A p38α-BLIMP1 signalling pathway is essential for plasma cell differentiation.

Plasma cells (PC) are antibody-secreting cells and terminal effectors in humoral responses. PCs differentiate directly from activated B cells in response to T cell-independent (TI) antigens or from germinal center B (GCB) cells in T cell-dependent (TD) antigen-induced humoral responses, both of which pathways are essentially regulated by the transcription factor BLIMP1. The p38 mitogen-activated protein kinase isoforms have already been implicated in B cell development, but the precise role of p38α in B cell differentiation is still largely unknown. Here we show that PC differentiation and antibody responses are severely impaired in mice with B cell-specific deletion of p38α, while B cell development and the GCB cell response are spared. By utilizing a Blimp1 reporter mouse model, we show that p38α-deficiency results in decreased BLIMP1 expression. p38α-driven BLIMP1 up-regulation is required for both TI and TD PCs differentiation. By combining CRISPR/Cas9 screening and other approaches, we identify TCF3, TCF4 and IRF4 as downstream effectors of p38α to control PC differentiation via Blimp1 transcription. This study thus identifies an important signalling pathway underpinning PC differentiation upstream of BLIMP1, and points to a highly specialized and non-redundant role for p38α among p38 isoforms.

NuSC: An Effective Local Search Algorithm for Solving the Set Covering Problem.

The set covering problem (SCP) is a fundamental NP-hard problem in computer science and has a broad range of important real-world applications. In practice, SCP instances transformed from real-world applications would be of large scale, so it is of significant importance to design effective heuristic algorithms, especially local search ones. However, there exist only few research works on developing local search algorithms for solving SCP. In this article, we propose a new local search algorithm for solving SCP, dubbed NuSC. In particular, NuSC introduces a new combined scoring function for subset selection, which combines different subset properties in an effective way and helps NuSC find more optimized solutions. Besides, NuSC incorporates a dynamic weighting scheme for elements, a tabu search strategy, and a novelty selection mechanism to further enhance its practical performance. In order to study the effectiveness and robustness of our proposed NuSC algorithm, we conduct extensive experiments to compare NuSC against many state-of-the-art competitors on various types of SCP instances. Our experimental results demonstrate that NuSC significantly outperforms its competitors on the majority of instances, indicating the superiority of NuSC. Also, our empirical evaluations confirm the effectiveness of each algorithmic technique underlying NuSC.

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.

Clause states based configuration checking in local search for satisfiability.

Two-mode stochastic local search (SLS) and focused random walk (FRW) are the two most influential paradigms of SLS algorithms for the propositional satisfiability (SAT) problem. Recently, an interesting idea called configuration checking (CC) was proposed to handle the cycling problem in SLS. The CC idea has been successfully used to improve SLS algorithms for SAT, resulting in state-of-the-art solvers. Previous CC strategies for SAT are based on neighboring variables, and prove successful in two-mode SLS algorithms. However, this kind of neighboring variables based CC strategy is not suitable for improving FRW algorithms. In this paper, we propose a new CC strategy which is based on clause states. We apply this clause states based CC (CSCC) strategy to both two-mode SLS and FRW paradigms. Our experiments show that the CSCC strategy is effective on both paradigms. Furthermore, our developed FRW algorithms based on CSCC achieve state-of-the-art performance on a broad range of random SAT benchmarks.