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Uncontrolled activation of c-Kit is closely related to the pathogenesis and progression of leukemia, gastrointestinal cancer, and other malignant diseases. Although there are several inhibitors available, due to the limitation of selectivity and the unfavorable side effects, designing and discovering highly selective inhibitors targeting c-Kit kinase, especially the gain of function mutation (for example c-Kit D816V), is still necessary. To identify novel c-Kit inhibitors, a metastable state-based virtual screening approach, which was successfully implemented in other kinase inhibitors, was employed in the current study. The results from our current study demonstrated the residues adjacent to the DFG motif within the activation loop could fold into short α-helices aside from the random coil, which was commonly found in the crystal structure. By expanding the conformation pool of the activation loop via PyRosetta-based ab initio folding protocol, we constructed a series of structural models of the c-Kit kinase intermediate between the inactive and active states. After evaluation of the thermal stability of the metastable state with molecular dynamics simulation, one structural model showed higher stability of α-helix, and the activation loop was retained. Considering the wild-type and D816V mutated KIT kinase shared similar metastable states during the kinase activation process, we developed a hypothesis that the identified intermediate might hold the potential to identify inhibitors targeting D816V mutations from the compound database. As expected, the intermediate structure showed higher selectivity to KIT D816V selective inhibitors, such as bezuclastinib, avapritinib, BLU-263, and elenestinib, than imatinib or masitinib. The virtual screening of the available KIT kinase inhibitor database further identified vorolanib, semaxanib, henatinib, and pexmetinib may possess potential inhibitory effects against wild type, as well as the mutated c-Kit kinase. The results from our current study not only proposed a novel structural model that could be used for the identification of selective c-Kit D816V inhibitors but also identified several potential inhibitors from available kinase inhibitors, which might shed new light on the design of new therapeutic approaches for c-Kit mutation-driven malignant diseases.

Vaccination-route-dependent adjuvanticity was identified as being associated with the specific features of antigen-carrying nanoparticles (NPs) in the present work. Here, we demonstrated that the mechanical properties and the decomposability of NP adjuvants play key roles in determining the antigen accessibility and thus the overall vaccine efficacy in the immune system when different vaccination routes were employed. We showed that soft nano-vaccines were associated with more efficient antigen uptake when administering subcutaneous (S.C.) vaccination, while the slow decomposition of hard nano-vaccines promoted antigen uptake when intravenous (I.V.) vaccination was employed. In comparison to the clinically used aluminum (Alum) adjuvant, the NP adjuvants were found to stimulate both humoral and cellular immune responses efficiently, irrespective of the vaccination route. For vaccination via S.C. and I.V. alike, the NP-based vaccines show excellent protection for mice from Staphylococcus aureus (S. aureus) infection, and their survival rates are 100% after lethal challenge, being much superior to the clinically used Alum adjuvant.

Nanoparticles have been identified in numerous studies as effective antigen delivery systems that enhance immune responses. However, it remains unclear whether this enhancement is a result of increased antigen uptake when carried by nanoparticles or the adjuvanticity of the nanoparticle carriers. Consequently, it is important to quantify antigen uptake by dendritic cells in a manner that is free from artifacts in order to analyze the immune response when antigens are carried by nanoparticles. In this study, we demonstrated several scenarios (antigens on nanoparticles or inside cells) that are likely to contribute to the generation of artifacts in conventional fluorescence-based quantification. Furthermore, we developed the necessary assay for accurate uptake quantification. PLGA NPs were selected as the model carrier system to deliver EsxB protein (a Staphylococcus aureus antigen) in order to testify to the feasibility of the established method. The results showed that for the same antigen uptake amount, the antigen delivered by PLGA nanoparticles could elicit 3.6 times IL-2 secretion (representative of cellular immune response activation) and 1.5 times IL-12 secretion (representative of DC maturation level) compared with pure antigen feeding. The findings above give direct evidence of the extra adjuvanticity of PLGA nanoparticles, except for their delivery functions. The developed methodology allows for the evaluation of immune cell responses on an antigen uptake basis, thus providing a better understanding of the origin of the adjuvanticity of nanoparticle carriers. Ultimately, this research provides general guidelines for the formulation of nano-vaccines.

Highly sensitive staphylococcal enterotoxin B (SEB) assay is of great importance for the prevention of toxic diseases caused by SEB. In this study, we present a gold nanoparticle (AuNP)-linked immunosorbent assay (ALISA) for detecting SEB in a sandwich format using a pair of SEB specific monoclonal antibodies (mAbs) performed in microplates. First, the detection mAb was labeled with AuNPs of different particle sizes (15, 40 and 60 nm). Then the sandwich immunosorbent assay for SEB detection was performed routinely in a microplate except for using AuNPs-labeled detection mAb. Next, the AuNPs adsorbed on the microplate were dissolved with aqua regia and the content of gold atoms was determined by graphite furnace atomic absorption spectrometry (GFAAS). Finally, a standard curve was drawn of the gold atomic content against the corresponding SEB concentration. The detection time of ALISA was about 2.5 h. AuNPs at 60 nm showed the highest sensitivity with an actual measured limit of detection (LOD) of 0.125 pg/mL and a dynamic range of 0.125–32 pg/mL. AuNPs at 40 nm had an actual measured LOD of 0.5 pg/mL and a dynamic range of 0.5 to 128 pg/mL. AuNPs at 15 nm had an actual measured LOD of 5 pg/mL, with a dynamic range of 5–1280 pg/mL. With detection mAb labeled with AuNPs at 60 nm, ALISA’s intra- and interassay coefficient variations (CV) at three concentrations (2, 8, and 20 pg/mL) were all lower than 12% and the average recovery level was ranged from 92.7% to 95.0%, indicating a high precision and accuracy of the ALISA method. Moreover, the ALISA method could be successfully applied to the detection of various food, environmental, and biological samples. Therefore, the successful establishment of the ALISA method for SEB detection might provide a powerful tool for food hygiene supervision, environmental management, and anti-terrorism procedures and this method might achieve detection and high-throughput analysis automatically in the near future, even though GFAAS testing remains costly at present.

Myeloid cell leukemia-1 (Mcl-1) is a crucial member of Bcl-2 family protein and is recognized as a promising therapeutic target for cancer treatment. Here, based on the lead compound we reported earlier, a focused library of analogues was designed, synthesized and evaluated for the inhibitory activity against Mcl-1. 2-oxy-3-phenylacrylic acid derivative III-2, turned out to be the most potent compound with good binding affinity for Mcl-1 and anti-proliferative activities. In addition, the effective inhibition of cell migration, the improvement of apoptosis and the decreased expression of Mcl-1 by compound III-2, as well as the molecule docking elucidated its mechanism of action. Taken together, 2-oxy-3-phenylacrylic acid derivatives may represent a new class of Mcl-1 inhibitors and deserve further study.

Mental disorders seriously affect people’s health and social stability. This Mendelian randomization (MR) study was designed to investigate the causal relationship between circulating vitamin C (VC) or 25-hydroxyvitamin D (25(OH)D) levels and mental disorders. The data used for the MR analysis were derived from the summary genome-wide association studies (GWAS) database for VC and 25(OH)D and from the FinnGen consortium for fourteen mental disorders. Based on the inverse variance weighted (IVW) method, we found a potential causal association between circulating VC and anxiety disorders (IVW:OR = 1.139, 95% CI: 1.023-1.269, P = 0.018). However, no causal association was found between VC or 25(OH)D and other mental disorders (P > 0.05). In the reverse MR analysis, individuals with Alzheimer’s disease was causally associated with higher concentrations of circulating VC (P = 0.012), while individuals with anxiety disorders had a negative association between the concentrations of 25(OH)D (P = 0.012). However, the current evidence does not support a causal relationship between VC or 25(OH)D and other mental disorders. In addition, there was no causal association between circulating VC and 25(OH)D (P > 0.05). Future studies are needed to confirm these findings and to elucidate the mechanisms of potential causality.

Transition metal carbides and nitrides (MXenes) are crystal nanomaterials with a number of surface functional groups such as fluorine, hydroxyl, and oxygen, which can be used as carriers for proteins and drugs. MXenes have excellent biocompatibility, electrical conductivity, surface hydrophilicity, mechanical properties and easy surface modification. However, at present, the stability of most MXenes needs to be improved, and more synthesis methods need to be explored. MXenes are good substrates for nerve cell regeneration and nerve reconstruction, which have broad application prospects in the repair of nervous system injury. Regarding the application of MXenes in neuroscience, mainly at the cellular level, the long-term in vivo biosafety and effects also need to be further explored. This review focuses on the progress of using MXenes in nerve regeneration over the last few years; discussing preparation of MXenes and their biocompatibility with different cells as well as the regulation by MXenes of nerve cell regeneration in two-dimensional and three-dimensional environments in vitro. MXenes have great potential in regulating the proliferation, differentiation, and maturation of nerve cells and in promoting regeneration and recovery after nerve injury. In addition, this review also presents the main challenges during optimization processes, such as the preparation of stable MXenes and long-term in vivo biosafety, and further discusses future directions in neural tissue engineering.

The development of neural tissue engineering has brought new hope to the treatment of spinal cord injury (SCI). Up to date, various scaffolds have been developed to induce the oriented growth and arrangement of nerves to facilitate the repair after injury. In this work, a conductive and anisotropic inverse opal substrate was presented by modifying polystyrene (PS) inverse opal films with carbon nanotubes and then stretching them to varying degrees. The film had good biocompatibility, and neural stem cells (NSCs) grown on the film displayed good orientation along the stretching direction. In addition, benefiting from the conductivity and anisotropy of the film, NSCs differentiated into neurons significantly. These results suggest that the conductive and anisotropic PS inverse opal substrates possess value in nerve tissue engineering regeneration.

Skipping breakfast is one of the most prevalent irregular eating habits. Several pieces of evidence have reported the association between breakfast omission and a higher risk of cardiovascular diseases. Numerous publications have focused on the impact of skipping breakfast on various cardiovascular risk factors. Therefore, the current systematic review and meta-analysis aimed to assess this impact, especially with regard to anthropometric measurements, serum lipid profiles, blood pressure, and glycemic control indicators. A comprehensive search was performed in PubMed, Web of Science, Embase, Scopus, and the Cochrane Central Register of Controlled Trials up to 1 April 2023. A total of 11 eligible trials were identified to evaluate the combined effects of skipping breakfast. Final integrated results demonstrated that breakfast omission significantly decreased the body weight (mean difference = −0.66, 95% CI: −1.09 to −0.24, p = 0.002, I2 = 0.0) and increased the level of serum low-density lipoprotein cholesterol (LDL-C) (mean difference = 9.89, 95% CI: 5.14 to 14.63, p = 0.000, I2 = 17.3). Subgroup analysis also revealed potential factors that may affect the outcomes, for example, the physiological condition of participants, duration, gender, and type of breakfast. In conclusion, skipping breakfast may reduce body weight while increasing the level of serum LDL-C at the same time. In view of the limited trials, further studies are needed to expound the role of breakfast omission in cardiovascular diseases.

We aimed to evaluate the effectiveness or efficacy of heterologous or homologous COVID-19 vaccine regimens against COVID-19-related outcomes after primary immunization with two doses of CoronaVac or Sinopharm COVID-19 vaccines. PubMed, EMBASE, Web of Science, and Cochrane Library databases were searched up to 31 October 2022. The primary measure was vaccine effectiveness against COVID-19 infection with homologous or heterologous booster. The results showed heterologous and homologous booster significantly improved effectiveness against COVID-19 infection compared to primary immunization. The effectiveness against COVID-19 infection was 89.19% (95%CI 78.49, 99.89) for heterologous mRNA vaccine booster, 87.00% (95%CI 82.14, 91.85) for non-replicating vector vaccine booster, 69.99% (95%CI 52.16, 87.82) for homologous booster, and 51.48% (95%CI 41.75, 61.21) for two doses of inactivated vaccine. Homologous and heterologous regimens were also effective against SARS-CoV-2 variants, and more evidence is still needed to confirm our findings.

Modification of corn starch using ultrasonic waves to improve its freeze-thaw resistance in frozen model doughs and buns. Analysis was performed by rheometry, low-field-intensity nuclear magnetic resonance imaging, Fourier infrared spectroscopy, and scanning electron microscopy. The results showed that the addition of ultrasonically modified corn starch reduced the migration of water molecules inside the model dough, weakened the decrease of elastic modulus, and enhanced the creep recovery effect; the decrease in α-helical and β-fold content in the model dough was reduced, the destruction of internal network structure was decreased, the exposed starch granules were reduced, and the internal interaction of the dough was enhanced; the texture of the buns became softer and the moisture content increased. In conclusion, ultrasound as a physical modification means can significantly improve the freeze-thaw properties of corn starch, providing new ideas for the development and quality improvement of corn-starch-based instant frozen pasta products.

Objectives: To investigate the pooled prevalence of cerebral palsy in China, analyse the differences between different subgroups, and explore the trend over the 32-year period from 1988 to 2020. Methods: All potential studies related to the prevalence of cerebral palsy among children and adolescents in China were identified from 3 English-language databases and 4 Chinese-language databases. Pooled prevalence was calculated to estimate the prevalence of cerebral palsy among 0-18 years old and different geographical regions in China, using a random-effects meta-analysis model. Continuous fractional polynomial regression modelling was used to estimate the trend in prevalence of cerebral palsy over time. Subgroup analysis and meta-regression were conducted to investigate heterogeneity. Funnel plots and Egger’s test were used to explore potential publication bias. Results: The pooled prevalence of cerebral palsy over the study period among 0–18 years old and different geographical regions in China was 2.07‰ (95% confidence interval (95% CI) 1.66–2.47‰), and the prevalence of cerebral palsy was higher in males compared with females (2.25‰ vs 1.59‰), and in rural residents compared with urban residents (2.75‰ vs 1.90‰), respectively. The prevalence of cerebral palsy varied significantly between different geographical regions. In subjects with birthweights 4 kg, the prevalence of cerebral palsy was significantly higher than in subjects with birthweights between 2.5 and 4 kg. The trend in pooled prevalence of cerebral palsy increased continuously over the period studied, and could be divided into 3 stages; the mean annual increase in prevalence from 1988 to 1996 and from 2008 to 2019 was more rapid. Multivariate meta-regression found that the year of study was one of the sources of heterogeneity among overall prevalence. (p-value = 0.006). Conclusion: The pooled prevalence of cerebral palsy over the 32-year period from 1988 to 2020 was 2.07‰. There was an increasing trend in prevalence of cerebral palsy among children and adolescents in China over this period.

Since the effects of mono-unsaturated fatty acids (MUFA) on lipid profile are still controversial, a meta-analysis of randomized controlled trials was conducted in the present study to assess the effect of MUFA-rich food on lipid profiles. The study was designed, conducted, and reported according to the guidelines of the 2020 preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement. A systematic and comprehensive search was performed in several databases from inception up to 30 January 2022. The results showed that the intake of edible oil-derived MUFA (EDM) could increase the blood HDL-C level (mean difference = 0.08; 95%CI: −0.01, 0.17, p = 0.03), but did not affect the level of TC, TG, or LDL-C. Moreover, the consumption of other food-derived MUFA (ODM) significantly decreased TG concentration (mean difference = −0.35; 95%CI: −0.61, −0.09, p = 0.01)), but did not affect the level of TC, LDL-C, or HDL-C. Findings from this study suggest that MUFA-rich food might be beneficial to modulate the blood lipid profile.