Tyrosine 842 in the activation loop is required for full transformation by the oncogenic mutant FLT3-ITD

The type III receptor tyrosine kinase FLT3 is frequently mutated in acute myeloid leukemia. Oncogenic FLT3 mutants display constitutive activity leading to aberrant cell proliferation and survival. Phosphorylation on several critical tyrosine residues is known to be essential for FLT3 signaling. Among these tyrosine residues, Y842 is located in the so-called activation loop. The position of this tyrosine residue is well conserved in all receptor tyrosine kinases. It has been reported that phosphorylation of the activation loop tyrosine is critical for catalytic activity for some but not all receptor tyrosine kinases. The role of Y842 residue in FLT3 signaling has not yet been studied. In this report, we show that Y842 is not important for FLT3 activation or ubiquitination but plays a critical role in regulating signaling downstream of the receptor as well as controlling receptor stability. We found that mutation of Y842 in the FLT3-ITD oncogenic mutant background reduced cell viability and increased apoptosis. Furthermore, the introduction of the Y842 mutation in the FLT3-ITD background led to a dramatic reduction in in vitro colony forming capacity. Additionally, mice injected with cells expressing FLT3-ITD/Y842F displayed a significant delay in tumor formation, compared to FLT3-ITD expressing cells. Microarray analysis comparing gene expression regulated by FLT3-ITD versus FLT3-ITD/Y842F demonstrated that mutation of Y842 causes suppression of anti-apoptotic genes. Furthermore, we showed that cells expressing FLT3-ITD/Y842F display impaired activity of the RAS/ERK pathway due to reduced interaction between FLT3 and SHP2 leading to reduced SHP2 activation. Thus, we suggest that Y842 is critical for FLT3-mediated RAS/ERK signaling and cellular transformation.     

新疆旅游业对经济增长影响的实证分析

近年来,旅游业已经成为很多地区拉动经济增长的重要产业之一。新疆具有浓郁的民族风情以及各种得天独厚的旅游资源,这为旅游业蓬勃发展提供了坚实基础。首先介绍了新疆旅游业的基本发展状况及趋势;其次,针对新疆2005-2017年的统计数据,运用Stata14.0软件对该数据进行多元回归,分析了旅游业对地区经济增长的贡献,并对新疆经济增长与旅游业之间的影响机制进行研究;最后根据实证分析得出的结论,提出了若干对策建议。     

Two Innovative Coalition Formation Models for Dynamic Task Allocation in Disaster Rescues

This paper addresses the problem of multi-objective coalition formation for task allocation. In disaster rescue, due to the dynamics of environments, heterogeneity and complexity of tasks as well as limited available agents, it is hard for the single-objective and single (task)-to-single (agent) task allocation approaches to handle task allocation in such circumstances. To this end, two multi-objective coalition formation for task allocation models are proposed for disaster rescues in this paper. First, through coalition formation, the proposed models enable agents to cooperatively perform complex tasks that cannot be completed by single agent. In addition, through adjusting the weights of multiple task allocation objectives, the proposed models can employ the linear programming to generate more adaptive task allocation plans, which can satisfy different task allocation requirements in disaster rescue. Finally, through employing the multi-stage task allocation mechanism of the dynamic programming, the proposed models can handle the dynamics of tasks and agents in disaster environments. Experimental results indicate that the proposed models have good performance on coalition formation for task allocation in disaster environments, which can generate suitable task allocation plans according to various objectives of task allocation.     

Data-Driven Leader-Follower Output Synchronization for Networked Non-Linear Multi-Agent Systems with Switching Topology and Time-Varying Delays

This paper studies the output synchronization problem for a class of networked non-linear multi-agent systems with switching topology and time-varying delays. To synchronize the outputs, a leader is introduced whose connectivity to the followers varies with time, and a novel data-driven consensus protocol based on model free adaptive control is proposed, where the reference input of each follower is designed to be the time-varying average of the neighboring agents’ outputs. Both the case when the leader is with a prescribed reference input and the case otherwise are considered. The proposed protocol allows for time-varying delays, switching topology, and does not use the agent structure or the dynamics information implicitly or explicitly. Sufficient conditions are derived to guarantee the closed-loop stability, and conditions for consensus convergence are obtained, where only a joint spanning tree is required. Numerical simulations and practical experiments are conducted to demonstrate the effectiveness of the proposed protocol.     

Exploring the Potency of Rich Pictures in a Systemic Lean Intervention Process

Systemic Practice and Action Research - This paper explores the usefulness of rich pictures as a method in Systemic Lean Intervention (SLI) process. It combines Lean and Systems Thinking analytical...     

Contours and Tight Clusters

Nested clusters arise independently in graph partitioning and in the study of contours. We take a step toward unifying these two instances of nested clusters. We show that the graph theoretical tight clusters introduced by Dress, Steel, Moulton and Wu in 2010 are a special case of nested clusters associated to contours.     

An empirical investigation on the risk-return relationship of carbon future market

This paper examines the risk-return relationship for the carbon future market during Phases I, II and III of the European Union Emission Trading Scheme (EU ETS). The risk factors derived from the newly developed LSW model, are embedded into a GARCH framework. This new specification is compared with several GARCH-M type models analyzing the risk-return relationship in the carbon market. The results show that the new specification consistently achieves a good fit and possesses superior explanatory power for the European Union Allowance (EUA) data. Some policy suggestions regarding market efficiency are also provided.