Search

Some studies have shown that lyophilization significantly improves the stability of mRNA-LNPs and enables long-term storage at 2–8 ℃. However, there is little research on the lyophilization process of mRNA-lipid nanoparticles (LNPs). Most previous studies have used empirical lyophilization with only a single lyoprotectant, resulting in low lyophilization efficiency, often requiring 40–100 h. In the present study, an efficient lyophilization method suitable for mRNA-LNPs was designed and optimized, shortening the total length of the lyophilization process to 8–18 h, which significantly reduced energy consumption and production costs. When the mixed lyoprotectant composed of sucrose, trehalose, and mannitol was added to mRNA-LNPs, the eutectic point and collapse temperature of the system were increased. The lyophilized product had a ginger root-shaped rigid structure with large porosity, which tolerated rapid temperature increases and efficiently removed water. In addition, the lyophilized mRNA-LNPs rapidly rehydrated and had good particle size distribution, encapsulation rate, and mRNA integrity. The lyophilized mRNA-LNPs were stable at 2–8 ℃, and they did not reduce immunogenicity in vivo or in vitro. Molecular dynamics simulation was used to compare the phospholipid molecular layer with the lyoprotectant in aqueous and anhydrous environments to elucidate the mechanism of lyophilization to improve the stability of mRNA-LNPs. This efficient lyophilization platform significantly improves the accessibility of mRNA-LNPs.

The current COVID-19 epidemic has greatly accelerated the application of mRNA technology to our real world, and during this battle mRNA has proven it's unique advantages compared to traditional biopharmaceutical and vaccine technology. In order to overcome mRNA instability in human physiological environments, mRNA chemical modifications and nano delivery systems are two key factors for their in vivo applications. In this review, we would like to summarize the challenges for clinical translation of mRNA-based therapeutics, with an emphasis on recent advances in innovative materials and delivery strategies. The nano delivery systems include lipid delivery systems (lipid nanoparticles and liposomes), polymer complexes, micelles, cationic peptides and so on. The similarities and differences of lipid nanoparticles and liposomes are also discussed. In addition, this review also present the applications of mRNA to other areas than COVID-19 vaccine, such as infectious diseases, tumors, and cardiovascular disease, for which a variety of candidate vaccines or drugs have entered clinical trials. Furthermore, mRNA was found that it might be used to treat some genetic disease, overcome the immaturity of the immune system due to the small fetal size in utero, treat some neurological diseases that are difficult to be treated surgically, even be used in advancing the translation of iPSC technology et al. In short, mRNA has a wide range of applications, and its era has just begun., Graphical abstract Image 1

A series of FeOx-MnO2-CeO2 catalysts were synthesized by the surfactant-templated coprecipitation method and applied for HCHO removal. The influence of Fe/Mn/Ce molar ratio on the catalytic performance was investigated, and the FeOx-MnO2-CeO2 catalyst exhibited excellent catalytic activity, with complete HCHO conversion at low temperatures (40 °C) when the molar ratio of Fe/Mn/Ce was 2/5/5. The catalysts were characterized by N2 adsorption and desorption, XRD, H2-TPR, O2-TPD and XPS techniques to illustrate their structure–activity relationships. The result revealed that the introduction of FeOx into MnO2-CeO2 formed a strong interaction between FeOx-MnO2-CeO2, which facilitated the improved dispersion of MnO2-CeO2, subsequently increasing the surface area and aiding pore development. This promotion effect of Fe enhanced the reducibility and produced abundant surface-active oxygen. In addition, a great number of Oα is beneficial to the intermediate decomposition, whereas the existence of Ce3+ favors the formation of oxygen vacancies on the surface of the catalyst, all of which contributed to HCHO oxidation at low temperatures.

Brucellosis is a highly infectious zoonotic disease caused by Brucella. It is necessary to control and eliminate brucellosis. The cell wall O-polysaccharides of pathogenic Brucella species are homopolymers of the rare sugar 4,6-dideoxy-4-formamido-α- d -mannopyranose. Herein, one neoglycoconjugate was successfully synthesized based on disaccharide [Rha4NFo(1 → 2)Rha4NFo] as epitope. Disaccharide specific antibodies were detected by ELISA and the immune protective effect was further evaluated with PBS as control. The result showed that the synthetic neoglycoconjugate can produce moderate immune responses in mice and significantly decreased splenic Brucella M5 burden comparing with control group. The chemically defined antigen identified the A antigenic determinant and provided a structural basis for understanding the fine specificity of polyclonal antibodies that bind the A antigen. The neoglycoconjugate shows the potential in detection reagent or vaccine development for brucellosis.

Structured, porous, and hollow tubular tin oxide (SnO 2 ) and reduced graphene oxide (RGO) composites were synthesized through a combination of electrospinning and hydrothermal procedures. The morphology and structural features of the samples were analyzed and their sensing performance was tested. RGO/SnO 2 composites exhibited a better sensing performance than SnO 2 . The optimum mass ratio of RGO in the composite was assessed as 1 w%, leading to an excellent sensing response of 10.0–32.2 ppm NO 2 at a temperature of 150 °C, approximately 10-fold that of SnO 2 . Thus, the enhancement of the gas sensing properties was attributed to the addition of RGO.

3'-Geranyl-mono-substituted chalcone Xanthoangelol (1b), a chalcone derivative, was previously reported to show selective cytotoxicity against human chronic myelogenous leukemia K562 cells with a half-maximal inhibitory concentration (IC50) of 3.98 μM. In the present study, we investigated the molecular mechanism underlying the cytotoxicity of 1b in K562 cells. Treatment with compound 1b caused K562 cells to adopt a typical apoptotic morphology. Flow cytometric analysis also confirmed the presence of an apoptotic cell population following treatment of Annexin-V-FITC and propidium iodide (PI) double-labeled K562 cells with 1b. Furthermore, we observed dissipation of the mitochondrial membrane potential, caspase-3 activation, and a reduction of the Bcl-2/Bax ratio in these cells, which suggest that the mitochondrial apoptotic pathway is induced by 1b in K562 cells. Collectively, our findings demonstrate that compound 1b notably induces mitochondrial-mediated apoptosis in K562 cells, which might have a potential anticancer activity.

With the rapid development of the movie industry, it is vital to evaluate and predict a movie’s quality. In this paper, a movie score prediction model is proposed based on the movie plots. Movie data was processed with the word2vec method, and the linear regression model and back propagation neural network algorithm were employed to establish the movie score prediction model. The high-quality classic movie plots of high-scoring movies summed up by big data contributed to a high synthesis of the wonderful content of the film. Experimental results show that it is effective in terms of movie evaluation and prediction, and helpful in understanding people’s preferences for movie plots.

Three series of prenylated and/or geranylated flavonoids were synthesized and evaluated for their α-glucosidase inhibitory activity. The 3',5'-digeranylated chalcone (16) was identified as a new α-glucosidase inhibitor whose activity (IC50=0.90 μM) was 50-fold more than that of acarbose (IC50=51.32 μM). Molecular docking studies revealed the existence of strong hydrophobic interaction and H-bonding between compound 16 and α-glucosidase's active site. The inhibitory mode analysis showed that 16 exhibited a competitive inhibitory mode.

Melanocortin 4 receptor (MC4R) is a key factor in regulating energy homeostasis, and null mutations occurring in the gene encoding MC4R cause severe early-onset morbid obesity in humans. Many obesity-causing mutations affecting MC4R clinically identified so far lead to failure of mutant receptors to shuttle to the plasma membrane. In this study, we show that a novel human MC4R antagonist, Ipsen 17, acted as an pharmacological chaperone of human MCR4. As tested with 12 obesity-causing human MC4R variants including S58C, E61K, N62S, I69T, P78L, C84R, G98R, T162I, R165W, W174C, C271Y, and P299H, Ipsen 17 was found to be the most universal pharmacological chaperone of MC4R reported so far because it can completely rescue nearly all mutant receptors (except P299H) with the highest potency (an EC50 value of approximately 10−8 M) and efficiency when compared with results for other tested pharmacological chaperones of MC4R including ML00253764, PBA, MTHP, PPPone, MPCI, DCPMP, and NBP described in the literature. Once restored to the plasma membrane, defective human MC4R variants responded to α-MSH stimulation with an EC50 value of approximately 10−8 M and displayed dramatically enhanced signaling ability (except for G98R) in a mutant-specific efficacy and potency profile. Taken together, these results indicate that Ipsen 17 represents a candidate for the development of a targeted treatment of severe early-onset morbid obesity caused by a large subset of inherited mutations in the human MC4R gene.

Regioselective synthesis of C-6 and C-8 monoiodo flavonoids, which are important intermediates for the synthesis of flavonoid natural products and drug molecules, was achieved by iodination of suitably alkylated flavonoids with N -iodosuccinimide (NIS) in DMF. The iodination gives either a C-6 or C-8 iodo flavonoid in high yield, depending on the protection pattern of the C-5 and C-7 OH groups. The mild and neutral conditions render this novel protocol particularly useful for the regioselective iodination of acid-sensitive substrates.

Aryl pyrazolone thioethers were synthesized via the I2-catalysed cross-coupling of pyrazolones with aryl sulphonyl hydrazides in the presence of p-toluenesulphonic acid, which has been proposed to promote the reaction by facilitating the decomposition of sulphonyl hydrazides.

Four natural chalcones bearing prenyl or geranyl groups, i.e., isobavachalcone (1), bavachalcone (2), xanthoangelol (3), and 2′,4′,4-trihydroxy-5′-geranylchalcone (isoxanthoangelol, 4) were synthesized by using a regio-selective iodination and the Suzuki coupling reaction as key steps. Among them, the first total synthesis of 2′,4′,4-trihydroxy-5′-geranylchalcone was achieved in 36% overall yield. Comparing with the reported methods based on C-alkylation or O-alkylation followed by Claisen rearrangement to introduce the side chain, this new strategy capitalizes on a precious regiochemical control during iodination. The overall yields for the synthesis of the first three chalcones were improved from 17% to 53%, 12% to 35%, and 28% to 50%, respectively.

Four natural chalcones bearing prenyl or geranyl groups, i.e., bavachalcone (1a), xanthoangelol (1b), isobavachalcone (1c), and isoxanthoangelol (1d) were synthesized by using a regio-selective iodination and the Suzuki coupling reaction as key steps. The first total synthesis of isoxanthoangelol (1d) was achieved in 36% overall yield. A series of diprenylated and digeranylated chalcone analogs were also synthesized by alkylation, regio-selective iodination, aldol condensation, Suzuki coupling and [1,3]-sigmatropic rearrangement. The structures of the 11 new derivatives were confirmed by 1H NMR, 13C NMR and HRMS. The anticancer activity of these new chalcone derivatives against human tumor cell line K562 were evaluated by MTT assay in vitro. SAR studies suggested that the 5′-prenylation/geranylation of the chalcones significantly enhance their cytotoxic activity. Among them, Bavachalcone (1a) displayed the most potent cytotoxic activity against K562 with IC50 value of 2.7 μM. The morphology changes and annexin-V/PI staining studies suggested that those chalcone derivatives inhibited the proliferation of K562 cells by inducing apoptosis.

Based on the regioselective iodination of the bis Mom-protected methyl aryl ketones (I) a convenient synthesis of bavachalcone (VIIa) and isoxanthoangelol (VIIb) is developed.

The iodination can be conveniently directed to either the C-6 or C-8 position by changing the protection pattern at the C-5 OH group.

The photoelectrical characteristics of field-effect phototransistors (FEPTs) are investigated experimentally based on a graphene–PbS quantum dot (QD) hybrid. The device presented a wide spectral response range from 300 to 1400 nm because of multiple-exciton generation of PbS QDs. The photoelectrical responsivity reached up to $2\times 10^{5}\ \hbox{A/W}$ at low bias voltage ( $\sim$ 10 mV) and became more sensitive with increasing bias voltage. The transient response of the hybrid FEPTs was also measured with the relaxation times and the decay times around several seconds. Such devices exhibit great competitiveness in wide spectral response, flexible integrated circuits with low cost, large area, low energy consumption, and high responsivity.