Synergistic Approaches in the Design and Applications of UCST Polymers.

This review summarizes recent progress in the synergistic design strategy for thermoresponsive polymers possessing an upper critical solution temperature (UCST) in aqueous systems. To achieve precise control of the responsive behavior of the UCST polymers, their molecular design can benefit from a synergistic effect of hydrogen bonding with other interactions or modification of the chemical structures. The combination of UCST behavior with other stimuli-responsive properties of the polymers may yield new functional materials with potential applications such as sensors, actuators, and controlled release devices. The advances in this area provide insight or inspiration into the understanding and design of functional UCST polymers for a wide range of applications.

[Recommendations for the diagnosis and treatment of gout in China].

Gout is a metabolic disease resulting from the accumulation of monosodium urate (MSU) in joints, leading to crystal-induced arthritis. In China, gout is common, but there is insufficient knowledge regarding standardized criteria for the diagnosis and treatment of this condition. Based on evidence and guidelines from China and other countries, the Chinese Rheumatology Association developed standardized criteria for the diagnosis and treatment of gout in China. The purpose was to standardize gout diagnosis methods as well as treatment opportunities and strategies in order to reduce misdiagnosis, missed diagnosis, and irreversible damage.

Using Nuclear Magnetic Resonance Spectroscopy to Probe Hydrogels Formed by Sodium Deoxycholate.

Hydrogels of bile acids and their salts are promising materials for drug delivery, cellular immobilization, and other applications. However, these hydrogels are poorly understood at the molecular level, and further study is needed to allow improved materials to be created by design. We have used NMR spectroscopy to probe hydrogels formed from mixtures of formic acid and sodium deoxycholate (NaDC), a common bile acid salt. By assaying the ratio of deoxycholate molecules that are immobilized as part of the fibrillar network of the hydrogels and those that can diffuse, we have found that 65% remain free under typical conditions. The network appears to be composed of both the acid and salt forms of deoxycholate, possibly because a degree of charge inhibits excessive aggregation and precipitation of the fibrils. Spin-spin relaxation times provided a molecular-level estimate of the temperature of gel-sol transition (42 °C), which is virtually the same as the value determined by analyzing macroscopic parameters. Saturation transfer difference (STD) NMR spectroscopy established that formic acid, which is present mainly as formate, is not immobilized as part of the gelating network. In contrast, HDO interacts with the network, which presumably has a surface with exposed hydrophilic groups that form hydrogen bonds with water. Moreover, the STD NMR experiments revealed that the network is a dynamic entity, with molecules of deoxycholate associating and dissociating reversibly. This exchange appears to occur preferentially by contact of the hydrophobic edges or faces of free molecules of deoxycholate with those of molecules immobilized as components of the network. In addition, DOSY experiments revealed that gelation has little effect on the diffusion of free NaDC and HDO.

[Recommendations for diagnosis and treatment of systemic sclerosis in China].

Systemic sclerosis (SSc) is an autoimmune rheumatic disease that is characterized by skin fibrosis with multi-organ involvement. In China, the standardized diagnosis and treatment for SSc is still lacking. Based on the diagnosis criteria and guidelines from China and abroad, Chinese Rheumatology Association developed the current standardization of diagnosis and treatment for SSc. The purposes of this guideline are to standardize clinical management for SSc in China, to interpret the key evaluation tools for SSc, and to recommend therapeutic principle and strategies.

[Recommendations of diagnosis and treatment of adult-onset Still's disease in China].

Adult-onset Still's disease (AOSD) is a rare systemic autoinflammatory disorder. In China, standardized diagnosis and treatment for AOSD is insufficient. Based on the evidence from China and other countries, Chinese Rheumatology Association developed standardization of diagnosis and treatment of AOSD in China. The purpose is to standardize the methods for diagnosis of AOSD, treatment strategies, and reduce misdiagnosis, missed diagnosis and irreversible damage.

Enzymatic Conversion of Galactose Polymers into Copolymers Containing Galactonic Acid by Glucose Oxidase.

Sugar oxidase can oxidize a carbohydrate substrate into an acid, but there have been no reports on the successful enzymatic conversion of glycopolymers containing carbohydrate pendants. We introduced a poly(ethylene glycol) (PEG) spacer between the carbohydrate and the methacrylic units, and glucose oxidase (GOx) showed enzymatic activity when the PEG spacer is sufficiently long, converting the galactose pendant into galactonic acid and yielding a copolymer. The glycopolymers with a PEG spacer showed stronger binding to the sugar-specific lectin than those without the spacer, while the binding was gradually weakened as the sugar pendants were converted to acid groups. To the best of our knowledge, this is the first example to use a hydrophilic PEG spacer to enzymatically convert a substrate attached on a polymer chain. The enzymatic conversion of such glycopolymers represents a useful green chemistry approach to obtain copolymers based on carbohydrates.

[Recommendations of diagnosis and treatment of gout in China].

Gout is a crystal associated arthritis caused by monosodium urate (MSU) accumulating in joint, and it belongs to metabolic rheumatic disease. In China, gout is common but it is insufficient for education of standardized diagnosis and treatment for gout. Based on the evidence and guidelines from China and other countries, Chinese gout Collaborative Research Group developed standardization of diagnosis and treatment of gout in China. The purpose is to standardize the methods for diagnosis of gout, treatment opportunity and strategies in order to reduce misdiagnosis, missed diagnosis and irreversible damage.

[Progress in respiratory toxicity of polyhexamethyleneguaidine disinfectant and mechanism exploration].

Polyhexamethylene guanidine (PHMG) is a high molecular guanidine compound with a broad spectrum of antibacterial effects. Since the outbreak of the 'humidifier disinfectant-induced lung injury' event in South Korea, the respiratory toxicity of PHMG had become a public concern. An epidemiological survey in Korea found that PHMG-containing disinfectants were an important risk factor for pulmonary fibrosis. Animal experiments also showed that the exposure to PHMG through the respiratory tract could cause irreversible fibrosis in the lungs. TGF-ß signaling pathway, epithelial-mesenchymal transition and pulmonary inflammation might be the main pathways that could mediate PHMG-induced pulmonary fibrosis. This article provided an overview of the characteristics of population exposure to PHMG and research progress in the field of respiratory toxicology and recommendations for the rational and standard of using PHMG-related products in China.

[Study on fibrosis changes in the lungs of mice caused by repeated inhalation of polyhexamethyleneguaidine disinfectant].

Objective: To explore the lung damage caused by repeated inhalation of polyhexamethyleneguanidine (PHMG) disinfectant aerosol and the corresponding toxicological characteristics. Methods: Thirty four-week-old mice of C57BL/6N strain were randomly divided into three groups, the control group, low-dose group, and high-dose group. Each group had 5 male mice and 5 female mice. Lab II-level purified water was used in the control group. The PHMG disinfectant aerosol was generated by using the ultrasonic atomization of the aqueous solution containing PHMG. The PHMG concentrations in the low-and high-dose groups were 0.1 mg/ml (0.01%) and 1 mg/ml (0.1%), respectively. The concentration of PHMG in the post-chemical exposure room was 1.03 mg/m(3) and 9.09 mg/m(3) according to the air sampler analysis. The experimental mice were exposed to the PHMG in dynamic respiratory exposure mode for 4 hours every day in 21 days. After 21-day exposure, bronchia alveolus lung fluids (BALFs) were used to evaluate the inflammatory cells in the lungs, and pathological evaluation, special staining and immunohistochemical methods were further performed to evaluate the key indicators of pulmonary fibrosis. Results: Compared to the control group, the body weight of mice in the high-dose group was significantly decreased (P<0.05), while that of mice in the low-dose group did not significantly differ (P>0.05). The number of inflammatory cells in BALFs of low-dose exposed mice was slightly reduced, and the lung tissue pathology began to show lung damage with early fibrosis symptoms (P<0.05). The pathological examination of mice in the high-dose group showed changes in pulmonary fibrosis. Immunohistochemical staining showed that pulmonary fibrosis marker, α-SMA, was significantly increased in low-dose group and high-dose group (P<0.05). Conclusion: The repeated inhalation of PHMG disinfectant could cause lung damage such as pulmonary fibrosis in mice. It could suggest that special warnings should be given to this common disinfectant and respiratory protection measures should be adopted during industrial production and daily use.

Core Cross-linked Micelles Made of Glycopolymers Bearing Dopamine and Cholic Acid Pendants.

A series of block glycopolymers bearing galactose, dopamine, and cholic acid (CA) pendants have been synthesized by RAFT polymerization. These copolymers can self-assemble into micelles in water. The dopamine moieties, located near the interface of the core and shell of the micelles, can self-polymerize in a weakly basic solution, stabilizing the micelles in both water and organic solvent (DMSO). The cross-linked micelles are smaller in size than the uncross-linked precursors. Introducing more CA groups into the copolymers promotes the self-assembly to form larger aggregates, controls the cross-linking of the stabilized micelles, and facilitates the encapsulation of hydrophobic compounds such as Nile Red (NR). The amount of CA comonomers added also helps to control the cross-linking density, which affects the loading and release of NR. The core cross-linked micelles displayed a slow but sustained NR release and interact effectively with lectin (RCA120), demonstrating their potential use as a biocompatible multifunctional platform for targeted release of drugs.

Bile Acid-Based Drug Delivery Systems for Enhanced Doxorubicin Encapsulation: Comparing Hydrophobic and Ionic Interactions in Drug Loading and Release.

Doxorubicin (Dox) is a drug of choice in the design of drug delivery systems directed toward breast cancers, but is often limited by loading and control over its release from polymer micelles. Bile acid-based block copolymers present certain advantages over traditional polymer-based systems for drug delivery purposes, since they can enable a higher drug loading via the formation of a reservoir through their aggregation process. In this study, hydrophobic and electrostatic interactions are compared for their influence on Dox loading inside cholic acid based block copolymers. Poly(allyl glycidyl ether) (PAGE) and poly(ethylene glycol) (PEG) were grafted from the cholic acid (CA) core yielding a star-shaped block copolymer with 4 arms (CA-(PAGE- b-PEG)4) and then loaded with Dox via a nanoprecipitation technique. A high Dox loading of 14 wt % was achieved via electrostatic as opposed to hydrophobic interactions with or without oleic acid as a cosurfactant. The electrostatic interactions confer a pH responsiveness to the system. 50% of the loaded Dox was released at pH 5 in comparison to 12% at pH 7.4. The nanoparticles with Dox loaded via hydrophobic interactions did not show such a pH responsiveness. The systems with Dox loaded via electrostatic interactions showed the lowest IC50 and highest cellular internalization, indicating the pre-eminence of this interaction in Dox loading. The blank formulations are biocompatible and did not show cytotoxicity up to 0.17 mg/mL. The new functionalized star block copolymers based on cholic acid show great potential as drug delivery carriers.

Self-Healing Hydrogels of Low Molecular Weight Poly(vinyl alcohol) Assembled by Host-Guest Recognition.

Poly(vinyl alcohol) (PVA) is a cytocompatible synthetic polymer and has been commonly used to prepare hydrogels. Bile acids and ß-cyclodextrin are both natural compounds and they form stable host-guest inclusion complexes. They are attached covalently onto a low molecular weight PVA separately. Self-healing hydrogels can be easily formed by mixing the aqueous solutions of these PVA based polymers. The mechanical properties of the hydrogels can be tuned by varying the molar fractions of bile acid units on PVA. The dynamic inclusion complexation of the host-guest pair of the hydrogel allows the self-healing rapidly under ambient atmosphere and their mechanical properties could recover their original values in 1 min after incision. These PVA based polymers exhibited the good cytocompatibility and high hemocompatibility as shown by their biological evaluations. The use of natural compounds for host-guest interaction make such gels especially convenient to use as biomaterials, an advantage over conventional hydrogels prepared through freeze-thaw method.

[Clinical applications of intelligent pressure control flexible ureteroscope for the treatment of renal calculi ≤2 cm].

Objective: To evaluate the effectiveness and safety of intelligent pressure control flexible ureteroscope for management of renal stones ≤2 cm. Methods: The clinical data of 267 cases of renal calculi treated with flexible ureteroscope lithotripsy at Department of Urology, Ganzhou People's Hospital from June 2015 to December 2017 were analyzed retrospectively. There were 129 male and 138 female patients, with a mean age of 51.2 years (ranging from 19 to 76 years). Among them, 145 patients underwent intelligent pressure control flexible ureteroscope (intelligent control group) and 122 patients underwent flexible ureteroscope ordinary (ordinary group). The t test, χ2 test or Fisher exact test were used for statistical analysis. The success rate of stone seeking, the stone free rates, the incidence of complications, the average operation time, the average hospital stay after operation were compared between the two groups. Results: The average mean operative time of the patients with intelligent control group was (26.17 ± 8.64) minutes, significantly shorter than (47.23±18.35) minutes of the ordinary group (t=1.968, P=0.000). The stone free rate of the patients with intelligent control group was 97.2%, it was higher than 86.0% of ordinary group (χ2=0.069, P=0.004). The complication rate of the patients with intelligent control group was 2.7%, which was significantly shorter than 18.0% of the ordinary group (χ2=17.586, P=0.000). However, there was no significant difference between the two groups in the success rate of stone seeking and postoperative hospital stay (P>0.05). Conclusion: Intelligent controlled pressure ureteral flexible ureteroscope has the advantages of short operation time, high stone free rate and less complications in the treatment of renal calculi ≤2 cm compared with flexible ureteroscope ordinary.

Self-Assembly of a Bile Acid Dimer in Aqueous Solutions: From Nanofibers to Nematic Hydrogels.

A mixture of a cholic acid dimer with a secondary amine group and formic acid at a molar ratio of 1/1 is regarded as an organic salt, and it self-assembles in aqueous solutions to form monodisperse nanofibers. The nanofibers are separated at low concentrations of the mixture but entangle with each other at high concentrations to form well-dispersed and randomly arranged 3D fibrous networks. Above the minimum gelation concentration of the dimer, the fibrous network is strong enough to gelate the aqueous solutions to form a hydrogel. Hydrogels obtained from the dimer salt at a lower concentration are isotropic and show extinction between crossed polarizers in the polarizing microscope, whereas they become anisotropic (i.e., nematic hydrogels) upon increasing the dimer salt concentration or under physical stirring. The parallel arrangement of nanofibers from randomly directed fibrous networks may be responsible for the formation of such nematic hydrogels.

Glycopolymers Bearing Galactose and Betulin: Synthesis, Encapsulation, and Lectin Recognition.

Betulin is a natural triterpene compound with anticarcinogen and antiviral activities. It is conjugated with methacrylate and then copolymerized with a galactose-bearing comonomer by RAFT polymerization to yield both random and block copolymers. These glycopolymers are designed to possess similar molecular weights and monomer compositions for easy comparison. They self-assembled into micelles, as shown by dynamic light scattering (DLS) and transmission electron microscopy. The smaller micelles formed by the random copolymers facilitated the encapsulation of Nile Red and released more of this hydrophobic model compound (46% in 4 days versus 32% released from the block copolymers). These glycopolymers interacted with lectins, such as RCA120, as studied by turbidity assay and DLS. The block copolymers formed larger aggregates and clustered faster than the random copolymers. The betulin-based glycopolymers may serve as biocompatible multifunctional biomaterials and carriers for use in targeted release of drugs.

Tunable Upper Critical Solution Temperatures for Acrylamide Copolymers with Bile Acid Pendants.

Acrylamide derivatives of bile acids are chosen as a hydrophobic comonomer to copolymerize with acrylamide via reversible addition and fragmentation chain transfer (RAFT) polymerization to afford a series of copolymers of P(AAm-co-CAA). These copolymers exhibit a sharp and reversible insoluble-soluble transition in water upon heating to a mixing temperature (Tmix) related to the upper critical solution temperature (UCST). Tmix of these copolymers can be conveniently tuned to a practical temperature range, around 37 °C for biomedical applications. Tmix rises with increasing molar fraction of the bile acid-based acrylamide and increasing concentration of the aqueous solution of the copolymers. The addition of a natural host molecule ß-cyclodextrin lowered the Tmix. The insoluble-soluble transition of the copolymers was also evidenced by dynamic light scattering and transmission electron microscopy. The biocompatible nature of the bile acids and ß-cyclodextrins may make these copolymers potentially useful for biomedical applications.

"Bitter-Sweet" Polymeric Micelles Formed by Block Copolymers from Glucosamine and Cholic Acid.

Natural compounds glucosamine and cholic acid have been used to make acrylic monomers which are subsequently used to prepare amphiphilic block copolymers by reversible addition-fragmentation chain transfer (RAFT) polymerization. Despite the striking difference in polarity and solubility, three diblock copolymers consisting of glucosamine and cholic acid pendants with different hydrophilic and hydrophobic chain lengths have been synthesized without the use of protecting groups. They are shown to self-assemble into polymeric micelles with a "bitter" bile acid core and "sweet" sugar shell in aqueous solutions, as evidenced by dynamic light scattering and transmission electron microscopy. The critical micelle concentration varies with the hydrophobic/hydrophilic ratio, ranging from 0.62 to 1.31 mg/L. Longer chains of polymers induced the formation of larger micelles in range of 50-70 nm. These micelles can solubilize hydrophobic compounds such as Nile Red in aqueous solutions. Their loading capacity mainly depends upon the hydrophobic/hydrophilic ratio of the polymers, and may be also related to the length of the hydrophilic block. These polymeric micelles allowed for a 10-fold increase in the aqueous solubility of paclitaxel and showed no cytotoxicity below the concentration of 500 mg/L. Such properties make these polymeric micelles interesting reservoirs for hydrophobic molecules and drugs for biomedical applications.

[DNT cell inhibits the growth of pancreatic carcinoma via NKG2D and MICA pathway in vivo].

Objective: To investigate the effects of natural killer group 2 member D (NKG2D) and its ligands major histocompatibility complex class Ⅰ chain-related molecules A(MICA) on DNT cell killing pancreatic carcinoma. Methods: Antibodies adsorption was used to separate DNT cell from human peripheral blood. Human pancreatic tumor models were established via implanting BXPC-3 cells into nude mice, and then mice were randomly divided mice into 3 groups, blank group, gemcitabine group and DNT group. Mice weights and mice tumor volumes were measured every 5 days. After 40 days mice were euthanized at cervical dislocation method. Tumor weights were measured. Relative tumor volume and tumor inhibition rate were calculated. Western blot and qPCR were used to detect the expressions of NKG2D and MICA in the transplanted tumors of the three groups. Results: The blank group tumor volume and weight of blank group were significantly larger than those of gemcitabine group and DNT group (858.7±35.7 mg, 251.1±19.7 mg, 278.5±17.3 mg, P<0.001), but there were no significantly difference between DNT group and gemcitabine group. The tumor inhibition rate of gemcitabine and DNT cell were 40.4% and 35.5%. Western blot and qPCR showed that MICA mRNA and protein levels in blank group were significantly higher than those in DNT group (P=0.001, P=0.003). NKG2D mRNA and protein levels in blank group were significantly lower than those in DNT cells group (P<0.001, P=0.001). Conclusion: DNT cell can significantly inhibit the growth of pancreatic carcinoma in vivo, and the mechanism may be involved in abnormal expressions of MICA and NKG2D.

Relatively stable response of fruiting stage to warming and cooling relative to other phenological events.

The timing of the fruit-set stage (i.e., start and end of fruit set) is crucial in a plant's life cycle, but its response to temperature change is still unclear. We investigated the timing of seven phenological events, including fruit-set dates during 3 yr for six alpine plants transplanted to warmer (approximately +3.5°C in soils) and cooler (approximately -3.5°C in soils) locations along an altitudinal gradient in the Tibetan area. We found that fruit-set dates remained relatively stable under both warming and cooling during the 3-yr transplant experiment. Three earlier phenological events (emergence of first leaf, first bud set, and first flowering) and two later phenological events (first leaf coloring and complete leaf coloring) were earlier by 4.8-8.2 d/°C and later by 3.2-7.1 d/°C in response to warming. Conversely, cooling delayed the three earlier events by 3.8-6.9 d/°C and advanced the two later events by 3.2-8.1 d/°C for all plant species. The timing of the first and/or last fruit-set dates, however, did not change significantly compared to earlier and later phenological events. Statistical analyses also showed that the dates of fruit set were not significantly correlated or had lower correlations with changes of soil temperature relative to the earlier and later phenological events. Alpine plants may thus acclimate to changes in temperature for their fruiting function by maintaining relatively stable timings of fruit set compared with other phenological events to maximize the success of seed maturation and dispersal in response to short-term warming or cooling.

Facile Assembly of Large-Area 2D Microgel Colloidal Crystals Using Charge-Reversible Substrates.

2D colloidal crystals (CCs) have important applications; however, the fabrication of large-area, high-quality 2D CCs is still far from being trivial, and the fabrication of 2D microgel CCs is even harder. Here, we have demonstrated that they can be facilely fabricated using charge-reversible substrates. The charge-reversible substrates were prepared by modification with amino groups. The amino groups were then protected by amidation with 2,2-dimethylsuccinic anhydride. At acidic pH, the surface charge of the modified substrate will change from negative to positive as a result of the hydrolysis of the amide bonds and the regeneration of the amino groups. 2D microgel CCs can be simply fabricated by applying a concentrated microgel dispersion on the modified substrate. The negatively charged surface of the substrate allows the negatively charged microgel spheres, especially those close to the substrate, to self-assemble into 3D CCs. With the gradual hydrolysis of the amide bonds and the charge reversal of the substrate, the first 111 plane of the 3D assembly is fixed in situ on the substrate. The resulting 2D CC has a high degree of ordering because of the high quality of the parent 3D microgel CC. Because large-area 3D microgel CCs can be facilely fabricated, this method allows for the fabrication of 2D CCs of any size. Nonplanar substrates can also be used. In addition, the interparticle distance of the 2D array can be tuned by the concentration of the microgel dispersion. Besides rigid substrates (such as glass slides, quartz slides, and silicon wafers), flexible polymer films, including polyethylene terephthalate and poly(vinyl chloride) films, were also successfully used as substrates for the fabrication of 2D microgel CCs.