Dysfunction of microglia is known to play an important role in Alzheimer's disease (AD). Here, we investigated the role of RIPK1 in microglia mediating the pathogenesis of AD. RIPK1 is highly expressed by microglial cells in human AD brains. Using the amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mouse model, we found that inhibition of RIPK1, using both pharmacological and genetic means, reduced amyloid burden, the levels of inflammatory cytokines, and memory deficits. Furthermore, inhibition of RIPK1 promoted microglial degradation of Aβ in vitro. We characterized the transcriptional profiles of adult microglia from APP/PS1 mice and identified a role for RIPK1 in regulating the microglial expression of and, a marker for disease-associated microglia (DAM), which encodes an endosomal/lysosomal cathepsin inhibitor named Cystatin F. We present evidence that RIPK1-mediated induction of Cst7 leads to an impairment in the lysosomal pathway. These data suggest that RIPK1 may mediate a critical checkpoint in the transition to the DAM state. Together, our study highlights a non-cell death mechanism by which the activation of RIPK1 mediates the induction of a DAM phenotype, including an inflammatory response and a reduction in phagocytic activity, and connects RIPK1-mediated transcription in microglia to the etiology of AD. Our results support that RIPK1 is an important therapeutic target for the treatment of AD.

Background We evaluated an inactivated SARS-CoV-2 vaccine for immunogenicity and safety in adults aged 18-59 years. Methods In this randomized, double-blinded and controlled trial, healthy adults received a medium (MD) or a high dose (HD) of the vaccine at an interval of either 14 days or 28 days. Neutralizing antibody (NAb) and anti-S and anti-N antibodies were detected at different times, and adverse reactions were monitored for 28 days after full immunization. Results A total of 742 adults were enrolled in the immunogenicity and safety analysis. Among subjects in the 0, 14 procedure, the seroconversion rates of NAb in MD and HD groups were 89% and 96% with GMTs of 23 and 30, respectively, at day 14 and 92% and 96% with GMTs of 19 and 21, respectively at day 28 after immunization. Anti-S antibodies had GMTs of 1883 and 2370 in MD and 2295 and 2432 in HD group. Anti-N antibodies had GMTs of 387 and 434 in MD group and 342 and 380 in HD group. Among subjects in the 0, 28 procedure, seroconversion rates for NAb at both doses were both 95% with GMTs of 19 at day 28 after immunization. Anti-S antibodies had GMTs of 937 and 929 for MD and HD group, and anti-N antibodies had GMTs of 570 and 494 for MD and HD group, respectively. No serious adverse events were observed during the study period. Conclusion Adults vaccinated with inactivated SARS-CoV-2 vaccine had NAb as well as anti-S/N antibody, and had a low rate of adverse reactions. Clinical trials registration NCT04412538.

this study has many limitations, such as the sample size, age group, sex composition, and physical characteristics. Continuously observing the persistence of the protection provided by vaccines in real cases and the effectiveness of a booster dose (a third dose), conducting long-term clinical trials, and obtaining post-clinical data are essential tasks.To some extent, this study showed that serum neutralizing antibody levels decreased after the second dose of inactivated vaccines. Importantly, the results suggest that a booster dose (a third dose) is necessary to maintain the effectiveness of inactivated vaccines regardless of sex and two-dose immunization procedure.

This study evaluated whether fish oil exerted a hepatoprotective effect in a LPS-induced liver injury model via regulation of TLR4 and nucleotide-binding oligomerization domain protein (NOD) signaling pathways. Twenty-four piglets were used in a 2 × 2 factorial design, and the main factors included diet (5% corn oil or 5% fish oil) and immunological challenge (LPS or saline). Fish oil resulted in enrichment of eicosapentaenoic acid, docosahexaenoic acid and total (n-3) polyunsaturated fatty acids in liver. Less severe liver injury was observed in pigs fed fish oil, as evidenced by improved serum biochemical parameters and less severe histological liver damage. In addition, higher expression of liver tight junction proteins, and lower hepatocyte proliferation and higher hepatocyte apoptosis were observed in pigs fed fish oil. The improved liver integrity in pigs fed fish oil was concurrent with reduced hepatic mRNA expression of TLR4, myeloid differentiation factor 88, IL-1 receptor-associated kinase 1 and TNF-α receptor-associated factor 6, and NOD1, NOD2 and receptor-interacting serine/threonine-protein kinase 2, as well as reduced hepatic protein expression of NF-κB p65, leading to reduced hepatic pro-inflammatory mediators. These results indicate that fish oil improves liver integrity partially via inhibition of TLR4 and NOD signaling pathways under an inflammatory condition.

Background This study examined the safety and immunogenicity of an inactivated SARS-CoV-2 vaccine. Method In a phase I randomized, double-blinded, placebo-controlled trial involving 192 healthy adults 18–59 years old, two injections of three doses (50 EU, 100 EU, 150 EU) of an inactivated SARS-CoV-2 vaccine or placebo were administered intramuscularly at a 2- or 4-week interval. The safety and immunogenicity of the vaccine were evaluated. Results Vaccination was completed in 191 subjects. Forty-four adverse reactions occurred within 28 days, most commonly mild pain and redness at the injection site or slight fatigue. At days 14 and 28, the seroconversion rates were 87.5% and 79.2% (50 EU), 100% and 95.8% (100 EU), and 95.8% and 87.5% (150 EU), respectively, with geometric mean titers (GMTs) of 18.1 and 10.6, 54.5 and 15.4, and 37.1 and 18.5, respectively, for the schedules with 2-week and 4-week intervals. Seroconversion was associated with synchronous upregulation of antibodies against the S protein, N protein and virion and a cytotoxic T lymphocyte (CTL) response. No cytokines and immune cells related to immunopathology were observed. Transcriptome analysis revealed the genetic diversity of immune responses induced by the vaccine. Interpretation In a population aged 18–59 years in this trial, this inactivated SARS-CoV-2 vaccine was safe and immunogenic. Trial registration: CTR20200943 and NCT04412538.