabilization of HIF-1 , includDirect secretion of VEGF-A is promoted by viral products such as glycoprotein b (gB) ,113, K1 Although not a direct promoter of angiogenesis via VEGF-A, K15 has been shown to induce angiogenic tube formation via a phospholipase Cγ1 (PLCγ1) VEGF-dependent pathway, even when the VEGF receptors were silenced . K15 hasAnother indirect promoter of angiogenesis is the KSHV miRNAs, which have been shown to target and downregulate THBS1, an inhibitor of angiogenesis that regulates VEGF and a potent activator of latent TGF-beta, both free and cell-associated ,117,118.VEGF induces activation of RAC1   markers of differentiation as well as blood endothelial cell markers (BEC). The prevailing idea is that BEC are reprogrammed to LEC ,134. KSHMatrix metalloproteinases are endopeptidases whose main function is extracellular matrix (ECM) remodeling in physiological conditions. In a study done by Pantanowitz et al. , it was Certain inflammatory cytokines are upregulated and others are downregulated as the result of viral infection . vIRFs wKSHV additionally encodes three chemokine homologs known as viral CC-chemokine ligand 1 , vCCL2 (K4) and vCCL3 (K4.1). These were previously known as viral macrophage inflammatory proteins (vMIPs). vCCL1 and vCCL attract Th2 and CD4 + CD25+ regulatory T cells that, in turn, serve to downregulate the immune response ,148,149.But why does KS occur predominantly in men? A recent study conducted by Ding et al. , shows tIn conclusion, KS is the result of a “perfect storm” comprised of viral infection, chronic inflammation , and oncogenesis .Classic KSEndemic KSEpidemic KSIatrogenic (post-transplant) KSKS, as previously mentioned, can be split into four main clinical-epidemiological types:KS has a heterogenic clinical presentation; some patients have indolent disease and others have an aggressive disease.Classic or sporadic KS is specific to older men of Mediterranean descent or Ashkenazi jews ,161. It Endemic KS is specific to Africa, where KSHV seroprevalence is over 40–50% ,163. TwoEpidemic or AIDS-related KS describes AIDS-associated tumors. KS is the second most common tumor after non-Hodgkin’s lymphoma. This variant is extremely aggressive, and infection can predate KS by 10 years . CD4 T-cIatrogenic or post-transplant KS occurs when a patient receives immunosuppression that causes the reactivation of a previously HHV8 infection, or when the patient received an infected organ . InterruA new entity has been described in several case reports and named non-epidemic KS ,169. MorThe clinical types of KS have no homogenous staging. In classic KS, clinical manifestation with patch/papules, plaque and tumor limited to the lower extremities describes the first three stages of disease. Stage 4 implies disseminated diseases. In AIDS-related KS, the immune status and systemic illness, along with tumor location, are criteria for staging. Endemic and post-transplant KS have no specific staging . In regard to the location where KS most commonly appears, mucocutaneous sites are most frequently seen. The cutaneous lesions are either flat or elevated, painless, pink to violaceous coloured and do not blanch under pressure . Lymph nAll four variants of KS show similar histological features, and there is no clear difference between them. The three previously mentioned clinical stages, namely patch/papules, plaque and the tumor stage are not necessary for microscopic diagnostic but do help in recognizing the various patterns of KS. The most defining feature of KS is spindle cell proliferation, with differing forms of sieve and slit-like spaces occupied by erythrocytes and hemosiderin deposits, with a plasma cell and lymphocyte infiltrate. Sometimes, the erythrocytes might be missing, and thus hemosiderin deposits should be looked at as proof of extravasation of the previously mentioned cells.The patch stage represents the earliest stage of KS. It is characterized by a subtle endothelial cell proliferation with minimal atypia, scant plasma cell and lymphocyte proliferate. The “promontory sign” can also be seen during this stage, which is characterized by other more mature structures (such as another vessel) protruding into the newly formed vessels , which also tend to wrap/and or dissect collagen bundles . The newPlaque stage is characterized by a more extensive vascular proliferation and plasma cell inflammatory infiltrate. Eccrine glands, if they are present on the slide, are sometimes useful for noticing an invasive process. Spindle cells will often be seen invading the eccrine glands or destroying them outright.The tumor stage is the final and most representative stage of spindle cell proliferation—it is also called “nodular” and the neoplastic cells form solid aggregates of intersected spindle cells dotted by slit and sieve-like spaces with erythrocytes inside. The proliferation is so extensive, that the entire dermal layer up to the epidermis may be occupied by the spindle cell proliferate. Certain periodic acid-Schiff (PAS) positive hyaline globules are found within neoplastic endothelial cells and are believed to be phagocytized erythrocytes . During early stages, using simple H&E stains, KS might mimic benign vascular proliferations, and during later stages might be confused with other malignant spindle cell tumors . As ancillary tests, the following immunohistochemical stains are used: CD34 (+), CD31 , surgery with local excision, cryosurgery, radiation therapy, chemotherapy and immunotherapy. Targeted therapy is a novel type of treatment that affects specific cells, thus causing less damage to normal cells. New therapies target the signals transduction pathways utilized by KSHV, such as inhibition of XPO1  or KSHV Surgical excision is appropriate for small and superficial lesions but has the major drawback of high recurrence rate. Cryosurgery has temporary effects on superficial lesions and induces hypopigmentation . AIDS-related KS is usually managed by ensuring an increase in CD4+ cells via HAART, which can lead to the regression of the tumor and improve the prognosis . ChemothAfter initiating HAART in patients with immunosuppression there is a risk of KS immune reconstitution inflammatory syndrome (IRIS). IRIS is an inflammatory disorder associated either with a clinical paradoxical worsening of preexisting KS or, rarely, with unmasking an undiagnosed KS. IRIS management is not standardized. Dependent on clinical evolution, continuing HAART and adding chemotherapy are both options for managing IRIS in KS. Glucocorticoids should be avoided as they may worsen KS ,190.Classical KS can be treated with radiation therapy and chemotherapy  ,192 withIatrogenic KS is usually treated by removal of immunosuppressive therapy. If such actions are not possible, radiation therapy can be used instead . TopicalImmunotherapy is considered a salvage therapy and involves administration of monoclonal antibodies to block immune checkpoints in refractory KS to other treatments . AlthougIn a recent study, Meng et al.  showed tK15 plays an essential role in lytic replication and, as such, may constitute a potential therapeutic target as noted by Abere et al. . TyrosinSulfonamide compounds could possibly contribute in clearing latent KSHV, thus inhibiting pathogenesis and, thereby, oncogenesis . Although remarkable progress has been made in understanding the pathogenesis of KSHV, extensive research is needed to understand the exact molecular mechanisms that are necessary for KS to appear. As previously outlined, infection by itself is not enough; the oncogenic properties of HHV8 and the immune system dysfunction are also needed for KS development. Therefore, any advance for a better understanding of KS pathogenesis provides hope for the discovery of new targeted therapeutics.


It can also be used by molecular simulation package developers to run representative test systems during development, increasing code correctness. The theoretical foundation of the physical validation tests were established by physical_validation package was first mentioned.Molecular simulations such as molecular dynamics (MD) and Monte Carlo (MC) simulations are powerful tools allowing the prediction of experimental observables in the study of systems such as proteins, membranes, and polymeric materials. The quality of predictions based on molecular simulations depend on the validity of the underlying physical assumptions.  For most of the history of molecular simulation-based research in chemistry, biophysics, physics and engineering, most users of molecular simulation packages were experts that contributed to the code bases themselves or were very familiar with the methodology used. Increased popularity of molecular simulation methods has led to a significantly increased user base and to an explosion of available methods. The simulation packages are faster and more powerful than ever, and even more than before require expertise to avoid using combinations of methods and parameters that could violate physical assumptions or affect reproducibility. Unphysical artifacts have frequently been reported to significantly affect physical observables such as the folding of proteins or DNA, the properties of lipid bilayers, the dynamics of peptides and polymers, or properties of simple liquids (see physical_validation tackles the problem of robustness in molecular simulations at two levels. The first level is the end-user level. physical_validation allows users to test their simulation results for a number of deviations from physical assumptions such as the distribution of the kinetic energy, the equipartition of kinetic energy throughout the system, the sampling of the correct ensemble in the configurational quantities, and the precision of the integrator. The combination of these tests allow to cover a wide range of potential unphysical simulation conditions (physical_validation also returns its conclusions in machine-readable form, it can be included in pipelines allowing results to be tested for physical validity without user interaction. The second level of usage is by code developers. Unphysical behavior might not only result from poor or incompatible parameters and models, it might also stem from coding errors in the simulation programs. physical_validation can therefore be used to regularly run representative simulations as end-to-end tests in a continuous integration setup, ensuring that code changes do not introduce bugs that lead to unphysical results. GROMACS (physical_validation since 2019 to test every release version with a comprehensive set of simulations covering all major code paths.nditions . This in GROMACS , one of physical_validation package. github.com/shirtsgroup/checkensemble. This script was used as a base for the ensemble validation tests in physical_validation. physical_validation and its use in the validation of GROMACS releases.μVT ensembles, covering the full set of ensembles described by In the three years since the publication, the software has matured into a stable release. The ensemble tests now also support