Cross talk between Wnt/β-catenin and Irf8 in leukemia progression and drug resistance

Progression and disease relapse of chronic myeloid leukemia (CML) depends on leukemia-initiating cells (LIC) that resist treatment. Using mouse genetics and a BCR-ABL model of CML, we observed cross talk between Wnt/{beta}-catenin signaling and the interferon-regulatory factor 8 (Irf8). In normal hematopoiesis, activation of {beta}-catenin results in up-regulation of Irf8, which in turn limits oncogenic {beta}-catenin functions. Self-renewal and myeloproliferation become dependent on {beta}-catenin in Irf8-deficient animals that develop a CML-like disease. Combined Irf8 deletion and constitutive {beta}-catenin activation result in progression of CML into fatal blast crisis, elevated leukemic potential of BCR-ABL-induced LICs, and Imatinib resistance. Interestingly, activated {beta}-catenin enhances a preexisting Irf8-deficient gene signature, identifying {beta}-catenin as an amplifier of progression-specific gene regulation in the shift of CML to blast crisis. Collectively, our data uncover Irf8 as a roadblock for {beta}-catenin-driven leukemia and imply both factors as targets in combinatorial therapy

Agonistic Interventions into Public Commemorative Art:An Innovative Form of Counter-memorial Practice?

In light of recent controversies around the removal or modification of public commemorative art, such as memorials and monuments, this paper interrogates the value of competing approaches to counter-memorial practice using the framework of agonistic memory. It argues that much counter-memorial practice today, as it relates to historical memory, is dominated by a “cosmopolitan” mode that fails to offer a convincing response to the rise of right-wing populism and its instrumentalization of conflicts over public commemorative art. The article investigates two case studies of counter-memorial interventions that focus on the memory of fascism in Europe today and seeks to identify and assess emergent agonistic practices

Deltaproteobacteria (Pelobacter) and Methanococcoides are responsible for choline-dependent methanogenesis in a coastal saltmarsh sediment

Coastal saltmarsh sediments represent an important source of natural methane emissions, much of which originates from quaternary and methylated amines, such as choline and trimethylamine. In this study, we combine DNA stable isotope probing with high throughput sequencing of 16S rRNA genes and 13C2-choline enriched metagenomes, followed by metagenome data assembly, to identify the key microbes responsible for methanogenesis from choline. Microcosm incubation with 13C2-choline leads to the formation of trimethylamine and subsequent methane production, suggesting that choline-dependent methanogenesis is a two-step process involving trimethylamine as the key intermediate. Amplicon sequencing analysis identifies Deltaproteobacteria of the genera Pelobacter as the major choline utilizers. Methanogenic Archaea of the genera Methanococcoides become enriched in choline-amended microcosms, indicating their role in methane formation from trimethylamine. The binning of metagenomic DNA results in the identification of bins classified as Pelobacter and Methanococcoides. Analyses of these bins reveal that Pelobacter have the genetic potential to degrade choline to trimethylamine using the choline-trimethylamine lyase pathway, whereas Methanococcoides are capable of methanogenesis using the pyrrolysine-containing trimethylamine methyltransferase pathway. Together, our data provide a new insight on the diversity of choline utilizing organisms in coastal sediments and support a syntrophic relationship between Bacteria and Archaea as the dominant route for methanogenesis from choline in this environment

Metabolite Profiling Uncovers Plasmid-Induced Cobalt Limitation under Methylotrophic Growth Conditions

BACKGROUND:The introduction and maintenance of plasmids in cells is often associated with a reduction of growth rate. The reason for this growth reduction is unclear in many cases. METHODOLOGY/PRINCIPAL FINDINGS:We observed a surprisingly large reduction in growth rate of about 50% of Methylobacterium extorquens AM1 during methylotrophic growth in the presence of a plasmid, pCM80 expressing the tetA gene, relative to the wild-type. A less pronounced growth delay during growth under non-methylotrophic growth conditions was observed; this suggested an inhibition of one-carbon metabolism rather than a general growth inhibition or metabolic burden. Metabolome analyses revealed an increase in pool sizes of ethylmalonyl-CoA and methylmalonyl-CoA of more than 6- and 35-fold, respectively, relative to wild type, suggesting a strongly reduced conversion of these central intermediates, which are essential for glyoxylate regeneration in this model methylotroph. Similar results were found for M. extorquens AM1 pCM160 which confers kanamycin resistance. These intermediates of the ethylmalonyl-CoA pathway have in common their conversion by coenzyme B(12)-dependent mutases, which have cobalt as a central ligand. The one-carbon metabolism-related growth delay was restored by providing higher cobalt concentrations, by heterologous expression of isocitrate lyase as an alternative path for glyoxylate regeneration, or by identification and overproduction of proteins involved in cobalt import. CONCLUSIONS/SIGNIFICANCE:This study demonstrates that the introduction of the plasmids leads to an apparent inhibition of the cobalt-dependent enzymes of the ethylmalonyl-CoA pathway. Possible explanations are presented and point to a limited cobalt concentration in the cell as a consequence of the antibiotic stress

The rumen microbial metagenome associated with high methane production in cattle

Acknowledgements The Rowett Institute of Nutrition and Health and SRUC are funded by the Rural and Environment Science and Analytical Services Division (RESAS) of the Scottish Government. The project was supported by Defra and the DA funded Agricultural Greenhouse Gas Inventory Research Platform, the Technology Strategy Board (Project No: TP 5903–40240) and the Biotechnology and Biological Sciences Research Council (BBSRC; BB/J004243/1, BB/J004235/1). Our thanks are due to the excellent support staff at the SRUC Beef and Sheep Research Centre, Edinburgh, and to Silvia Ramos Garcia for help in interrogating the data. MW and RR contributed equally to the paper and should be considered as joint last authors.Peer reviewedPublisher PD