The SMAC mimetic LCL-161 selectively targets JAK2V617F mutant cells.

Background:Evasion from programmed cell death is a hallmark of cancer and can be achieved in cancer cells by overexpression of inhibitor of apoptosis proteins (IAPs). Second mitochondria-derived activator of caspases (SMAC) directly bind to IAPs and promote apoptosis; thus, SMAC mimetics have been investigated in a variety of cancer types. particularly in diseases with high inflammation and NFĸB activation. Given that elevated TNFα levels and NFĸB activation is a characteristic feature of myeloproliferative neoplasms (MPN), we investigated the effect of the SMAC mimetic LCL-161 on MPN cell survival in vitro and disease development in vivo. Methods:To investigate the effect of the SMAC mimetic LCL-161 in vitro, we utilized murine and human cell lines to perform cell viability assays as well as primary bone marrow from mice or humans with JAK2V617F-driven MPN to interrogate myeloid colony formation. To elucidate the effect of the SMAC mimetic LCL-161 in vivo, we treated a JAK2V617F-driven mouse model of MPN with LCL-161 then assessed blood counts, splenomegaly, and myelofibrosis. Results:We found that JAK2V617F-mutated cells are hypersensitive to the SMAC mimetic LCL-161 in the absence of exogenous TNFα. JAK2 kinase activity and NFĸB activation is required for JAK2V617F-mediated sensitivity to LCL-161, as JAK or NFĸB inhibitors diminished the differential sensitivity of JAK2V617F mutant cells to IAP inhibition. Finally, LCL-161 reduces splenomegaly and may reduce fibrosis in a mouse model of JAK2V617F-driven MPN. Conclusion:LCL-161 may be therapeutically useful in MPN, in particular when exogenous TNFα signaling is blocked. NFĸB activation is a characteristic feature of JAK2V617F mutant cells and this sensitizes them to SMAC mimetic induced killing even in the absence of TNFα. However, when exogenous TNFα is added, NFĸB is activated in both mutant and wild-type cells, abolishing the differential sensitivity. Moreover, JAK kinase activity is required for the differential sensitivity of JAK2V617F mutant cells, suggesting that the addition of JAK2 inhibitors to SMAC mimetics would detract from the ability of SMAC mimetics to selectively target JAK2V617F mutant cells. Instead, combination therapy with other agents that reduce inflammatory cytokines but preserve JAK2 signaling in mutant cells may be a more beneficial combination therapy in MPN

Interbank Exposures: An Empirical Examination of Systemic Risk in the Belgian Banking System

Robust (cross-border) interbank markets are important for the well functioning of modern financial systems.Yet, a network of interbank exposures may lead to domino effects following the event of an initial bank failure.The structure of the interbank market is a potential important driving factor in the risk and impact of interbank contagion.We investigate the evolution of contagion risk for the Belgian banking system over the period 1993-2002 using detailed information on aggregate interbank exposures of individual banks and on large bilateral interbank exposures.We find that a change from a complete structure (where all banks have symmetric links) towards a multiple money centre structure (where the money centres are symmetrically linked to some banks, which are themselves not linked together) as well as a more concentrated banking market have decreased the risk and impact of contagion.Moreover, an increase in the proportion of cross-border interbank assets has lowered the risk and impact of local contagion.Yet, this reduction was probably accompanied by an increase in contagion risk generated by foreign banks, although even here the contagion risk appears fairly limited.banking systems;risk;stability;monetary integration

Interacting partially directed self avoiding walk. From phase transition to the geometry of the collapsed phase

In this paper, we investigate a model for a $1+1$ dimensional self-interacting and partially directed self-avoiding walk, usually referred to by the acronym IPDSAW. The interaction intensity and the free energy of the system are denoted by $\beta$ and $f$, respectively. The IPDSAW is known to undergo a collapse transition at $\beta_c$. We provide the precise asymptotic of the free energy close to criticality, that is we show that $f(\beta_c-\epsilon)\sim \gamma \epsilon^{3/2}$ where $\gamma$ is computed explicitly and interpreted in terms of an associated continuous model. We also establish some path properties of the random walk inside the collapsed phase $(\beta>\beta_c)$. We prove that the geometric conformation adopted by the polymer is made of a succession of long vertical stretches that attract each other to form a unique macroscopic bead, we identify the horizontal extension of the random walk inside the collapsed phase and we establish the convergence of the rescaled envelope of the macroscopic bead towards a deterministic Wulff shape.Comment: Accepted for publication in the Annals of Probabilit

A new root-knot nematode, Meloidogyne moensi n. sp. (Nematoda : Meloidogynidae), parasitizing Robusta coffee from Western Highlands, Vietnam

A new root-knot nematode, parasitizing Robusta coffee in Dak Lak Province, Western Highlands of Vietnam, is described as Meloidogyne moensi n. sp. Morphological and molecular analyses demonstrated that this species differs clearly from other previously described root-knot nematodes. Morphologically, the new species is characterized by a swollen body of females with a small posterior protuberance that elongated from ovoid to saccate; perineal patterns with smooth striae, continuous and low dorsal arch; lateral lines marked as a faint space or linear depression at junction of the dorsal and ventral striate; distinct phasmids; perivulval region free of striae; visible and wide tail terminus surrounding by concentric circles of striae; medial lips of females in dumbbell-shaped and slightly raised above lateral lips; female stylet is normally straight with posteriorly sloping stylet knobs; lip region of second stage juvenile (J2) is not annulated; medial lips and labial disc of J2 formed dumbbell shape; lateral lips are large and triangular; tail of J2 is conoid with rounded unstriated tail tip; distinct phasmids and hyaline; dilated rectum. Meloidogyne moensi n. sp. is most similar to M. africana, M. ottersoni by prominent posterior protuberance. Results of molecular analysis of rDNA sequences including the D2-D3 expansion regions of 28S rDNA, COI, and partial COII/16S rRNA of mitochondrial DNA support for the new species status

Determining key research areas for healthier diets and sustainable food systems in Viet Nam

Vietnamese food systems are undergoing rapid transformation, with important implications for human and environmental health and economic development. Poverty has decreased, and diet quality and undernutrition have improved significantly since the end of the Doi Moi reform period (1986-1993) as a result of Viet Nam opening its economy and increasing its regional and global trade. Yet poor diet quality is still contributing the triple burden of malnutrition, with 25 percent stunting among children under age 5, 26 percent and 29 percent of women and children, respectively, anemic, and 21 percent of adults overweight. Agricultural production systems have shifted from predominantly diverse smallholder systems to larger more commercialized and specialized systems, especially for crops, while the ‘meatification’ of the Vietnamese diet is generating serious trade-offs between improved nutrition and sustainability of the Vietnamese food systems. The food processing industry has developed rapidly, together with food imports, resulting in new and processed food products penetrating the food retail outlets, trending towards an increase in the Westernized consumption patterns that are shifting nutrition-related problems towards overweight and obesity and, with it, an increase of non-communicable disease-related health risks. While regulatory policies exist across the food system, these are not systematically implemented, making food safety a major concern for consumers and policy makers alike. Where data exists, it is not easy to aggregate with data from across food system dimensions, making it difficult for Viet Nam to make an informed analysis of current and potential food system trade-offs. In our research, we reviewed existing literature and data, and applied a food systems framework to develop an initial food systems profile for Viet Nam and to identify a comprehensive set a of research questions to fill current data gaps identified through the review. Insights on these would provide the comprehensive evidence needed to inform policy makers on how to develop new food systems policies for Viet Nam, and further refine and improve existing policies to achieve better quality diets and more sustainable food systems in Viet Nam. Based on these, we then engaged with stakeholders to develop research priorities in the Viet Nam context and identified 25 priority research questions. This paper aims to stimulate such reflections by clearly outlining key areas for research, government policy, and development programs on priority investment to build the evidence base around inclusive food systems interventions that aim to result in healthier diets and more sustainable food systems for Viet Nam

EAGLE—A Scalable Query Processing Engine for Linked Sensor Data

Recently, many approaches have been proposed to manage sensor data using semantic web technologies for effective heterogeneous data integration. However, our empirical observations revealed that these solutions primarily focused on semantic relationships and unfortunately paid less attention to spatio–temporal correlations. Most semantic approaches do not have spatio–temporal support. Some of them have attempted to provide full spatio–temporal support, but have poor performance for complex spatio–temporal aggregate queries. In addition, while the volume of sensor data is rapidly growing, the challenge of querying and managing the massive volumes of data generated by sensing devices still remains unsolved. In this article, we introduce EAGLE, a spatio–temporal query engine for querying sensor data based on the linked data model. The ultimate goal of EAGLE is to provide an elastic and scalable system which allows fast searching and analysis with respect to the relationships of space, time and semantics in sensor data. We also extend SPARQL with a set of new query operators in order to support spatio–temporal computing in the linked sensor data context.EC/H2020/732679/EU/ACTivating InnoVative IoT smart living environments for AGEing well/ACTIVAGEEC/H2020/661180/EU/A Scalable and Elastic Platform for Near-Realtime Analytics for The Graph of Everything/SMARTE