Polarity protein AF6 functions as a modulator of necroptosis by regulating ubiquitination of RIPK1 in liver diseases.

AF6, a known polarity protein, contributes to the maintenance of homeostasis while ensuring tissue architecture, repair, and integrity. Mice that lack AF6 display embryonic lethality owing to cell-cell junction disruption. However, we show AF6 promotes necroptosis via regulating the ubiquitination of RIPK1 by directly interact with the intermediate domain of RIPK1, which was mediated by the deubiquitylase enzyme USP21. Consistently, while injection of mice with an adenovirus providing AF6 overexpression resulted in accelerated TNFα-induced necroptosis-mediated mortality in vivo, we observed that mice with hepatocyte-specific deletion of AF6 prevented hepatocytes from necroptosis and the subsequent inflammatory response in various liver diseases model, including non-alcoholic steatohepatitis (NASH) and the systemic inflammatory response syndrome (SIRS).Together, these data suggest that AF6 represents a novel regulator of RIPK1-RIPK3 dependent necroptotic pathway. Thus, the AF6-RIPK1-USP21 axis are potential therapeutic targets for treatment of various liver injuries and metabolic diseases.

Establishment of Reference Values for Early Auditory Preverbal Skills of Children with Cochlear Implants.

Auditory and verbal abilities of children with early cochlear implant (CI) surgery usually take some time to develop, and a reference index of early development for horizontal comparisons is urgently needed to guide the mapping process and adjust rehabilitation programs. Therefore, the aim of this study was to establish a reference value for early auditory preverbal skills development in children with CI and investigate the developmental curve and influencing factors for these children. The LittlEARS® Auditory Questionnaire (LEAQ) scores of 287 eligible Chinese participants were obtained at 1, 2, 3, 6, 9, 12, 18, 24, 28, and 36 months interval after CI activation. The median and standard deviation of the LEAQ score of each hearing stage for these children with different activation ages were calculated to establish the reference values. Quadratic regression was conducted to fit the expected developmental curve of the LEAQ score (y=-0.057x2+2.55x+5.45 [0 to 20 months]). With a linear mixed-effects model, we found that the receptive auditory behavior increased rapidly after CI activation, while expressive language skills developed at a steady rate. We also found that the following factors all significantly influenced the LEAQ: the duration of CI use, the development quotient, age of implantation and activation, and the presence of large vestibular aqueduct syndrome or auditory neuropathy spectrum disorder. The reference values and the expected developmental curve for the LEAQ in children with CI established by the present study provides guidance to clinicians and parents as well as realistic expectations regarding language and speech outcomes.

Comparison of foramen magnum decompression with and without duraplasty in the treatment of adult Chiari malformation Type I: a meta-analysis and systematic review.

AIM: Some meta-analyses have focused on foramen magnum decompression with duraplasty (PFDD) and without duraplasty (PFD) in paediatric or mixed populations. Nevertheless, no meta-analysis has evaluated adults only. This study aimed to include new relevant findings in a systematic review to provide the first comparison of PFDD and PFD in adult CM-I. MATERIAL AND METHODS: We retrospectively searched Web of Science, PubMed, Embase and ClinicalTrials.gov to summarize all relevant published papers on adults. A systemic review was adopted to evaluate clinical or radiological improvement, surgical complications, and reoperation rates between the PFD and PFDD groups. RESULTS: Nine papers containing information on 497 adult participants met the criteria. PFDD was related to a lower revision rate (RR=2.96, 95% CI: 1.34-6.51, P=0.007) but a higher complication rate (RR=0.35, 95% CI: 0.22-0.55, P 0.00001). No significant difference was noted between PFD and PFDD in terms of overall symptom improvement (RR=0.93, 95% CI: 0.84-1.03, P = 0.17) or syringomyelia reduction (RR=0.84, 95% CI: 0.63-1.12, P = 0.24). No significant difference in symptom improvement was observed between patients with syringomyelia (RR=0.86, 95% CI: 0.69-1.08, P = 0.20) and patients without syringomyelia (RR=0.94, 95% CI: 0.68-1.30, P = 0.73). CONCLUSION: This systematic review of observational studies reveals that PFDD may provide lower revision rates but pose a higher risk than PFD in the management of CM-I in adults. However, PFD is similar to PFDD in clinical and radiological improvements.

Amentoflavone attenuates Listeria monocytogenes pathogenicity through an LLO-dependent mechanism.

BACKGROUND AND PURPOSE: L. monocytogenes remain a leading cause of foodborne infection. Listeriolysin O (LLO), an indispensable virulence determinant involved in diverse pathogenic mechanisms of L. monocytogenes infection, represents a promising therapeutic target. In this study, we sought to identify an effective inhibitor of LLO pore formation and its mechanism of action in the treatment of L. monocytogenes infection. EXPERIMENTAL APPROACH: Haemolysis assays were carried out to screen an effective LLO inhibitor. The interaction between candidate and LLO was investigated using surface plasmon resonance and molecular docking. The effect of candidate on LLO-mediated cytotoxicity, barrier disruption and immune response were investigated. Finally, the in vivo effect of candidate on mice challenged with L. monocytogenes was examined. KEY RESULTS: Amentoflavone, a natural flavone present in traditional Chinese herbs, effectively inhibited LLO pore formation by engaging the residues Lys93, Asp416, Tyr469 and Lys505 in LLO. Amentoflavone dose-dependently reduced L. monocytogenes-induced cell injury in an LLO-dependent manner. In the Caco-2 monolayer model, amentoflavone maintained the integrity of the epithelial barrier exposed to LLO. Amentoflavone inhibited the inflammatory response evoked by L. monocytogenes in an LLO-dependent manner, and inhibition was attributed to ability to block perforation-associated K+ efflux and Ca2+ influx. In the mouse infection model, amentoflavone treatment significantly reduced bacterial burden and pathological lesions in target organs, with a significant increase in survival rate. CONCLUSIONS AND IMPLICATIONS: Amentoflavone reduced the pathogenicity of L. monocytogenes by specifically inhibiting LLO pore formation, and this may represent a potential treatment for L. monocytogenes infection.

Surface-enhanced Raman scattering activities of graphene-wrapped Cu particles by chemical vapor deposition assisted with thermal annealing.

We presented a graphene-wrapped Cu particle hybrid system (G@Cu) to be used as a high performance surface-enhanced Raman scattering (SERS) substrate. The Cu particles wrapped by a few-layer graphene shell were directly synthesized on SiO2/Si by chemical vapor deposition assisted with thermal annealing in a mixture of methane and hydrogen. The detailed explanation on the different morphology of Cu particles induced by different thermal annealing condition was carried out with both qualitative and quantitative analysis and a series of G@Cu 3D models of Cu particles with different shape anisotropy and inter-particle gap were also built for further study of Raman enhancement mechanism. The G@Cu showed fine SERS activities, including the fluorescence quenching effect, the stability of Raman signals, chemical and optical stability, with an enhancement factor (EF) of ~1.5 × 106.

A comparative study on the effects of pristine and functionalized single-walled carbon nanotubes on osteoblasts: ultrastructural and biochemical properties.

A comparative study was performed to investigate the ultrastructural and biomolecular properties of osteoblasts induced by three types of single-walled carbon nanotubes (SWNTs). The results on cellular uptake and ultrastructural alteration indicate that SWNTs enter osteoblasts by endocytosis. SWNTs-COOH and SWNTs-OH particles were freely dispersed in the cytoplasm, while pristine SWNTs were localized to the periphery of the cell. Both SWNTs-OH and SWNTs-COOH promoted cell changes in cell activity regarding mRNA expression at doses of 50 and 100 µg/mL in the first 24 h. When treated with 50 µg/mL SWNTs-COOH for 48 h, the expression of type I collagen increased by 6.3-fold (for MG63) or 9.1-fold (for primary osteoblasts) compared with the control group. The present study observed for the first time that SWNTs-COOH initiated the prompt and the maximum upregulation of type I collagen gene expression, and simultaneously induced the expansion of the endoplasmic reticulum for increased protein synthesis, which in turn accelerated the mineralization process. However, impaired cell properties and mitochondrial injury were detected following treatment with SWNTs at 100 µg/mL after 48 h. In conclusion, we believe that SWNTs-COOH is a good candidate for the fabrication of biomedical scaffolds for bone regeneration.