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.     

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.     

Eustigmaeus floridensis sp. nov., a new mite species of the genus Eustigmaeus Berlese, 1910 (Acari: Stigmaeidae) from citrus in Florida

Eustigmaeus floridensis sp. nov. is described and illustrated based on female specimens collected from citrus trees in Florida, USA. The new species is closely related to Eustigmaeus arcuata, Eustigmaeus segnis and Eustigmaeus microsegnis, all known to occur in Florida. Eustigmaeus floridensis sp. nov. can be distinguished by larger dimples associated with setae sce, d₂ and e₁ containing at least four or more vacuoles centrally; dorsal body setae broadly lanceolate and feather-like, except c₂, which is slender; anogenital area with striae and one pair of serrated aggenital (ag1) and three pairs of serrated pseudanal (ps_1?3) setae. A key to the Eustigmaeus species known to occur across USA is also provided.     

Forecasting of dependence,market, and investment risks of a global index portfolio

This paper undertakes an in-sample and rolling-window comparative analysis of dependence, market, and portfolio investment risks on a 10-year global index portfolio of developed, emerging, and commodity markets. We draw our empirical results by fitting vine copulas (e.g., r-vines, c-vines, d-vines), IGARCH(1,1) RiskMetrics value-at-risk (VaR), and portfolio optimization methods based on risk measures such as the variance, conditional value-at-risk, conditional drawdown-at-risk, minimizing regret (Minimax), and mean absolute deviation. The empirical results indicate that all international indices tend to correlate strongly in the negative tail of the return distribution; however, emerging markets, relative to developed and commodity markets, exhibit greater dependence, market, and portfolio investment risks. The portfolio optimization shows a clear preference towards the gold commodity for investment, while Japan and Canada are found to have the highest and lowest market risk, respectively. The vine copula analysis identifies symmetry in the dependence dynamics of the global index portfolio modeled. Large VaR diversification benefits are produced at the 95% and 99% confidence levels by the modeled international index portfolio. The empirical results may appeal to international portfolio investors and risk managers for advanced portfolio management, hedging, and risk forecasting.     

Wolves in sheep’s clothing: three new cases of aggressive mimicry in Red Sea coral reef fishes

ABSTRACT

Here we document three cases of mimicry in coral reef fishes not previously reported in the literature involving two groupers (Epinephelus leucogrammicus and Plectropomus marisrubri) and a soapfish (Diploprion drachi) as mimics, and two wrasses (Larabicus quadrilineatus and Cheilinus quinquecinctus) and a blenny (Meiacanthus nigrolineatus) as models. All three cases are of aggressive mimicry, with a predatory species mimicking a harmless one, and in one of the cases, the mimicry is also Müllerian, where both the predator and harmless species are unpalatable.     

Diversity and dispersal history of the talitrids (Crustacea: Amphipoda: Talitridae) of Bermuda

Five taxa of talitrid amphipods were found in the archipelago of Bermuda, of which three were recorded there for the first time. Four of these are supralittoral wrack generalists: Platorchestia monodi BOLD:AAB3402, (a unique Molecular Operational Taxonomic Unit according to the Barcode Index Number system), a related species recognized by molecular methods, Platorchestia platensis BOLD:AAA2949, Mexorchestia carpenteri carpenteri BOLD:AAC1491 and Tethorchestia antillensis; and one a terrestrial leaf-litter generalist: Talitroides alluaudi. A key is provided to discriminate between the formally described talitrids of Bermuda. Dispersal mechanisms from the American continent to Bermuda were considered for all taxa based on species distributions along the North American Atlantic coast and also investigated by molecular methods, using genetic population differentiation and haplotype network analysis based on the barcode region of cytochrome c oxidase subunit I gene. For P. monodi BOLD:AAB3402 the genetic results suggest that some dispersal events occurred before human colonization of Bermuda but are equivocal about the source population and therefore the direction of dispersal. Some very recent synanthropic dispersal is possible with this species. For the other two species studied genetically, P. platensis BOLD:AAA2949 and M. c. carpenteri BOLD:AAC1491, the small population samples analysed support dispersal to Bermuda from the American mainland, before human occupation of Bermuda, although the available sample size was limited for these species. The available limited direct, non-genetic evidence supports synanthropic transport for Talitroides alluaudi. Platorchestia monodi BOLD:AAB3402 is found in the same wrack habitat as P. platensis BOLD:AAA2949 on Bermuda, apparently without interbreeding. No evidence was found that driftwood specialist talitrids had become established in Bermuda.     

Creating Action Research Quality in Organization Development: Rigorous,Reflective and Relevant

The purpose of the paper is to present a framework that enables action researchers to create quality action research projects within the organization development (OD) domain using the broad criteria of being rigorous, reflective and relevant and so contribute to the realm of practical knowing. What constitutes good quality action research within OD is a difficult question, given the broad range of approaches that operates in a wide variety of settings and with great diversity. It advances specific dimensions by which action researchers can create, review and assess quality in action research work. This integrative framework and criteria are practical tools to enable action researchers to create quality action research in OD.