Acid ceramidase is upregulated in AML and represents a novel therapeutic target

There is an urgent unmet need for new therapeutics in acute myeloid leukemia (AML) as standard therapy has not changed in the past three decades and outcome remains poor for most patients. Sphingolipid dysregulation through decreased ceramide levels and elevated sphingosine 1-phosphate (S1P) promotes cancer cell growth and survival. Acid ceramidase (AC) catalyzes ceramide breakdown to sphingosine, the precursor for S1P. We report for the first time that AC is required for AML blast survival. Transcriptome analysis and enzymatic assay show that primary AML cells have high levels of AC expression and activity. Treatment of patient samples and cell lines with AC inhibitor LCL204 reduced viability and induced apoptosis. AC overexpression increased the expression of anti-apoptotic Mcl-1, significantly increased S1P and decreased ceramide. Conversely, LCL204 induced ceramide accumulation and decreased Mcl-1 through post-translational mechanisms. LCL204 treatment significantly increased overall survival of C57BL/6 mice engrafted with leukemic C1498 cells and significantly decreased leukemic burden in NSG mice engrafted with primary human AML cells. Collectively, these studies demonstrate that AC plays a critical role in AML survival through regulation of both sphingolipid levels and Mcl-1. We propose that AC warrants further exploration as a novel therapeutic target in AML

Treating glucosphingolipid disorders by chemotherapy: Use of approved drugs and over-the-counter remedies

The accumulation of a glucosphingolipid (GSL) in individuals lacking an adequate level of hydrolase activity could be minimized by chemotherapeutic measures that slow the formation of the GSL and stimulate the defective hydrolase. By achieving a balance in the rates of formation and breakdown, one should be able to alleviate the symptoms of excess storage and achieve a satisfactory accommodation. While several drugs seem to be specifically suitable for this purpose, only one of these has been approved for human use. However, less effective drugs and over-the-counter substances are available for human use and may prove satisfactory for a few years until better ones are made available. The proposed materials and the evidence behind the recommendations are presented in this paper.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42500/1/10545_2004_Article_319707.pd

Evolutionary Conservation of the Functional Modularity of Primate and Murine LINE-1 Elements

LINE-1 (L1) retroelements emerged in mammalian genomes over 80 million years ago with a few dominant subfamilies amplifying over discrete time periods that led to distinct human and mouse L1 lineages. We evaluated the functional conservation of L1 sequences by comparing retrotransposition rates of chimeric human-rodent L1 constructs to their parental L1 counterparts. Although amino acid conservation varies from ∼35% to 63% for the L1 ORF1p and ORF2p, most human and mouse L1 sequences can be functionally exchanged. Replacing either ORF1 or ORF2 to create chimeric human-mouse L1 elements did not adversely affect retrotransposition. The mouse ORF2p retains retrotransposition-competency to support both Alu and L1 mobilization when any of the domain sequences we evaluated were substituted with human counterparts. However, the substitution of portions of the mouse cys-domain into the human ORF2p reduces both L1 retrotransposition and Alu trans-mobilization by 200–1000 fold. The observed loss of ORF2p function is independent of the endonuclease or reverse transcriptase activities of ORF2p and RNA interaction required for reverse transcription. In addition, the loss of function is physically separate from the cysteine-rich motif sequence previously shown to be required for RNP formation. Our data suggest an additional role of the less characterized carboxy-terminus of the L1 ORF2 protein by demonstrating that this domain, in addition to mediating RNP interaction(s), provides an independent and required function for the retroelement amplification process. Our experiments show a functional modularity of most of the LINE sequences. However, divergent evolution of interactions within L1 has led to non-reciprocal incompatibilities between human and mouse ORF2 cys-domain sequences

Comics Telling Refugee Stories

This chapter begins with an indicative survey of comics responding to the current ‘refugee crisis’. The comics in question adopt one of two distinct and established approaches. The first is reportage, usually featuring the author/creator as a central device, while the second re-works and renders testimony in visual form. In their different ways, both contribute to a wider repertoire of positive and sympathetic representations of refugees, offering a counter-point to hostile media and political discourse, often by a focus on the stories of individuals. Mobilizing compassion and moral responses through personal stories of hardship, trauma, tenacity, and survival has long been a tactic of reformist agendas and humanitarian advocacy. By their qualitative difference from dominant forms of factual discourse, comics offer certain advantages. They may also circumvent certain problems associated with photographic representations of suffering. Such comics can nevertheless run the risk of re-producing established victim tropes, and just as with other forms of representation, human-interest angles carry the potential to obscure political dimensions. In an attempt to consider and situate these concerns, the analysis considers the various positions and relations that constitute ‘refugee comics’: subjects, readers, creators, (im)materiality, and circulation

Complex Deleterious Interactions Associated with Malic Enzyme May Contribute to Reproductive Isolation in the Copepod Tigriopus californicus

Dobzhansky-Muller incompatibilities can result from the interactions of more than a single pair of interacting genes and there are several different models of how such complex interactions can be structured. Previous empirical work has identified complex conspecific epistasis as a form of complex interaction that has contributed to postzygotic reproductive isolation between taxa, but other forms of complexity are also possible. Here, I probe the genetic basis of reproductive isolation in crosses of the intertidal copepod Tigriopus californicus by looking at the impact of markers in genes encoding metabolic enzymes in F2 hybrids. The region of the genome associated with the locus ME2 is shown to have strong, repeatable impacts on the fitness of hybrids in crosses and epistatic interactions with another chromosomal region marked by the GOT2 locus in one set of crosses. In a cross between one of these populations and a third population, these two regions do not appear to interact despite the continuation of a large effect of the ME2 region itself in both crosses. The combined results suggest that the ME2 chromosomal region is involved in incompatibilities with several unique partners. If these deleterious interactions all stem from the same factor in this region, that would suggest a different form of complexity from complex conspecific epistasis, namely, multiple independent deleterious interactions stemming from the same factor. Confirmation of this idea will require more fine-scale mapping of the interactions of the ME2 region of the genome

A Genome-Wide Analysis Reveals No Nuclear Dobzhansky-Muller Pairs of Determinants of Speciation between S. cerevisiae and S. paradoxus, but Suggests More Complex Incompatibilities

The Dobzhansky-Muller (D-M) model of speciation by genic incompatibility is widely accepted as the primary cause of interspecific postzygotic isolation. Since the introduction of this model, there have been theoretical and experimental data supporting the existence of such incompatibilities. However, speciation genes have been largely elusive, with only a handful of candidate genes identified in a few organisms. The Saccharomyces sensu stricto yeasts, which have small genomes and can mate interspecifically to produce sterile hybrids, are thus an ideal model for studying postzygotic isolation. Among them, only a single D-M pair, comprising a mitochondrially targeted product of a nuclear gene and a mitochondrially encoded locus, has been found. Thus far, no D-M pair of nuclear genes has been identified between any sensu stricto yeasts. We report here the first detailed genome-wide analysis of rare meiotic products from an otherwise sterile hybrid and show that no classic D-M pairs of speciation genes exist between the nuclear genomes of the closely related yeasts S. cerevisiae and S. paradoxus. Instead, our analyses suggest that more complex interactions, likely involving multiple loci having weak effects, may be responsible for their post-zygotic separation. The lack of a nuclear encoded classic D-M pair between these two yeasts, yet the existence of multiple loci that may each exert a small effect through complex interactions suggests that initial speciation events might not always be mediated by D-M pairs. An alternative explanation may be that the accumulation of polymorphisms leads to gamete inviability due to the activities of anti-recombination mechanisms and/or incompatibilities between the species' transcriptional and metabolic networks, with no single pair at least initially being responsible for the incompatibility. After such a speciation event, it is possible that one or more D-M pairs might subsequently arise following isolation

Human cell types important for Hepatitis C Virus replication in vivo and in vitro. Old assertions and current evidence

Hepatitis C Virus (HCV) is a single stranded RNA virus which produces negative strand RNA as a replicative intermediate. We analyzed 75 RT-PCR studies that tested for negative strand HCV RNA in liver and other human tissues. 85% of the studies that investigated extrahepatic replication of HCV found one or more samples positive for replicative RNA. Studies using in situ hybridization, immunofluorescence, immunohistochemistry, and quasispecies analysis also demonstrated the presence of replicating HCV in various extrahepatic human tissues, and provide evidence that HCV replicates in macrophages, B cells, T cells, and other extrahepatic tissues. We also analyzed both short term and long term in vitro systems used to culture HCV. These systems vary in their purposes and methods, but long term culturing of HCV in B cells, T cells, and other cell types has been used to analyze replication. It is therefore now possible to study HIV-HCV co-infections and HCV replication in vitro

An overview of progress in electrolytes for secondary zinc-air batteries and other storage systems based on zinc

The revived interest and research on the development of novel energy storage systems with exceptional inherent safety, environmentally benign and low cost for integration in large scale electricity grid and electric vehicles is now driven by the global energy policies. Within various technical challenges yet to be resolved and despite extensive studies, the low cycle life of the zinc anode is still hindering the implementation of rechargeable zinc batteries at industrial scale. This review presents an extensive overview of electrolytes for rechargeable zinc batteries in relation to the anode issues which are closely affected by the electrolyte nature. Widely studied aqueous electrolytes, from alkaline to acidic pH, as well as non-aqueous systems including polymeric and room temperature ionic liquids are reported. References from early rechargeable Zn-air research to recent results on novel Zn hybrid systems have been analyzed. The ambition is to identify the challenges of the electrolyte system and to compile the proposed improvements and solutions. Ultimately, all the technologies based on zinc, including the more recently proposed novel zinc hybrid batteries combining the strong points of lithium-ion, redox-flow and metal-air systems, can benefit from this compilation in order to improve secondary zinc based batteries performance.Basque Country University (ZABALDUZ2012 program), and the Basque Country Government (Project: CIC energiGUNÉ16 of the ELKARTEK program) and the European Commission through the project ZAS: “Zinc Air Secondary innovative nanotech based batteries for efficient energy storage” (Grant Agreement 646186