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 obser-vations 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 com-plexity 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.

Empirical investigation of stochastic local search for maximum satisfiability

The maximum satisfiability (MAX-SAT)problem is an important NP-hard problem in theory,and has a broad range of applications in practice.Stochastic local search (SLS)is becoming an increasingly popular method for solving MAX-SAT.Recently,a powerful SLS algorithm called CCLS shows efficiency on solving random and crafted MAX-SAT instances.However,the performance of CCLS on solving industrial MAX-SAT instances lags far behind.In this paper,we focus on experimentally analyzing the performance of SLS algorithms for solving industrial MAXSAT instances.First,we conduct experiments to analyze why CCLS performs poor on industrial instances.Then we propose a new strategy called additive BMS (Best from Multiple Selections)to ease the serious issue.By integrating CCLS and additive BMS,we develop a new SLS algorithm for MAXSAT called CCABMS,and related experiments indicate the efficiency of CCABMS.Also,we experimentally analyze the effectiveness of initialization methods on SLS algorithms for MAX-SAT,and combine an effective initialization method with CCABMS,resulting in an enhanced algorithm.Experimental results show that our enhanced algorithm performs better than its state-of-the-art SLS competitors on a large number of industrial MAX-SAT instances.