RIP1-dependent linear and nonlinear recruitments of caspase-8 and RIP3 respectively to necrosome specify distinct cell death outcomes

There remains a significant gap in our quantitative understanding of crosstalk between apoptosis and necroptosis pathways. By employing the SWATH-MS technique, we quantified absolute amounts of up to thousands of proteins in dynamic assembling/de-assembling of TNF signaling complexes. Combining SWATH-MS-based network modeling and experimental validation, we found that when RIP1 level is below ~1000 molecules/cell (mpc), the cell solely undergoes TRADD-dependent apoptosis. When RIP1 is above ~1000 mpc, pro-caspase-8 and RIP3 are recruited to necrosome respectively with linear and nonlinear dependence on RIP1 amount, which well explains the co-occurrence of apoptosis and necroptosis and the paradoxical observations that RIP1 is required for necroptosis but its increase down-regulates necroptosis. Higher amount of RIP1 (>~46,000 mpc) suppresses apoptosis, leading to necroptosis alone. The relation between RIP1 level and occurrence of necroptosis or total cell death is biphasic. Our study provides a resource for encoding the complexity of TNF signaling and a quantitative picture how distinct dynamic interplay among proteins function as basis sets in signaling complexes, enabling RIP1 to play diverse roles in governing cell fate decisions.

Effect of oral / 南方医科大学学报

OBJECTIVE@#To explore the effects of intervention with oral probiotic @*METHODS@#This study were conducted among 155 women in the third trimester of pregnancy with positive results of GBS culture in the Outpatient Department of Zhujiang Hospital from March to November, 2019. After excluding 32 patients who received lactobacillus intervention for less than 2 weeks or underwent postpartum GBS retesting, the women were divided into oral probiotics intervention group (60 cases) and non-intervention group (63 cases). According to the results of GBS retesting, the 60 women in the intervention group were divided into GBS-negative group (18 cases) and persistent GBS-positive group (42 cases). At the end of the intervention, the rates of negative GBS culture result were calculated and the pregnancy outcomes were compared. From 5 women randomly selected from the intervention group, samples of vaginal secretions were collected before and after the intervention for amplicon sequencing and bioinformatics analysis.@*RESULTS@#At the end of the intervention, the GBS-negative rate in the intervention group was 30% (18/60), as compared with 23% (3/13) in the non-intervention group. Probiotic intervention significantly reduced the incidence of premature rupture of membranes (@*CONCLUSIONS@#Intervention with oral probiotics can reduce vaginal GBS colonization in late pregnancy and improve the pregnancy outcome.