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Susceptibility of Hamsters to Clostridium difficile Isolates of Differing Toxinotype  [PDF]
Anthony M. Buckley, Janice Spencer, Lindsay M. Maclellan, Denise Candlish, June J. Irvine, Gillian R. Douce
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0064121
Abstract: Clostridium difficile is the most commonly associated cause of antibiotic associated disease (AAD), which caused ~21,000 cases of AAD in 2011 in the U.K. alone. The golden Syrian hamster model of CDI is an acute model displaying many of the clinical features of C. difficile disease. Using this model we characterised three clinical strains of C. difficile, all differing in toxinotype; CD1342 (PaLoc negative), M68 (toxinotype VIII) & BI-7 (toxinotype III). The naturally occurring non-toxic strain colonised all hamsters within 1-day post challenge (d.p.c.) with high-levels of spores being shed in the faeces of animals that appeared well throughout the entire experiment. However, some changes including increased neutrophil influx and unclotted red blood cells were observed at early time points despite the fact that the known C. difficile toxins (TcdA, TcdB and CDT) are absent from the genome. In contrast, hamsters challenged with strain M68 resulted in a 45% mortality rate, with those that survived challenge remaining highly colonised. It is currently unclear why some hamsters survive infection, as bacterial & toxin levels and histology scores were similar to those culled at a similar time-point. Hamsters challenged with strain BI-7 resulted in a rapid fatal infection in 100% of the hamsters approximately 26 hr post challenge. Severe caecal pathology, including transmural neutrophil infiltrates and extensive submucosal damage correlated with high levels of toxin measured in gut filtrates ex vivo. These data describes the infection kinetics and disease outcomes of 3 clinical C. difficile isolates differing in toxin carriage and provides additional insights to the role of each toxin in disease progression.
Cross-reactions between engineered xylose and galactose pathways in recombinant Saccharomyces cerevisiae
Rosa Garcia Sanchez, B?rbel Hahn-H?gerdal, Marie F Gorwa-Grauslund
Biotechnology for Biofuels , 2010, DOI: 10.1186/1754-6834-3-19
Abstract: In the absence of PGM2 overexpression, the combined overexpression of XK, the non-ox PPP and deletion of the GRE3 gene significantly delayed aerobic growth on galactose, whereas no difference was observed between the control strain and the xylose-engineered strain when the PGM2 gene was overexpressed. Under anaerobic conditions, the overexpression of the PGM2 gene increased the ethanol yield and the xylose consumption rate in medium containing xylose as the only carbon source. The possibility of Pgm2p acting as a xylose isomerase (XI) could be excluded by measuring the XI activity in both strains. The additional copy of the PGM2 gene also resulted in a shorter fermentation time during the co-consumption of galactose and xylose. However, the effect was lost upon addition of glucose to the growth medium.PGM2 overexpression was shown to benefit xylose and galactose fermentation, alone and in combination. In contrast, galactose fermentation was impaired in the engineered xylose-utilizing strain harbouring extra copies of the non-ox PPP genes and a deletion of the GRE3 gene, unless PGM2 was overexpressed. These cross-reactions are of particular relevance for the fermentation of mixed sugars from lignocellulosic feedstock.The use of renewable lignocellulosic biomass as raw material for the production of second-generation bioethanol is an alternative to sugar- and starch-containing feedstocks, which are also used for food and feed production. Lignocellulosic biomass can contain a significant fraction of pentose sugars such as xylose [1] that is not naturally fermented by the preferred microorganism for industrial bioethanol production, baker's yeast Saccharomyces cerevisiae [2]. Therefore recombinant xylose-fermenting S. cerevisiae strains have been generated to increase the overall ethanol yield from lignocellulosic biomass [3].Xylose utilization by S. cerevisiae has been achieved either by expression of the P. stipitis XYL1 and XYL2 genes encoding the NAD(P)H-dependent x
UDP-Galactose 4′-Epimerase Activities toward UDP-Gal and UDP-GalNAc Play Different Roles in the Development of Drosophila melanogaster  [PDF]
Jennifer M. I. Daenzer,Rebecca D. Sanders,Darwin Hang,Judith L. Fridovich-Keil
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1002721
Abstract: In both humans and Drosophila melanogaster, UDP-galactose 4′-epimerase (GALE) catalyzes two distinct reactions, interconverting UDP-galactose (UDP-gal) and UDP-glucose (UDP-glc) in the final step of the Leloir pathway of galactose metabolism, and also interconverting UDP-N-acetylgalactosamine (UDP-galNAc) and UDP-N-acetylglucosamine (UDP-glcNAc). All four of these UDP-sugars serve as vital substrates for glycosylation in metazoans. Partial loss of GALE in humans results in the spectrum disorder epimerase deficiency galactosemia; partial loss of GALE in Drosophila melanogaster also results in galactose-sensitivity, and complete loss in Drosophila is embryonic lethal. However, whether these outcomes in both humans and flies result from loss of one GALE activity, the other, or both has remained unknown. To address this question, we uncoupled the two activities in a Drosophila model, effectively replacing the endogenous dGALE with prokaryotic transgenes, one of which (Escherichia coli GALE) efficiently interconverts only UDP-gal/UDP-glc, and the other of which (Plesiomonas shigelloides wbgU) efficiently interconverts only UDP-galNAc/UDP-glcNAc. Our results demonstrate that both UDP-gal and UDP-galNAc activities of dGALE are required for Drosophila survival, although distinct roles for each activity can be seen in specific windows of developmental time or in response to a galactose challenge. By extension, these data also suggest that both activities might play distinct and essential roles in humans.
Signaling Pathways from the Endoplasmic Reticulum and Their Roles in Disease  [PDF]
Hisae Kadowaki,Hideki Nishitoh
Genes , 2013, DOI: 10.3390/genes4030306
Abstract: The endoplasmic reticulum (ER) is an organelle in which newly synthesized secretory and transmembrane proteins are assembled and folded into their correct tertiary structures. However, many of these ER proteins are misfolded as a result of various stimuli and gene mutations. The accumulation of misfolded proteins disrupts the function of the ER and induces ER stress. Eukaryotic cells possess a highly conserved signaling pathway, termed the unfolded protein response (UPR), to adapt and respond to ER stress conditions, thereby promoting cell survival. However, in the case of prolonged ER stress or UPR malfunction, apoptosis signaling is activated. Dysfunction of the UPR causes numerous conformational diseases, including neurodegenerative disease, metabolic disease, inflammatory disease, diabetes mellitus, cancer, and cardiovascular disease. Thus, ER stress-induced signaling pathways may serve as potent therapeutic targets of ER stress-related diseases. In this review, we will discuss the molecular mechanisms of the UPR and ER stress-induced apoptosis, as well as the possible roles of ER stress in several diseases.
Diverse Roles of JNK and MKK Pathways in the Brain  [PDF]
Tokiwa Yamasaki,Hiroshi Kawasaki,Hiroshi Nishina
Journal of Signal Transduction , 2012, DOI: 10.1155/2012/459265
Abstract: The c-Jun NH2-terminal protein kinase (JNK) plays important roles in a broad range of physiological processes. JNK is controlled by two upstream regulators, mitogen-activated protein kinase kinase (MKK) 4 and MKK7, which are activated by various MAPKKKs. Studies employing knockout mice have demonstrated that the JNK signaling pathway is involved in diverse phenomena in the brain, regulating brain development and maintenance as well as animal metabolism and behavior. Furthermore, examination of single or combined knockout mice of Jnk1, Jnk2, and Jnk3 has revealed both functional differences and redundancy among JNK1, JNK2, and JNK3. Phenotypic differences between knockouts of MKK4 and MKK7 have also been observed, suggesting that the JNK signaling pathway in the brain has a complex nature and is intricately regulated. This paper summarizes the functional properties of the major JNK signaling components in the developing and adult brain. 1. Introduction The c-Jun NH2-terminal protein kinases (JNKs, also called stress-activated protein kinases (SAPKs)) are members of the evolutionarily conserved mitogen-activated protein kinase (MAPK) family [1, 2]. The JNK subfamily consists of three related genes: Jnk1, Jnk2, and Jnk3. In mammals, the JNK1 and JNK2 proteins are ubiquitously expressed, whereas JNK3 is found almost exclusively in the brain and testis. JNKs are activated by many types of external stress, including heat shock, UV irradiation, and inflammatory cytokines. JNKs phosphorylate numerous important substrates, including the transcription factors AP-1 and c-Jun, various apoptotic proteins, and microtubule-associated proteins (MAPs) [3–7]. Through phosphorylation of these substrates, JNKs regulate gene expression governing stress responses as well as the normal physiological processes of cell proliferation, apoptosis, differentiation, and cell migration. Activation of JNK is catalyzed by two kinases, mitogen-activated protein kinase kinase (MKK) 4 and MKK7 [8–10]. Although MKK4 and MKK7 are both dual-specificity Thr and Tyr kinases, previous studies of JNK activation have shown that MKK4 preferentially phosphorylates the Tyr residue of the TPY motif in the activation loop of JNKs, whereas MKK7 preferentially phosphorylates the Thr residue [11, 12]. The activation of MKK4 and MKK7 is mediated by various MAPKKKs, including mixed lineage protein kinases (MLKs), apoptosis signal-regulating kinases (ASKs) and dual leucine zipper kinase (DLK) [13]. In addition to regulation by these upstream kinases, the JNK signaling pathway is modulated by various
The adaptive filter of the yeast galactose pathway  [PDF]
Serge Smidtas,Vincent Schachter,Francois Kepes
Quantitative Biology , 2006,
Abstract: In the yeast Saccharomyces cerevisiae, the interplay between galactose, Gal3p, Gal80p and Gal4p determines the transcriptional status of the genes required for galactose utilization. After an increase in galactose concentration, galactose molecules bind onto Gal3p. This event leads via Gal80p to the activation of Gal4p, which then induces GAL3 and GAL80 gene transcription. Here we propose a qualitative dynamic model, whereby these molecular interaction events represent the first two stages of a functional feedback loop that closes with the capture of activated Gal4p by newly synthesized Gal3p and Gal80p, decreasing transcriptional activation and creating again the protein complex that can bind incoming galactose molecules. Based on the differential time scales of faster protein interactions versus slower biosynthetic steps, this feedback loop functions as a derivative filter where galactose is the input step signal, and released Gal4p is the output derivative signal. One advantage of such a derivative filter is that GAL genes are expressed in proportion to the cellular requirement. Furthermore, this filter adaptively protects the cellular receptors from saturation by galactose, allowing cells to remain sensitive to variations in galactose concentrations rather than to absolute concentrations. Finally, this feedback loop, by allowing phosphorylation of some active Gal4p, may be essential to initiate the subsequent long-term response.
Metal ions in macrophage antimicrobial pathways: emerging roles for zinc and copper  [cached]
Sian?L. Stafford,Nilesh?J. Bokil,Maud?E. S. Achard,Ronan Kapetanovic
Bioscience Reports , 2013, DOI: 10.1042/bsr20130014
Abstract: The immunomodulatory and antimicrobial properties of zinc and copper have long been appreciated. In addition, these metal ions are also essential for microbial growth and survival. This presents opportunities for the host to either harness their antimicrobial properties or limit their availability as defence strategies. Recent studies have shed some light on mechanisms by which copper and zinc regulation contribute to host defence, but there remain many unanswered questions at the cellular and molecular levels. Here we review the roles of these two metal ions in providing protection against infectious diseases in vivo, and in regulating innate immune responses. In particular, we focus on studies implicating zinc and copper in macrophage antimicrobial pathways, as well as the specific host genes encoding zinc transporters (SLC30A, SLC39A family members) and CTRs (copper transporters, ATP7 family members) that may contribute to pathogen control by these cells.
Emerging Roles for Intersectin (ITSN) in Regulating Signaling and Disease Pathways  [PDF]
Michael P. Hunter,Angela Russo,John P. O'Bryan
International Journal of Molecular Sciences , 2013, DOI: 10.3390/ijms14047829
Abstract: Intersectins (ITSNs) represent a family of multi-domain adaptor proteins that regulate endocytosis and cell signaling. ITSN genes are highly conserved and present in all metazoan genomes examined thus far. Lower eukaryotes have only one ITSN gene, whereas higher eukaryotes have two ITSN genes. ITSN was first identified as an endocytic scaffold protein, and numerous studies reveal a conserved role for ITSN in endocytosis. Subsequently, ITSNs were found to regulate multiple signaling pathways including receptor tyrosine kinases (RTKs), GTPases, and phosphatidylinositol 3-kinase Class 2beta (PI3KC2β). ITSN has also been implicated in diseases such as Down Syndrome (DS), Alzheimer Disease (AD), and other neurodegenerative disorders. This review summarizes the evolutionary conservation of ITSN, the latest research on the role of ITSN in endocytosis, the emerging roles of ITSN in regulating cell signaling pathways, and the involvement of ITSN in human diseases such as DS, AD, and cancer.
Saponins from Aralia taibaiensis Attenuate D-Galactose-Induced Aging in Rats by Activating FOXO3a and Nrf2 Pathways  [PDF]
Ying-Na Li,Yu Guo,Miao-Miao Xi,Pei Yang,Xue-Ying Zhou,Shuang Yin,Chun-Xu Hai,Jin-Gang Li,Xu-Jun Qin
Oxidative Medicine and Cellular Longevity , 2014, DOI: 10.1155/2014/320513
Abstract: Reactive oxygen species (ROS) are closely related to the aging process. In our previous studies, we found that the saponins from Aralia taibaiensis have potent antioxidant activity, suggesting the potential protective activity on the aging. However, the protective effect of the saponins and the possible underlying molecular mechanism remain unknown. In the present study, we employed a D-galactose-induced aging rat model to investigate the protective effect of the saponins. We found that D-galactose treatment induced obvious aging-related changes such as the decreased thymus and spleen coefficients, the increased advanced glycation end products (AGEs) level, senescence-associated β-galactosidase (SAβ-gal) activity, and malondialdehyde (MDA) level. Further results showed that Forkhead box O3a (FOXO3a), nuclear factor-erythroid 2-related factor 2 (Nrf2), and their targeted antioxidants such as superoxide dismutase 2 (SOD2), catalase (CAT), glutathione reductase (GR), glutathione (GSH), glutamate-cysteine ligase (GCL), and heme oxygenase 1 (HO-1) were all inhibited in the aging rats induced by D-galactose treatment. Saponins supplementation showed effective protection on these changes. These results demonstrate that saponins from Aralia taibaiensis attenuate the D-galactose-induced rat aging. By activating FOXO3a and Nrf2 pathways, saponins increase their downstream multiple antioxidants expression and function, at least in part contributing to the protection on the D-galactose-induced aging in rats. 1. Introduction Aging is a biological process characterized by a progressive deterioration in physiological functions and metabolic processes that leads to morbidity and mortality. Numerous studies have shown that reactive oxygen species (ROS) play a critical role in the aging process since the free radical theory was first proposed by Harman in 1956 [1–4]. Even though there are contradictory reports whether or not increasing antioxidant capacity should increase organismal life span, it is recognized that increasing antioxidant capacity may at least attenuate the degree of aging and the related oxidative damages. ROS are O2-derived active free radicals, such as superoxide anion ( ), hydroxyl (HO?), peroxyl ( ), and alkoxyl (RO?) radicals, as well as nonradical species such as hydrogen peroxide (H2O2). Physiological levels of ROS are appreciated to function as signaling molecules to regulate a wide variety of physiology (e.g., signal transduction, gene expression, and redox regulation) [5], while high levels of ROS induce oxidative stress. The persistent
Timing and Variability of Galactose Metabolic Gene Activation Depend on the Rate of Environmental Change  [PDF]
Truong D. Nguyen-Huu?,Chinmaya Gupta?,Bo Ma?,William Ott?,Kre?imir Josi??,Matthew R. Bennett
PLOS Computational Biology , 2015, DOI: 10.1371/journal.pcbi.1004399
Abstract: Modulation of gene network activity allows cells to respond to changes in environmental conditions. For example, the galactose utilization network in Saccharomyces cerevisiae is activated by the presence of galactose but repressed by glucose. If both sugars are present, the yeast will first metabolize glucose, depleting it from the extracellular environment. Upon depletion of glucose, the genes encoding galactose metabolic proteins will activate. Here, we show that the rate at which glucose levels are depleted determines the timing and variability of galactose gene activation. Paradoxically, we find that Gal1p, an enzyme needed for galactose metabolism, accumulates more quickly if glucose is depleted slowly rather than taken away quickly. Furthermore, the variability of induction times in individual cells depends non-monotonically on the rate of glucose depletion and exhibits a minimum at intermediate depletion rates. Our mathematical modeling suggests that the dynamics of the metabolic transition from glucose to galactose are responsible for the variability in galactose gene activation. These findings demonstrate that environmental dynamics can determine the phenotypic outcome at both the single-cell and population levels.
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