Comparative investigations on the incorporation of biogenic Fe products into anaerobic granular sludge of different sources: Fe loading capacity, physicochemical properties, microbial community and long-term methanogenesis performance.

Anaerobic granular sludge (AGS) has been regarded as the core of lots of advanced anaerobic reactors. Formation of biogenic Fe products and their incorporation into AGS could influence interspecies electron transfer and methanogenesis performance. In this study, with anaerobic granular sludge (AGS) from different sources (brewery, chemical plant, paper mill, citric acid factory, and food factory) as the research targets, the formation of biogenic iron products in AGS through the biologically induced mineralization process was studied. Furthermore, the influences of physicochemical properties and microbial community on methanogenesis were investigated. Results showed that all the AGS of different sources possessed the capacity to form biogenic Fe products through dissimilatory iron-reduction process, and diverse Fe minerals including magnetite (Fe3O4), hematite (Fe2O3), goethite (FeOOH), siderite (FeCO3) and wustite (FeO) were incorporated into AGS. The AGS loaded with Fe minerals (Fe-AGS) showed increased conductivity, magnetism and zeta-potential comparing to the control. Those Fe-AGS of different sources demonstrated different methanogenesis performance during the long-term operation (50 days). Methane production was increased for the Fe-AGS of citric acid (6.99-32.50%), food (8.33-37.46%), chemical (2.81-7.22%) and brewery plants (2.27-2.81%), but decreased for the Fe-AGS of paper mill (54.81-72.2%). The changes of microbial community and microbial correlations in AGS as a response to Fe minerals incorporation were investigated. For the Fe-AGS samples with enhanced methane production capability, it was widely to find the enriched populations of fermentative and dissimilatory iron reducing bacteria Clostridium_sensu_stricto_6, Bacteroidetes_vadinHA17 and acetoclastic methanogens Methanosaeta, and positive correlations between them. This study provides comprehensive understanding on the effects of incorporation biogenic Fe products on AGS from different sources.

Reduced Surface Trap States of PbS Quantum Dots by Acetonitrile Treatment for Efficient SnO2-Based PbS Quantum Dot Solar Cells.

The solution-phase ligand-exchange strategy offers a simple pathway to prepare PbS quantum dots (QDs) and their corresponding solar cells. However, the production of high-quality PbS QDs with reduced surface trap state density for efficient PbS QD solar cells (QDSCs) still faces challenges. As the hydroxyl group (-OH) has been demonstrated to be the primary source of the surface trap states on PbS QDs in the general oleic acid method, here, we present an effective and facile strategy for reducing the surface -OH content of PbS QDs by using acetonitrile (ACN) as precipitant to wash the surface of QDs, which significantly decreases the trap state density and enables the preparation of superior PbS QDs. The resulting solar cell with an ITO/SnO2/n-PbS/p-PbS/Au structure obtained an improved photoelectric conversion efficiency (PCE) from 8.53 to 10.49% with an enhanced air storage stability, realizing a high PCE for SnO2-based PbS QDSCs.

Identification of dihydroquinolizinone derivatives with nitrogen heterocycle moieties as new anti-HBV agents.

The sustained loss of HBsAg is considered a pivotal indicator for achieving functional cure of HBV. Dihydroquinolizinone derivatives (DHQs) have demonstrated remarkable inhibitory activity against HBsAg both in vitro and in vivo. However, the reported neurotoxicity associated with RG7834 has raised concerns regarding the development of DHQs. In this study, we designed and synthesized a series of DHQs incorporating nitrogen heterocycle moieties. Almost all of these compounds exhibited potent inhibition activity against HBsAg, with IC50 values at the nanomolar level. Impressively, the compound (S)-2a (10 µM) demonstrated a comparatively reduced impact on the neurite outgrowth of HT22 cells and isolated mouse DRG neurons in comparison to RG7834, thereby indicating a decrease in neurotoxicity. Furthermore, (S)-2a exhibited higher drug exposures than RG7834. The potent anti-HBV activity, reduced neurotoxicity, and favorable pharmacokinetic profiles underscore its promising potential as a lead compound for future anti-HBV drug discovery.

Enhancing methane production and interspecies electron transfer of anaerobic granular sludge by the immobilization of magnetic biochar.

Supplementation of conductive materials has been proved to be a promising approach for enhancing microbial interspecies electron transfer (IET) in anaerobic digestion systems. In this study, magnetic bamboo-based biochar was prepared at temperatures of 400-800 °C via a ball milling/carbonization method, and it immobilized in mature anaerobic granular sludge (AGS) aimed to enhance methane production by improving the IET process between syntrophic microbial communities in the AGS. Results showed that the AGS with magnetic biochar immobilization demonstrated increased glucotrophic and acetotrophic methane production by 69.54-77.56 % and 39.96-54.92 %, respectively. Magnetic biochar prepared at 800 °C with a relatively higher Fe content (0.37 g/g magnetic biochar) displayed a stronger electron charge/discharge capacity (36.66 F/g), and its immobilization into AGS promoted methane production most. The conductivity of AGS increased by 52.13-87.32 % after incorporating magnetic biochar. Furthermore, the extracellular polymeric substance (EPS) of AGS showed an increased capacitance and decreased electron transfer resistance possibly due to the binding of magnetic biochar and more riboflavin secretion in EPS, which could contribute to the accelerated IET process in the inner AGS. In addition, the immobilization of magnetic biochar could promote the production of volatile fatty acids by 15.36-22.50 %. All these improvements may jointly lead to the enhanced methane production capacity of AGS. This study provided a fundamental understanding of the role of incorporated magnetic biochar in AGS in promoting anaerobic digestion performance.

Establishment of an efficient callus transient transformation system for Vitis vinifera cv. 'Chardonnay'.

Grape (Vitis L.), a highly valued fruit crop, poses significant challenges in genetic transformation and functional characterization of genes. Therefore, there is an urgent need for the development of a rapid and effective method for grape transformation and gene function identification. Here, we introduce a streamlined Agrobacterium-mediated transient transformation system for grape calli. Optimal conditions were established with a leaf-derived callus induction medium; chiefly B5 medium supplemented with 0.05 mg/L NAA, 0.5 mg/L 2,4-D, and 2.0 mg/L KT; and a callus proliferation medium (B5 medium supplemented with 0.5 mg/L NAA and 2.0 mg/L 6-BA), respectively. Notably, GUS enzyme activity peaked (352.96 ± 33.95 mol 4-MU/mg/min) by sonication with Agrobacterium tumefaciens EHA105 and 100 µM AS for 4 min, followed by vacuum infection for 5 min, and co-culture at 25 °C in the dark for 1 day using callus as explants at an optical density (OD600) of 0.8. VaCIPK18 gene was transiently transformed into calli, and transcripts of the gene (endogenous and exogenous) were detected at higher levels than in non-transformed calli (endogenous). Moreover, after 10 days of treatment at 4 °C or -4 °C, the callus net weight of transformed callus was significantly higher than that of the untransformed callus, indicating that the VaCIPK18-overexpressing grape callus could improve cold tolerance. Overall, we establish a simple but effective transient transformation approach for grape callus, which could serve as a useful tool for the rapid assessment of gene function in this important crop.

Exogenous Melatonin Promotes Cold Tolerance in Grape Seedlings: Physiological, Transcriptomic, and Functional Evidence.

Melatonin (MEL) is an antioxidant molecule that enhances plant tolerance to environmental stress. However, the mechanisms by which MEL regulates cold signaling pathways in grapes under cold stress remain elusive. Here, we investigated the physiological and transcriptomic changes in grape seedlings treated with exogenous MEL to determine their protective role under cold stress. Results showed that 150 µM MEL effectively attenuated cold-induced cell damage by reducing reactive oxygen species (ROS) and preserving the chloroplast structure and function. MEL also inhibited tannin degradation, which contributed to its protective effect. Exogenous MEL promoted the synthesis of endogenous MEL, abscisic acid, auxin, and cytokinin while inhibiting gibberellin. Transcriptomic profiling revealed 776 differentially expressed transcripts in MEL-treated samples compared to controls. Functional analysis of a candidate hub gene, VvHSFA6b, showed that its overexpression in grape calli enhances cold tolerance by activating jasmonic acid synthesis pathway genes, promoting JA accumulation, and inhibiting JAZ-repressed transcription factors.

Decoding VaCOLD1 Function in Grapevines: A Membrane Protein Enhancing Cold Stress Tolerance.

In globally cultivated grapevines, low-temperature stress poses a persistent challenge. Although COLD1 is recognized as a cold receptor in rice, its function in grapevine cold signaling is unclear. Here, we identified VaCOLD1, a transmembrane protein from the cold-tolerant Vitis amurensis Rupr, which is primarily located on plasma and endoplasmic reticulum membranes. Broadly expressed across multiple tissues, VaCOLD1 responds to various environmental stresses, particularly to cold. Its promoter contains distinct hormone- and stress-responsive elements, with GUS assays confirming widespread expression in Arabidopsis thaliana. Validation of interaction between VaCOLD1 and VaGPA1, together with their combined expression in yeast and grape calli, notably improved cold endurance. Overexpression of VaCOLD1 enhances cold tolerance in Arabidopsis by strengthening the CBF-COR signaling pathway. This is achieved through shielding against osmotic disturbances and modifying the expression of ABA-mediated genes. These findings emphasize the critical role of the VaCOLD1-VaGPA1 complex in mediating the response to cold stress via the CBF-COR pathway.

Investigation of novel 5'-amino adenosine derivatives with potential anti-Zika virus activity.

The Zika virus (ZIKV) infections remains a global health threat. However, no approved drug for treating ZIKV infection. We previously found TZY12-9, a 5'-amino NI analog, that showed anti-ZIKV activity without chemical phosphorylation. Here, a series of 5'-amino NI analogs were synthesized and evaluated. The compound XSJ2-46 exhibited potent in vitro activity without requiring chemical phosphorylation, favorable pharmacokinetic and acute toxicity profiles. Preliminary mechanisms of anti-ZIKV activity of XSJ2-46 were investigated via a series of ZIKV non-structural protein inhibition assays and host cell RNA-seq. XSJ2-46 acted at the replication stage of viral infection cycle, and exhibited reasonable inhibition of RNA-dependent RNA polymerases (RdRp) with an IC50 value of 8.78 µM, while not affecting MTase. RNA-seq analysis also revealed differential expression genes involved in cytokine and cytokine receptor pathway in ZIKV-infected U87 cells treated with XSJ2-46. Importantly, treatment with XSJ2-46 (10 mg/kg/day) significantly enhanced survival protection (70% survival) in ZIKV-infected ICR mice. Additionally, XSJ2-46 administration resulted in a significant decrease in serum levels of ZIKV viral RNA in the IFNα/ß receptor-deficient (Ifnar-/-) A129 mouse model. Therefore, the remarkable in vitro and in vivo anti-ZIKV activity of compound XSJ2-46 highlights the promising research direction of utilizing the 5'-amino NI structure skeleton for developing antiviral NIs.

Defunctioning stoma and anastomotic stricture in rectal cancer surgery: a propensity score matching study.

BACKGROUND: In cases of rectal cancer surgery, patients at high risk of anastomotic leakage often receive a defunctioning stoma (DS). However, its role in postoperative anastomotic strictures (AS) remains unclear. This study aimed to investigate the correlation between DS and AS and outcomes of transanal endoscopic microsurgery (TEM) in treating rectal AS. METHODS: This retrospective study was conducted from January 2019 to September 2021 and included patients who underwent rectal cancer surgery. A 1:1 ratio was used for propensity score matching (PSM). Univariate analyses were performed to identify statistically significant variables, and multivariate analyses were conducted to determine the factors affecting AS. RESULTS: This study included 383 patients. The results of the univariate analysis suggested that surgery time (HR 4.597, 95% CI 1.563-13.525, P=0.006), postoperative anastomotic leakage (HR 11.830, 95% CI 3.773-37.094, P<0.001), and DS (HR 15.475, 95% CI 6.042-39.641, P<0.001) were significantly associated with AS. In the multivariate analysis, postoperative anastomotic leakage (HR 7.596, 95% CI 1.987-29.044, P= 0.003) and DS (HR 11.252, 95% CI 4.113-30.779, P<0.001) were identified as significant risk factors for AS. After matching, the univariate analysis revealed that postoperative anastomotic leakage (HR 8.333, 95% CI 1.541-45.052, P= 0.014) and DS (HR 9.965, 95% CI 2.200-45.142, P= 0.003) were associated with AS. The multivariate analysis indicated that postoperative anastomotic leakage (HR 14.549, 95% CI 1.765-119.913, P= 0.013) and DS (HR 12.450, 95% CI 2.418-64.108, P= 0.003) were significant risk factors for AS. CONCLUSIONS: This study provides evidence that DS is independently associated with AS, and postoperative anastomotic leakage increases the risk of AS. Furthermore, this study suggests that TEM could be a valuable treatment option for AS.

Biodegradable electrospun fibers as sustained-release carriers of insect pheromones for field trapping of Spodoptera litura (Lepidoptera: Noctuidae).

BACKGROUND: Insect pheromones are highly effective and environmentally friendly, and are widely used in the monitoring and trapping of pests. However, many researchers have found that various factors such as ultraviolet light and temperature in the field environment can accelerate the volatilization of pheromones, thus affecting the actual control effect. In recent years, electrospinning technology has demonstrated remarkable potential in the preparation of sustained carriers. Moreover, the utilization of biodegradable materials in electrospinning presents a promising avenue for the advancement of eco-friendly carriers. RESULTS: In this study, homogeneous and defect-free pheromone carriers were obtained by electrospinning using fully biodegradable polyhydroxybutyrate materials and pheromones of Spodoptera litura. The electrospun fibers with porous structure could continuously release pheromone (the longest can be ≤80 days). They also had low light transmission, hydrophobic protection. More importantly, the pheromone-loaded electrospun fiber carriers showed stable release and good trapping effect in the field. They could trap pests for at least 7 weeks in the field environment without other light stabilizers added. CONCLUSION: Sustained-release carriers constructed by electrospinning and green materials could improve the efficacy of pheromones and ensure environmental friendliness, and provided a tool for the management of S. litura and other pests and sustainable development of agricultural. © 2023 Society of Chemical Industry.

Crystalline versus Amorphous: High-Performance Hafnium Phosphonate Framework for the Separation of Uranium and Transuranium Elements.

Metal phosphonate frameworks (MPFs) consisting of tetravalent metal ions and aryl-phosphonate ligands feature a large affinity for actinides and excellent stabilities in harsh aqueous environments. However, it remains elusive how the crystallinity of MPFs influences their performance in actinide separation. To this end, we prepared a new category of porous, ultrastable MPF with different crystallinities for uranyl and transuranium separation. The results demonstrated that crystalline MPF was generally a better adsorbent for uranyl than the amorphous counterpart and ranked as the top-performing one for uranyl and plutonium in strong acidic solutions. A plausible uranyl sequestration mechanism was unveiled by using powder X-ray diffraction in tandem with vibrational spectroscopy, thermogravimetry, and elemental analysis.

Design, synthesis and antitubercular activity of novel N-(amino)piperazinyl benzothiazinones with improved safety.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB) remains a major global health problem and new therapeutic antitubercular agents are urgent needed. Among the novel antituberculosis drugs in the pipeline, Benzothiazinones (BTZs) are among the most potent antituberculosis agents against both drug-susceptible and multidrug-resistant (MDR) tuberculosis. Our group has focused on structural modifications of the side chain at C-2 position of the BTZ core and WAP-2101/2102 with excellent in vitro activity were discovered in our lab. However, the severe in vivo toxicity was observed during subsequent acute toxicity evaluation. Herein, a series of novel N-(amino)piperazinyl benzothiazinone derivatives were designed and synthesized as new anti-TB agents to reduce the in vivo toxicity. Our results show that majority of them exhibit the same potent or comparable activity against both MTB H37Rv and MDR-MTB strains (MIC: 4.00 - <1 ng/mL) as PBTZ169. Especially, compound 2c with low cardiac toxicity, low cell cytotoxicity and acceptable oral pharmacokinetic (PK) profiles have low acute toxicity in mice (LD50 > 500 mg/kg), suggesting it may serve as a promising lead compound for further antitubercular drug discovery.

Identity-Guided Spatial Attention for Vehicle Re-Identification.

In vehicle re-identification, identifying a specific vehicle from a large image dataset is challenging due to occlusion and complex backgrounds. Deep models struggle to identify vehicles accurately when critical details are occluded or the background is distracting. To mitigate the impact of these noisy factors, we propose Identity-guided Spatial Attention (ISA) to extract more beneficial details for vehicle re-identification. Our approach begins by visualizing the high activation regions of a strong baseline method and identifying noisy objects involved during training. ISA generates an attention map to mask most discriminative areas, without the need for manual annotation. Finally, the ISA map refines the embedding feature in an end-to-end manner to improve vehicle re-identification accuracy. Visualization experiments demonstrate ISA's ability to capture nearly all vehicle details, while results on three vehicle re-identification datasets show that our method outperforms state-of-the-art approaches.

Impact of resampling interpolation FIR filter in the practical Kramers-Kronig receiver.

The practical Kramers-Kronig (KK) receiver has been a competitive receiving technique in the data-center, medium reach, and even long-haul metropolitan networks. Nevertheless, an extra digital resampling operation is required at both ends of the KK field reconstruction algorithm due to the spectrum broadening caused by adopting the nonlinear function. Generally, the digital resampling function can be implemented by using linear interpolation (LI-ITP), the Lagrange cubic interpolation (LC-ITP), the spline cubic interpolation (SC-ITP), time-domain anti-aliasing finite impulse response (FIR) filter method (TD-FRM) scheme, and fast Fourier transform (FFT)-based scheme. However, the performance and the computational complexity analysis of different resampling interpolation schemes in the KK receiver have not been thoroughly investigated yet. Different from the interpolation schemes of conventional coherent detection, the interpolation function of the KK system is followed by the nonlinear operation, which will broaden the spectrum significantly. Due to the frequency-domain transfer function of different interpolation schemes, the broadened spectrum will have a potential spectrum aliasing, which will cause serious inter-symbol interference (ISI) and further impair the KK phase retrieval performance. We experimentally investigate the performance of different interpolation schemes under different digital up-sampling rates (i.e. the computational complexity) as well as the cut-off frequency, the tap number of the anti-aliasing filter, and the shape factor of the TD-FRM scheme in a 112-Gbit/s SSB DD 16-QAM system over 1920-km Raman amplification (RFA)-based standard single-mode fiber (SSMF). The experimental results involve that the TD-FRM scheme outperforms other interpolation schemes and the complexity is reduced by at least 49.6%. In fiber transmission results, take 20% soft decision-forward error correction (SD-FEC) of 2×10-2 as the threshold, the LI-ITP and LC-ITP schemes only reach 720-km while others can reach up to 1440-km.

Development and Psychometric Properties of a Scale Measuring Barriers to Perioperative Hypothermia Prevention for Anesthesiologists and Nurses.

PURPOSE: To develop a scale that measures barriers to perioperative hypothermia prevention (BPHP) as perceived by anesthesiologists and nurses. DESIGN: A methodological and prospective psychometric study. METHODS: Based on the theoretical domains framework, the item pool was created through a literature review, qualitative interviews, and expert consultation. The scale was pretested with a sample of 154 key stakeholders in perioperative temperature management and then field tested with 416 anesthesiologists and nurses working at three hospitals in Southeast China. Item analysis, and reliability and validity analysis were performed. FINDINGS: The average content validity index was 0.94. According to exploratory factor analysis, seven factors were obtained that could explain 70.283% of the total variance. Confirmatory factor analysis showed excellent or acceptable goodness-of-fit indices. The reliability analysis demonstrated that the scale had high internal consistency and temporal stability, with Cronbach's α, split-half coefficient and test-retest values of 0.926, 0.878 and 0.835, respectively. CONCLUSIONS: The BPHP scale meets the psychometric criteria for reliability and validity and promises to be a useful quality measure for IPH management during the perioperative period. Further investigations on educational or resource needs and the development of an optimal perioperative hypothermia prevention protocol to narrow the gap between research evidence and clinical practice should be performed.

Bacteria-Targeted Combined with Photothermal/NO Nanoparticles for the Treatment and Diagnosis of MRSA Infection In Vivo.

Currently, undeveloped diagnosis and delayed treatment of bacteria-infected sites in vivo not only expand the risk of tissue infection but are also a major clinical cause of multiple drug-resistant bacterial infections. Herein, an efficient nanoplatform for near-infrared (NIR)-light-controlled release and bacteria-targeted delivery of nitric oxide (NO) combined with photothermal therapy (PTT) is presented. Using maltotriose-decorated mesoporous polydopamine (MPDA-Mal) and BNN6, a smart antibacterial (B@MPDA-Mal) is developed to combine bacterial targeting, gas-controlled release, and PTT. Utilizing bacteria's unique maltodextrin transport system, B@MPDA-Mal can accurately distinguish bacterial infection from sterile inflammation and target the bacteria-infected sites for efficient drug enrichment. Moreover, NIR-light causes MPDA to generate heat, which not only effectively induces BNN6 to produce NO, but also raises the temperature to harm the bacteria further. NO/photothermal combination therapy effectively eliminates biofilm and drug-resistant bacteria. The myositis model of methicillin-resistant Staphylococcus aureus infection is established and indicates that B@MPDA-Mal can successfully eradicate inflammation and abscesses in mice. Meanwhile, magnetic resonance imaging technology is used to monitor the treatment procedure and healing outcomes. Given the aforementioned advantages, the smart antibacterial nanoplatform B@MPDA-Mal can be used as a potential therapeutic tool in the biomedical field against drug-resistant bacterial infections.

Cu-Catalyzed Decarboxylative Annulation of N-Phenylglycines with Maleimides: Synthesis of 1H-Pyrrolo[3,4-c]quinoline-1,3(2H)-diones.

A novel protocol for the construction of functionalized 1H-pyrrolo[3,4-c]quinoline-1,3(2H)-diones (PQLs, 3) from N-phenylglycines and maleimides was developed. The cascade reaction was enabled by heating a mixture of the two substrates in the presence of di-tert-butyl peroxide (DTBP) as an oxidant and anhydrous CuBr as a catalyst in chlorobenzene. Consequently, a diverse series of PQLs 3 were synthesized in moderate-to-good yields (43-73%). The synthesis of the PQLs was enabled via a one-pot cascade reaction that proceeded through subsequent oxidative decarboxylation, 1,2-addition, intramolecular cyclization, tautomerization, and aromatization reactions. This protocol can be used for the synthesis of functionalized PQLs via a one-pot oxidative decarboxylation annulation reaction rather than through a series of multistep reactions, making it suitable for both combinatorial and parallel syntheses of PQLs.

Influencing aspects of clinical nurses' interactive continuous learning behaviour based on in-service online network videos: A grounded theory approach.

OBJECTIVES: This study explores the influencing aspects of nurses' continuous interactive learning behaviour based on In-Service online network videos to facilitate their knowledge development and improve their engagement in online learning. Also, to provide a theoretical model for enhancing the quality of learning and teaching by promoting online nursing education. DESIGN: The qualitative research design of grounded theory methodology (Glaser and Strauss, 1967) was used to develop a theory of clinical nurses' interactive continuous learning behaviours. METHOD: A grounded theory approach and qualitative research method were adopted in this research. A three-level coding technique was used to extract data, which involved collecting 16,018 pieces of "Synchronous online feedback data" original data from interactive online in-service learning videos. The synchronous online feedback data were analysed using a constant comparative method and then utilised to construct the theoretical model of influencing aspects for nurses' interactive continuous learning. There were 11,083 Synchronous online feedback data of Clinical Nurses (N = 132 participants) based on 32 interactive learning video series from a single centre. The sampling method was based on initial purposive and then theoretical sampling techniques. The data were analysed and extracted using a three-level coding technique with a constant comparison analysis method. RESULTS: The study identified four major categories of influencing aspects for nurses' satisfaction in online learning. These categories include 1. individual aspects; 2. curriculum aspects; 3. teachers' aspects; and 4. nurses' interactive behaviour. These aspects were found to influence the learning satisfaction among nurses and nurses' interactive continuous learning behaviours. CONCLUSION: The findings provide a reference for maximising the value of In-Service online video learning resources and the sustainable development of educational informatisation. In addition, interactive continuous learning behaviour can promote adherence to a positive learning attitude and build an excellent online learning ecology.

Enhanced Bacterial-Infected Wound Healing by Nitric Oxide-Releasing Topological Supramolecular Nanocarriers with Self-Optimized Cooperative Multi-Point Anchoring.

Polymeric systems that provide cationic charges or biocide-release therapeutics are used to treat the bacteria-infected wound. However, most antibacterial polymers based on topologies with restricted molecular dynamics still do not satisfy the clinical requirements due to their limited antibacterial efficacy at safe concentrations in vivo. Here a NO-releasing topological supramolecular nanocarrier with rotatable and slidable molecular entities is reported to provide conformational freedom to promote the interactions between the carrier and the pathogenic microbes, hence greatly improving the antibacterial performance. With improved contacting-killing and efficient delivery of NO biocide from the molecularly dynamic cationic ligand design, the NO-loaded topological nanocarrier achieves excellent antibacterial and anti-biofilm effects via destroying the bacterial membrane and DNA. MRSA-infected rat model is also brought out to demonstrate its wound-healing effect with neglectable toxicity in vivo. Introducing flexible molecular motions into therapeutic polymeric systems is a general design to enhance the healing of a range of diseases.

Discovery and pharmacological characterization of a novel benzimidazole TRPV4 antagonist with cyanocyclobutyl moiety.

GSK-Bz, a TPRV4 antagonist discovered by GSK, displayed potent in vitro TRPV4 inhibition activity, and demonstrated ability to inhibit TRPV4-mediated pulmonary edema in an in vivo rat model. In this study, a series of GSK-Bz derivatives were designed and synthesized based on our previous findings. Compound 2b with cyanocyclobutyl moiety (IC50 = 22.65 nM) was found to be 5.3-fold more potent than GSK-Bz (IC50 = 121.6 nM) in the calcium imaging experiment. Patch-clamp experiments confirmed that compound 2b (IR = 77.1%) also gave significantly improved potency on TRPV4 currents measured at -60 mV. Furthermore, 2b effectively suppressed the permeability response to LPS in HUVEC with negligible cytotoxicity (CC50 > 100 µM). The in vivo protective effects of compounds 2b on acute lung injury were finally assessed in an LPS-induced ALI mice model. Notably, 2b gave better results than HC-067047 against all of the tested indexes (lung W/D ratios, the concentrations of BALF protein and pathological scores), indicating that 2b is a novel and highly potent TRPV4 antagonist which is worth for further development. Currently, evaluation for the drug-like properties of 2b is underway.