Potent Therapeutic Strategies for COVID-19 with Single-Domain Antibody Immunoliposomes Neutralizing SARS-CoV-2 and Lip/cGAMP Enhancing Protective Immunity.

The worldwide spread of COVID-19 continues to impact our lives and has led to unprecedented damage to global health and the economy. This highlights the need for an efficient approach to rapidly develop therapeutics and prophylactics against SARS-CoV-2. We modified a single-domain antibody, SARS-CoV-2 VHH, to the surface of the liposomes. These immunoliposomes demonstrated a good neutralizing ability, but could also carry therapeutic compounds. Furthermore, we used the 2019-nCoV RBD-SD1 protein as an antigen with Lip/cGAMP as the adjuvant to immunize mice. Lip/cGAMP enhanced the immunity well. It was demonstrated that the combination of RBD-SD1 and Lip/cGAMP was an effective preventive vaccine. This work presented potent therapeutic anti-SARS-CoV-2 drugs and an effective vaccine to prevent the spread of COVID-19.

Encapsulation of STING Agonist cGAMP with Folic Acid-Conjugated Liposomes Significantly Enhances Antitumor Pharmacodynamic Effect.

Background: 2',3'-cGAMP (2',3'-cyclic AMP-GMP) has been reported as an agonist of the STING (stimulator of interferon genes) signaling pathway. However, cGAMP has poor membrane permeability and can be hydrolyzed by ectonucleotide pyrophosphatase/phosphodiesterase (ENPP1), limiting its ability to activate the STING-IRF3 pathway. This study aimed to investigate that the folate-targeted liposomal cGAMP could overcome the defects of free cGAMP to enhance the antitumor effect. Materials and Methods: cGAMP was encapsulated in PEGylated folic acid-targeted liposomes to construct a carrier-delivered formulation. The particle size and morphology were detected by dynamic light scattering and transmission electron microscopy. The sustained-release ability was measured by drug release and pharmacokinetics. Animal models were applied to evaluate the tumor inhibition efficiency in vivo. Flow cytometry, enzyme-linked immunosorbent assay, and real-time polymerase chain reaction were used to detect the expression of immune cells, secreted cytokines, and target genes. The activation of the STING-IRF3 pathway was evaluated by immunofluorescence. Results: Physical characters of liposomes revealed that the prepared liposomes were stable in neutral humoral environments and released more internal drugs in acidic tumor tissues. Systemic therapy with liposomes on Colorectal 26 tumor-bearing mice in vivo effectively inhibited tumor growth via stimulating the expression of CD8+ T cells and reversed the immunosuppressed tumor microenvironment (TME). Conclusions: The study suggests that the folic acid-targeted cGAMP-loaded liposomes deliver drugs to the TME to enhance the STING agonist activity, improving the efficiency of tumor therapy via the cGAMP-STING-IRF3 pathway.

Comprehensive understanding the impacts of dietary exposure to polyethylene microplastics on genetically improved farmed tilapia (Oreochromis niloticus): tracking from growth, microbiota, metabolism to gene expressions.

Microplastics (MPs) pollution has been recognized as a threat to sustainable fisheries due to the risks of MPs contamination in the process of feed production and susceptibility of fish to ingest MPs from the aquatic environment. In this study, we applied comprehensive approaches to investigate the impacts of polyethylene microplastics (PE-MPs) on juvenile genetically improved farmed tilapia (GIFT, Oreochromis niloticus) through 9-week dietary exposure based on growth performance, gut microbiota, liver metabolism, and gene expressions in brain and liver tissues. Dietary exposure to two kinds of PE-MPs with different median size (27 µm and 63 µm, respectively) concentration-dependently decreased weight gain (WG), while increased feed conversion ratio (FCR) and hepatosomatic index (HSI) of the tilapia. Dietary administration of PE-MPs also significantly reduced the activities of intestinal protease and amylase. PE-MPs particles of the larger size groups (63 µm) were mainly detected in feces, but those of the smaller ones (27 µm) tended to be accumulated in intestine. PE-MPs ingestion resulted in the alteration of gut microbiota composition, with Fusobacteria, Verrucomicrobia and Firmicutes as the overrepresented bacterial taxa. Metabolomic assays of liver samples in fish fed the diets containing 8 % of PE-MPs revealed the particle size-specific variations in composition of differential metabolites and metabolism pathways such as amino acid and glycerophospholipid metabolism. Gene expressions of brain and liver samples were analyzed by RNA-seq. Photoperiodism and circadian rhythm were the representative biological processes enriched for the differentially expressed genes (DEGs) identified from the brain. Citrate cycle (TCA cycle) was the most enriched pathway revealed by a joint transcriptomic and metabolic pathway analysis for the liver, followed by propanoate and pyruvate metabolism. Furthermore, an integration analysis of the gut microbiome and liver transcriptome data identified significant associations between several pathogenic bacteria taxa and immune pathways. Our findings demonstrated that the sizes and concentrations of PE-MPs are critically related to their toxic impacts on microbiota community, metabolism, gene expressions and thus fish growth.

Highly Sensitive Determination of 2,4,6-Trichlorophenol by Using a Novel SiO2@MIPIL Fluorescence Sensor with a Double Recognition Functional Monomer.

A novel SiO2@ MIPIL fluorescence sensor for the highly sensitive detection of 2,4,6-trichlorophenol was prepared by using surface molecularly imprinting technology with SiO2 microspheres as carriers and 3,3'-(anthracene-9,10-diylbis(methylene))bis(1-vinyl-1H-imidazole-3-ium) chloride as a double recognition fluorescence functional monomer. The prepared molecularly imprinted polymer (SiO2@MIPIL) was characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, transmission electron microscopy, laser confocal microscopy, and nuclear magnetic resonance. Compared with the polymer obtained via bulk polymerization (MIPIL), the surface molecularly imprinted polymer (SiO2@MIPIL) has a better linear range (0.1-50 nM), lower detection limit (89 pM), and shorter detection time (approximately 1.5 min). The fluorescence sensor also shows good specificity, high sensitivity, good stability, and reusability. Satisfactory results were obtained when using this sensor in industrial wastewater and spiked environmental water.

NMR study of the dynamics of cationic gemini surfactant 14-2-14 in mixed solutions with conventional surfactants.

Three kinds of conventional surfactants, namely, two nonionic surfactants [polyethylene glycol (23) lauryl ether (Brij-35) and Triton X-100 (TX-100)], one cationic surfactant [n-tetradecyltrimethyl ammonium bromide (TTAB)], and an anionic surfactant [sodium n-dodecyl sulfate (SDS)}, were mixed into the quaternary ammonium gemini surfactant [C(14)H(29)N(+)(CH(3))(2)](2)(CH(2))(2).2Br(-) (14-2-14) in aqueous solution. The exchange rate constants between 14-2-14 molecules in the mixed micelles and those in the bulk solution were detected using two nuclear magnetic resonance (NMR) methods: one-dimensional (1D) line shape analysis and two-dimensional (2D) exchange spectroscopy (EXSY). The results obtained from these two methods were consistent. Both showed that mixing a nonionic conventional surfactant, either Brij-35 or TX-100, enhanced the exchange process between the 14-2-14 molecules in the mixed micelles and those in the bulk solution. In contrast, the anionic surfactant SDS and the cationic surfactant TTAB slowed the process slightly.

Rapid-response, reversible and flexible humidity sensing platform using a hydrophobic and porous substrate.

Flexible humidity sensors enabling the real-time monitoring of the humidity level in the environment or around the human body have increasing application prospects in electronic skin and personal healthcare. Tremendous efforts have been devoted to improve the performance of humidity sensors, but little effort has been made to investigate the effect of the substrate. This work reveals the vital role of the sensor substrate in determining the humidity sensing performance by performing a comparative study. A porous, hydrophobic and flexible liquid crystal polymer (LCP) substrate is employed to speed up the response and recovery processes and boost the sensitivity simultaneously. Graphene oxide-based sensors fabricated on the LCP substrate exhibit 8.1 and 3.2 times higher response and recovery speeds, respectively, and 1.37 times higher sensitivity than corresponding sensors generated on a smooth SiO2 substrate. Similar performance improvement is observed when reduced graphene oxide and carbon nanocoils are deployed as the humidity sensing materials. These distinct structure-related properties enable the fabrication of humidity sensors to monitor various human activities, including fast and normal respiration, skin hydration, finger movement, etc. Furthermore, a positive correlation between the sensitivity and the oxygen content in carbon materials is revealed.

Rapid and reliable determination of p-nitroaniline in wastewater by molecularly imprinted fluorescent polymeric ionic liquid microspheres.

Rapid and efficient detecting trace amount of environmental p-nitroaniline (p-NA) is in urgent need for security concerns and pollution supervision. In this work we report the use of molecularly imprinted polymeric ionic liquid (MIPIL) microspheres to construct recognizable surfaces for detection of p-NA through fluorescence quenching. The p-NA imprinted microspheres are synthesized by precipitation polymerization upon co-polymerization of 3-(anthracen-9-ylmethyl)-1-vinyl-1H-imidazol-3-ium chloride (Fluorescent IL monomer) with ethyleneglycol dimethacrylate (EGDMA). The electron-rich group alkenyl imidazole in IL functional monomer can dramatically improve the emission of anthracene fluorophore and the π-π stacking, electronic, and hydrogen bond between p-NA and MIPIL can efficiently enhance the selective recognition force. The as-synthesized MIPIL microspheres present spherical shape, high fluorescence emission intensity and specific recognition, which showed rapid detection rate (1min), stable reusable property (at least 4 time recycles), wonderful selectivity over several structural analogs, wide linear range (10nM to 10M) with a correlation coefficient of 0.992, and excellent sensitivity (LOD, 9nM). As synthesis and surface functionalization of MIPIL microspheres are well established, the methods reported in this work are facile, rapid and efficient for monitoring p-NA in environmental wastewater.

A dynamic discount pricing strategy for viral marketing.

Viral marketing has been one of the main marketing modes. However, theoretical study of viral marketing is still lacking. This paper focuses on the problem of developing a cost-effective dynamic discount pricing strategy for a viral marketing campaign. First, based on a novel word-of-mouth propagation model, we model the original problem as an optimal control problem. Second, we show that the optimal control problem admits an optimal control and present the optimality system for solving the optimal control problem. Next, we solve some optimal control models to get their respective optimal dynamic discount pricing strategies. Finally, we examine the effect of some factors on the maximum marketing profit. These results contribute to gaining insight into viral marketing.

[Ex vivo assessment of the potency of optical coherence tomography for the detection of early occlusal caries].

OBJECTIVE: This study aimed to evaluate the potency of optical coherence tomography (OCT) to detect early occlusal caries compared with clinical visual examination. METHODS: Approximately 97 sites of occlusal fissures on 77 extracted accessional human teeth were scored by three examiners using conventional visual examination and OCT. Results of histological examination on these sites obtained by polarimicroscope served as a gold standard to analyze the sensitivity (SE), specificity (SP), positive predictive value (PPV), and negative predictive value (NPV). Results of the area under receiver operating characteristic (ROC) curve (AUC) by visual examination and OCT were also analyzed. The Spearman's rank correlation coefficient with histology and the inter-examiner reliability were compared. RESULTS: For sites of enamel demineralization limited to the outer 1/2 of the enamel layer, the detection rate of OCT (14/25) was obviously higher than that of the clinical and visual examination (3/25). SE, SP, PPV and NPV of OCT during diagnosis of the early occlusal caries (0.83, 0.64, 0.87 and 0.57) were higher than that of the visual examination (0.79, 0.60, 0.85 and 0.50). AUC (95%CI) of OCT and the visual examination were 0.737 (0.569-0.822) and 0.696 (0.614-0.859), respectively. No statistically significant difference was observed between the results. Results of OCT correlated well with histology (r=0.559, P<0.05). The inter-examiner reliability of OCT was medium. CONCLUSIONS: OCT can accurately detect early occlusal lesions atraumatically with high sensitivity and effectiveness. OCT exhibits the potential of auxiliary clinical diagnosis enhancing detection rate and finally implementing early diagnosis and early intervention of early occlusal lesions in clinical practice.

A three-field breast treatment technique with precise geometric matching using multileaf collimator-equipped linear accelerators.

PURPOSE: Many authors have studied the problems associated with the three-field breast treatment, yet the proposed solutions present their own difficulties. This study presents a technique that overcomes these difficulties, reduces scatter to the contralateral breast, and improves setup reproducibility. METHODS AND MATERIALS: Patients are set up with both arms raised superiorly on a breast board. A precise field-match is achieved by rotating the couch and collimator of the tangents, while the supraclavicular field is half-beam blocked using an independent jaw. The posterior borders of the tangents are conformally defined by multileaf collimation. Measurements were performed to verify the field matching and evaluate scatter doses. RESULT: A smooth dose transition was found at the match line at all depths. Corner blocks and lower wedges were not used, which reduced the scatter to the contralateral breast compared with our prior technique. CONCLUSION: The technique achieves a precise match while removing constraints on the tangents' length and decreasing scatter dose. Procedures for simulation, planning, and treatment have been devised, along with a new patient setup routine incorporating orthogonal setup films and tattoos. This technique has been successfully implemented in routine treatment since September 2001. A program calculating the setup parameters is available at our website.

[Evaluation of facial aesthetics in young population with beautiful faces in Nanchang city].

PURPOSE: To analyze the full-face and lateral aesthetical standards among fine looking young people in Jiangxi province, in order to provide reference for orthodontic treatment. METHODS: Fourteen young males and fifteen young females from universities in Nanchang city were selected through audition of young beauty within Jiangxi province. Their full-face and lateral pictures were then taken. Ten orthodontists and 85 non-orthodontists in different ages and sexuality who were randomly selected were asked to rank all of the selected pictures in descending order of attractiveness independently and also pick out the most beautiful male and female photos according to their own judgments. Comparisons were carried out to select the universally recognized beautiful males and females and analyze their soft tissue facial profile. RESULTS: Orthodontists held significantly different opinions on the facial esthetic profile for males and females, especially for males. On the other hand, although the non-professionals also had different views on the profiles, the evaluations for males were quite consistent. To be specific, young people selected No.13 male and No.1 female while the old people preferred to select No.7 male and the No.9 female. At the same time, men selected No.7 and No.13 male, and No.1 and No.9 female while women selected No.13 male and No.1 female. CONCLUSIONS: Both orthodontists and non-orthodontists have different opinions on the facial esthetic profile for young males and females. During orthodontic treatments, orthodontists should respect the opinions of the patients and their family members on the matter of facial improvements.