Re-assessing the toxicity of particles from biodiesel combustion: A quantitative analysis of in vitro studies

Biofuels may reduce road transport carbon intensity; however, it is uncertain whether displacing fossil diesel would alter the engine-derived particulate toxicity. The primary objective of this work was to determine whether there is a fuel effect on the comparative in vitro toxicity of biodiesel exhaust particulates relative to those from fossil diesel. A secondary aim was to determine qualitatively whether the observed outcome is related to the organic phase, namely Polycyclic Aromatic Hydrocarbons (PAHs). In vitro and acellular exposure studies were recovered from a literature survey following the PRISMA framework. Biological responses attributable to biodiesel and paired fossil diesel particles, including particle-extracts were selected. To qualify for inclusion, either of the paired responses must differ statistically significantly (p < 0.05) from the control or each other. Paired responses were assigned to one-of-five categories which best represents the pathophysiological role of the biomarker: inflammation, oxidative stress, cytotoxicity, genotoxicity and mutagenicity. Biodiesel reduced particle toxicity in two-thirds of paired responses, however, there were large differences between biodiesels for category-specific biomarkers. Particles derived from Rapeseed oil Methyl Ester (RME) were less inflammatory, whereas Soybean oil Methyl Ester (SME) particles were more inflammatory than fossil diesel on average. Conversely, SME reduced oxidative stress while few trends emerged for mutagenicity and genotoxicity. The largest fuel effect was observed for cytotoxicity: Waste Cooking Oil Methyl Ester (WCOME) increased and Palm oil Methyl Ester (PME) decreased particle cytotoxicity. Particle-phase PAH emissions compiled on a mass-of-soot basis also followed this trend, however, literature focusing on both these aspects is limited; careful consideration of fuel composition and use of normal primary human cell types and omics technologies, could resolve this open question. This assessment systematically compares biological responses from particulate only exposure, with co-exposure necessarily excluded due to an absence of understanding of how gaseous components modify particulate toxicity

Transcript profiling in Candida albicans reveals new cellular functions for the transcriptional repressors CaTup1, CaMig1 and CaNrg1.

The pathogenic fungus, Candida albicans contains homologues of the transcriptional repressors ScTup1, ScMig1 and ScNrg1 found in budding yeast. In Saccharomyces cerevisiae, ScMig1 targets the ScTup1/ScSsn6 complex to the promoters of glucose repressed genes to repress their transcription. ScNrg1 is thought to act in a similar manner at other promoters. We have examined the roles of their homologues in C. albicans by transcript profiling with an array containing 2002 genes, representing about one quarter of the predicted number of open reading frames (ORFs) in C. albicans. The data revealed that CaNrg1 and CaTup1 regulate a different set of C. albicans genes from CaMig1 and CaTup1. This is consistent with the idea that CaMig1 and CaNrg1 target the CaTup1 repressor to specific subsets of C. albicans genes. However, CaMig1 and CaNrg1 repress other C. albicans genes in a CaTup1-independent fashion. The targets of CaMig1 and CaNrg1 repression, and phenotypic analyses of nrg1/nrg1 and mig1/mig1 mutants, indicate that these factors play differential roles in the regulation of metabolism, cellular morphogenesis and stress responses. Hence, the data provide important information both about the modes of action of these transcriptional regulators and their cellular roles. The transcript profiling data are available at http://www.pasteur.fr/recherche/unites/RIF/transcriptdata/

Retargeted adenoviruses for radiation-guided gene delivery

The combination of radiation with radiosensitizing gene delivery or oncolytic viruses promises to provide an advantage that could improve the therapeutic results for glioblastoma. X-rays can induce significant molecular changes in cancer cells. We isolated the GIRLRG peptide that binds to radiation-inducible 78 kDa glucose-regulated protein (GRP78), which is overexpressed on the plasma membranes of irradiated cancer cells and tumor-associated microvascular endothelial cells. The goal of our study was to improve tumor-specific adenovirus-mediated gene delivery by selectively targeting the adenovirus binding to this radiation-inducible protein. We employed an adenoviral fiber replacement approach to conduct a study of the targeting utility of GRP78-binding peptide. We have developed fiber-modified adenoviruses encoding the GRP78-binding peptide inserted into the fiber-fibritin. We have evaluated the reporter gene expression of fiber-modified adenoviruses in vitro using a panel of glioma cells and a human D54MG tumor xenograft model. The obtained results demonstrated that employment of the GRP78-binding peptide resulted in increased gene expression in irradiated tumors following infection with fiber-modified adenoviruses, compared with untreated tumor cells. These studies demonstrate the feasibility of adenoviral retargeting using the GRP78-binding peptide that selectively recognizes tumor cells responding to radiation treatment

In Vivo Systematic Analysis of Candida albicans Zn2-Cys6 Transcription Factors Mutants for Mice Organ Colonization

The incidence of fungal infections in immuno-compromised patients increased considerably over the last 30 years. New treatments are therefore needed against pathogenic fungi. With Candida albicans as a model, study of host-fungal pathogen interactions might reveal new sources of therapies. Transcription factors (TF) are of interest since they integrate signals from the host environment and participate in an adapted microbial response. TFs of the Zn2-Cys6 class are specific to fungi and are important regulators of fungal metabolism. This work analyzed the importance of the C. albicans Zn2-Cys6 TF for mice kidney colonization. For this purpose, 77 Zn2-Cys6 TF mutants were screened in a systemic mice model of infection by pools of 10 mutants. We developed a simple barcoding strategy to specifically detect each mutant DNA from mice kidney by quantitative PCR. Among the 77 TF mutant strains tested, eight showed a decreased colonization including mutants for orf19.3405, orf19.255, orf19.5133, RGT1, UGA3, orf19.6182, SEF1 and orf19.2646, and four an increased colonization including mutants for orf19.4166, ZFU2, orf19.1685 and UPC2 as compared to the isogenic wild type strain. Our approach was validated by comparable results obtained with the same animal model using a single mutant and the revertant for an ORF (orf19.2646) with still unknown functions. In an attempt to identify putative involvement of such TFs in already known C. albicans virulence mechanisms, we determined their in vitro susceptibility to pH, heat and oxidative stresses, as well as ability to produce hyphae and invade agar. A poor correlation was found between in vitro and in vivo assays, thus suggesting that TFs needed for mice kidney colonization may involve still unknown mechanisms. This large-scale analysis of mice organ colonization by C. albicans can now be extended to other mutant libraries since our in vivo screening strategy can be adapted to any preexisting mutants

Mitochondrial control of iron homeostasis - A genome wide analysis of gene expression in a yeast frataxin-deficient strain

Deletion of YFH1, the yeast frataxin homologue gene, elicits mitochondrial iron accumulation and alters cellular iron homeostasis. Here, we report a genome wide analysis of gene expression in a yfh1(Delta YFH1) deleted strain. Frataxin deficiency results in enhanced expression of some 70 genes including a set of genes, called the iron regulon, that are under the control of the iron-sensing transcription factor AFT1. Five new ALF1-dependent genes, YOR382w, YOR383c, YDR534c, YLR136c, and YLR205c were found. The first three genes presumably encode cell-wall glycosylphosphatidylinositol anchor proteins and exhibit a 30-100-fold increased expression. The triple deletion of these genes decreases efficiency in utilization of the iron of ferrioxamine B by the yeast cell. YLR136c bears homology to tristetraproline proteins, which are post-transcriptional regulators in mammalian cells. Deletion of YLR136c increases the mRNA levels of iron regulon members. YLR205c bears homology to heme oxygenases. Our data show that frataxin deficiency elicits iron mobilization from all iron sources in an AFT1-dependent manner. Wild-type and Delta YFH1 glycerol-grown cells exhibit similar high respiration rates, no mitochondrial iron accumulation, and high expression of the iron regulon, suggesting that under these conditions little iron is extruded from mitochondria. These data suggest that the activity of Yfh1p is not essential in cells grown on glycerol. This study has also revealed unexpected links between mitochondria and remote metabolic pathways since frataxin deficiency also enhances the expression of genes such as HSP30, that escape to AFT1 control. Finally, no oxidative stress gene is induced

A numerical algorithm for computing the inverse of a Toeplitz pentadiagonal matrix

In the current paper, we present a computationally efficient algorithm for obtaining the inverse of a pentadiogonal toeplitz matrix. Few conditions are required, and the algorithm is suited for implementation using computer algebra systems

Cis- and trans-acting elements determining induction of the genes of the gamma-aminobutyrate (GABA) utilization pathway in Saccharomyces cerevisiae.

In S. cerevisiae, gamma-aminobutyrate (GABA) induces transcription of the UGA genes required for its utilization as a nitrogen source. Analysis of the 5' region of the UGA1 and UGA4 genes led to the identification of a conserved GC-rich sequence (UASGABA) essential to induction by gamma-aminobutyrate. Alone, this UASGABA element also supported some levels of reporter gene transcription in the presence of gamma-aminobutyrate. To be effective, UASGABA requires two positive-acting proteins that both contain a Cys6-Zn2 type zinc-finger motif, namely pathway-specific Uga3p and pleiotropic Uga35p(Dal81p/DurLp). Further analysis of the UGA4 gene revealed that Gln3p, a global nitrogen regulatory protein containing a GATA zinc-finger domain, is required in order to reach high levels of gamma-aminobutyrate-induced transcription. The Gln3p factor exerts its function mainly through a cluster of 5'-GAT(A/T)A-3'(UASGATA) situated just upstream from UASGABA. The role of Gln3p is less predominant in UGA1 than in UGA4 gene expression. We propose that tight coupling between the UASGABA and UASGATA elements enables the cell to integrate, according to its nitrogen status, the induced expression levels of UGA4

Convergence in distribution of random compact sets in Polish spaces

Let [phi],[phi]1,[phi]2,... be a sequence of random compact sets on a complete and separable metric space (S,d). We assume that P{[phi]n[intersection]B=[empty set]}-->P{[phi][intersection]B=[empty set]} for all B in some suitable class and show that this assumption determines if the sequence {[phi]n} converges in distribution to [phi]. This is an extension to general Polish spaces of the weak convergence theory for random closed sets on locally compact Polish spaces found in Norberg [1984. Convergence and existence of random set distributions. Ann. Probab. 12, 726-732.]Convergence in distribution Random compact sets Polish spaces

KNR4 is a member of the PKC1 signalling pathway and genetically interacts with BCK2, a gene involved in cell progression in Saccharomyces cerevisiae

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