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Sample records for metabolism final progress

  1. 2001 Gordon Research Conference on Archaea: Ecology [sic], Metabolism. Final progress report [agenda and attendee list

    SciTech Connect

    Daniels, Charles

    2001-08-10

    The Gordon Research Conference on Archaea: Ecology, Metabolism [and Molecular Biology] was held at Proctor Academy, Andover, New Hampshire, August 5-10, 2001. The conference was attended by 135 participants. The attendees represented the spectrum of endeavor in this field, coming from academia, industry, and government laboratories, and included US and foreign scientists, senior researchers, young investigators, and students. Emphasis was placed on current unpublished research and discussion of the future target areas in this field. There was a conscious effort to stimulate discussion about the key issues in the field today. Session topics included the following: Ecology and genetic elements; Genomics and evolution; Ecology, genomes and gene regulation; Replication and recombination; Chromatin and transcription; Gene regulation; Post-transcription processing; Biochemistry and metabolism; Proteomics and protein structure; Metabolism and physiology. The featured speaker addressed the topic: ''Archaeal viruses, witnesses of prebiotic evolution?''

  2. Final Progress Report

    SciTech Connect

    Josef Michl

    2011-10-31

    In this project we have established guidelines for the design on organic chromophores suitable for producing high triplet yields via singlet fission. We have proven their utility by identifying a chromophore of a structural class that had never been examined for singlet fission before, 1,3-diphenylisobenzofuran, and demonstrating in two independent ways that a thin layer of this material produces a triplet yield of 200% within experimental error. We have also designed a second chromophore of a very different type, again of a structural class that had not been examined for singlet fission before, and found that in a thin layer it produces a 70% triplet yield. Finally, we have enhanced the theoretical understanding of the quantum mechanical nature of the singlet fission process.

  3. Teratogen metabolism. Final report

    SciTech Connect

    Braun, A.G.

    1983-01-31

    This study indicates Thalidomide is metabolized by a classic cytochrome P450 monoxygenase system to a product which inhibits attachment of cells to concanavalin A coated dishes. Hydrolysis products of Thalidomide and its active metabolite do not inhibit attachement. We have initiated additional studies with methylene chloride extracts of particulate and of volatile hydrocarbon emissions of a domestic oil burner. These studies show low levels of inhibitory activity are uniformly present in these extracts.

  4. Final Performance Progress Report

    SciTech Connect

    Houldin, Joseph; Saboor, Veronica

    2016-03-30

    about assessing a company’s technical assets, broadening our view of the business to go beyond what they make or what NAICS code they have…to better understand their capacity, capability, and expertise, and to learn more about THEIR customers. Knowing more about the markets they serve can often provide insight into their level of technical knowledge and sophistication. Finally, in the spirit of realizing the intent of the Accelerator we strove to align and integrate the work and activities supported by the five funding agencies to leverage each effort. To that end, we include in the Integrated Work Plan a graphic that illustrates that integration. What follows is our summary report of the project, aggregated from prior reports.

  5. Progressive utterance-final lengthening in syllables with final fricatives.

    PubMed

    Berkovits, R

    1993-01-01

    The generality of the pattern of progressively greater lengthening within the utterance-final syllable, previously found with respect to final stops, is shown to extend to syllables in Hebrew with final fricatives. Seven native speakers of Hebrew read matched sentence pairs in which bisyllabic key words appeared in non-final and sentence-final position. Final fricatives showed almost four times as much utterance-final lengthening as the preceding stressed vowel. Final lengthening affected the duration of each segment of the final syllable, and also extended to the initial unstressed syllable of the final word. Though final fricatives showed more lengthening in sentence-final position than final-stop closures, no difference was found in the lengthening of the vowels preceding these consonants. The greater lengthening of the final fricative relative to the preceding vowel resulted in C/V ratios which failed to distinguish between the voiceless fricative in non-final position and the voiced fricative in utterance-final position. These results suggest that sentence position is taken into account in the perception of voicing, such that the C/V ratio applicable in non-final position is increased by a factor of two in final position.

  6. IRIS Final Technical Progress Report

    SciTech Connect

    M. D. Carelli

    2003-11-03

    OAK-B135 This NERI project, originally started as the Secure Transportable Autonomous Light Water Reactor (STAR-LW) and currently known as the International Reactor Innovative and Secure (IRIS) project, had the objective of investigating a novel type of water-cooled reactor to satisfy the Generation IV goals: fuel cycle sustainability, enhanced reliability and safety, and improved economics. The research objectives over the three-year (1999-2002) program were as follows: First year: Assess various design alternatives and establish main characteristics of a point design; Second year: Perform feasibility and engineering assessment of the selected design solutions; Third year: Complete reactor design and performance evaluation, including cost assessment These objectives were fully attained and actually they served to launch IRIS as a full fledged project for eventual commercial deployment. The program did not terminate in 2002 at the end of the NERI program, and has just entered in its fifth year. This has been made possible by the IRIS project participants which have grown from the original four member, two-countries team to the current twenty members, nine countries consortium. All the consortium members work under their own funding and it is estimated that the value of their in-kind contributions over the life of the project has been of the order of $30M. Currently, approximately 100 people worldwide are involved in the project. A very important constituency of the IRIS project is the academia: 7 universities from four countries are members of the consortium and five more US universities are associated via parallel NERI programs. To date, 97 students have worked or are working on IRIS; 59 IRIS-related graduate theses have been prepared or are in preparation, and 41 of these students have already graduated with M.S. (33) or Ph.D. (8) degrees. This ''final'' report (final only as far as the NERI program is concerned) summarizes the work performed in the first four

  7. Regulation of terpene metabolism. Progress report

    SciTech Connect

    Croteau, R.

    1983-01-01

    Progress is reported in the following research areas: function of monoterpene catabolism; pathways and enzymes of monoterpene catabolism; ultrastructure of oil glands; pathways and enzymes of monoterpene biosynthesis; and regulation of metabolism in peppermints. (ACR)

  8. 1995 PVUSA progress report. Final report

    SciTech Connect

    1996-03-01

    Photovoltaics for Utility Scale Applications (PVUSA) is a national public-private partnership that is assessing and demonstrating the viability of utility-scale (US) photovoltaic (PV) electric generation systems and recent developments in PV module technology. This report updates the project`s progress, reviews the status and performance of the various PV installations during 1995, summarizes key accomplishments and conclusions, and serves as the final report under Pacific Gas and Electric Company`s project management.

  9. Metabolic imbalance and prostate cancer progression

    PubMed Central

    Burton, Anya J; Tilling, Kate M; Holly, Jeff M; Hamdy, Freddie C; Rowlands, Mari-Anne E; Donovan, Jenny L; Martin, Richard M

    2010-01-01

    There is substantial evidence implicating environmental factors in the progression of prostate cancer. The metabolic consequences of a western lifestyle, such as obesity, insulin resistance and abnormal hormone production have been linked to prostate carcinogenesis through multiple overlapping pathways. Insulin resistance results in raised levels of the mitogens insulin and insulin-like growth factor-1, both of which may affect prostate cancer directly, or through their effect on other metabolic regulators. Obesity is associated with abnormal levels of adipocyte-derived peptides (adipokines), sex hormones and inflammatory cytokines. Adipokines have been shown to influence prostate cancer in both cell culture studies and observational, population level studies. Testosterone appears to have a complex relationship with prostate carcinogenesis, and it has been suggested that the lower levels associated with obesity may select for more aggressive androgen independent prostate cancer cells. Prostatic inflammation, caused by infection, urinary reflux or dietary toxins, frequently occurs prior to cancer development and may influence progression to advanced disease. High levels of ω-6 fatty acids in the diet may lead to the production of further inflammatory molecules that may influence prostate cancer. Increased fatty acid metabolism occurs within tumour cells, providing a potential target for prostate cancer therapies. Aberrations in amino acid metabolism have also been identified in prostate cancer tissue, particularly in metastatic cancer. This evidence indicates lifestyle interventions may be effective in reducing the incidence of clinical disease. However, much more research is needed before recommendations are made. PMID:21532839

  10. Final Technical Progress Report NANOSTRUCTURED MAGNETIC MATERIALS

    SciTech Connect

    Charles M. Falco

    2012-09-13

    This report describes progress made during the final phase of our DOE-funded program on Nanostructured Magnetic Materials. This period was quite productive, resulting in the submission of three papers and presentation of three talks at international conferences and three seminars at research institutions. Our DOE-funded research efforts were directed toward studies of magnetism at surfaces and interfaces in high-quality, well-characterized materials prepared by Molecular Beam Epitaxy (MBE) and sputtering. We have an exceptionally well-equipped laboratory for these studies, with: Thin film preparation equipment; Characterization equipment; Equipment to study magnetic properties of surfaces and ultra-thin magnetic films and interfaces in multi-layers and superlattices.

  11. Poultry waste digester. Final progress report

    SciTech Connect

    Shih, J.C.H.

    1983-01-01

    A simple and low-cost poultry waste digester (PWD) was constructed at North Carolina State University's Poultry Research Farm at Raleigh, N.C. The PWD system was designed to process a daily output of 600 kg of manure from 4000 caged laying hens. The system consisted of two digesters connected in series, a heating system, a hot water tank, and other metering equipment. The primary and secondary digesters were horizontal cylinders located partially below ground level. They were made of Red Mud plastic lining, supported in the insulated trenches, and covered with insulated roofs. The primary digester volume was 15 m/sup 3/ with an 8 m/sup 3/ liquid volume and a gas head-space above the liquid. The secondary digester volume was 30 m/sup 3/ with a 16 m/sup 3/ liquid volume. The temperature (50/sup 0/C) of the primary digester was maintained by the hot dilution water added with manure and a SolaRoll heating mat laid underneath the plastic lining. The design, operation, performance, energy balance, and economics of the digester are discussed and evaluated in this final progress report.

  12. (Regulation of teopene metabolism). Progress report. [Mentha piperita

    SciTech Connect

    Croteau, R.

    1985-01-01

    Progress in elucidating the biosynthesis of several monoterpenes in the peppermint is described. Tracer studies were performed to clarify metabolic pathways involved. Several growth regulators were screened for their influence on monoterpene composition and yield in peppermint and sage. (DT)

  13. [Carbon monoxide metabolism by photosynthetic bacteria]. Progress report

    SciTech Connect

    Not Available

    1989-12-31

    Research continued on the metabolism of carbon monoxide by Rhodospirillum rubrum. This report discusses progress on the activity, induction, inhibition, and spectroscopic analysis of the enzyme Carbon Monoxide Dehydrogenase. (CBS)

  14. (Regulation of terpene metabolism: Final report)

    SciTech Connect

    Croteau, R.

    1991-01-01

    We have completed studies on the key pathways of monoterpene biosynthesis in sage and peppermint, and on biosynthetic enzymes. We have confirmed that monoterpene turnover does occur, have deciphered the function of this process in plants, delineated the essential features of the catabolic pathways for camphor and menthone, and initiated studies on the relevant enzymology. We have made a strong case, based on analytical, in vivo, and in vitro studies, that terpene accumulation (yield and composition) depends on the balance between biosynthetic and catabolic events, and provided supporting evidence that these processes are developmentally regulated and very closely associated with senescence (collapse) of the oil glands. We have demonstrated that foliar applied bioregulators influence terpene composition and yield, probably by a combination of effects in oil gland development and by more direct alteration of enzyme levels. These studies have provided a practical means for modifying terpene composition and yield and, moreover, have provided a powerful approach to studying developmental regulation in intact plants, explants and tissue culture systems. We have thus developed the fundamental background knowledge needed as well as the necessary experimental tools for studying the regulation of terpene metabolism.

  15. [Regulation of terpene metabolism: Final report

    SciTech Connect

    Croteau, R.

    1991-12-31

    We have completed studies on the key pathways of monoterpene biosynthesis in sage and peppermint, and on biosynthetic enzymes. We have confirmed that monoterpene turnover does occur, have deciphered the function of this process in plants, delineated the essential features of the catabolic pathways for camphor and menthone, and initiated studies on the relevant enzymology. We have made a strong case, based on analytical, in vivo, and in vitro studies, that terpene accumulation (yield and composition) depends on the balance between biosynthetic and catabolic events, and provided supporting evidence that these processes are developmentally regulated and very closely associated with senescence (collapse) of the oil glands. We have demonstrated that foliar applied bioregulators influence terpene composition and yield, probably by a combination of effects in oil gland development and by more direct alteration of enzyme levels. These studies have provided a practical means for modifying terpene composition and yield and, moreover, have provided a powerful approach to studying developmental regulation in intact plants, explants and tissue culture systems. We have thus developed the fundamental background knowledge needed as well as the necessary experimental tools for studying the regulation of terpene metabolism.

  16. Regulation of terpene metabolism. Progress report, 1983

    SciTech Connect

    Croteau, R.

    1986-01-01

    Studies on the metabolism of terpenes by peppermint (Menta piperita) are described. The studies describe the characterization of enzymes involved in the biosynthesis and catabolism of terpenes and the ultrastructure of the oil glands. 10 refs. (DT)

  17. Progress in metabolic engineering of Saccharomyces cerevisiae.

    PubMed

    Nevoigt, Elke

    2008-09-01

    The traditional use of the yeast Saccharomyces cerevisiae in alcoholic fermentation has, over time, resulted in substantial accumulated knowledge concerning genetics, physiology, and biochemistry as well as genetic engineering and fermentation technologies. S. cerevisiae has become a platform organism for developing metabolic engineering strategies, methods, and tools. The current review discusses the relevance of several engineering strategies, such as rational and inverse metabolic engineering, evolutionary engineering, and global transcription machinery engineering, in yeast strain improvement. It also summarizes existing tools for fine-tuning and regulating enzyme activities and thus metabolic pathways. Recent examples of yeast metabolic engineering for food, beverage, and industrial biotechnology (bioethanol and bulk and fine chemicals) follow. S. cerevisiae currently enjoys increasing popularity as a production organism in industrial ("white") biotechnology due to its inherent tolerance of low pH values and high ethanol and inhibitor concentrations and its ability to grow anaerobically. Attention is paid to utilizing lignocellulosic biomass as a potential substrate.

  18. Progress in Metabolic Engineering of Saccharomyces cerevisiae

    PubMed Central

    Nevoigt, Elke

    2008-01-01

    Summary: The traditional use of the yeast Saccharomyces cerevisiae in alcoholic fermentation has, over time, resulted in substantial accumulated knowledge concerning genetics, physiology, and biochemistry as well as genetic engineering and fermentation technologies. S. cerevisiae has become a platform organism for developing metabolic engineering strategies, methods, and tools. The current review discusses the relevance of several engineering strategies, such as rational and inverse metabolic engineering, evolutionary engineering, and global transcription machinery engineering, in yeast strain improvement. It also summarizes existing tools for fine-tuning and regulating enzyme activities and thus metabolic pathways. Recent examples of yeast metabolic engineering for food, beverage, and industrial biotechnology (bioethanol and bulk and fine chemicals) follow. S. cerevisiae currently enjoys increasing popularity as a production organism in industrial (“white”) biotechnology due to its inherent tolerance of low pH values and high ethanol and inhibitor concentrations and its ability to grow anaerobically. Attention is paid to utilizing lignocellulosic biomass as a potential substrate. PMID:18772282

  19. Integrated Proteomic and Metabolic Analysis of Breast Cancer Progression

    PubMed Central

    Shaw, Patrick G.; Chaerkady, Raghothama; Wang, Tao; Vasilatos, Shauna; Huang, Yi; Van Houten, Bennett; Pandey, Akhilesh; Davidson, Nancy E.

    2013-01-01

    One of the most persistent hallmarks of cancer biology is the preference of tumor cells to derive energy through glycolysis as opposed to the more efficient process of oxidative phosphorylation (OXPHOS). However, little is known about the molecular cascades by which oncogenic pathways bring about this metabolic switch. We carried out a quantitative proteomic and metabolic analysis of the MCF10A derived cell line model of breast cancer progression that includes parental cells and derivatives representing three different tumor grades of Ras-driven cancer with a common genetic background. A SILAC (Stable Isotope Labeling by Amino acids in Cell culture) labeling strategy was used to quantify protein expression in conjunction with subcellular fractionation to measure dynamic subcellular localization in the nucleus, cytosol and mitochondria. Protein expression and localization across cell lines were compared to cellular metabolic rates as a measure of oxidative phosphorylation (OXPHOS), glycolysis and cellular ATP. Investigation of the metabolic capacity of the four cell lines revealed that cellular OXPHOS decreased with breast cancer progression independently of mitochondrial copy number or electron transport chain protein expression. Furthermore, glycolytic lactate secretion did not increase in accordance with cancer progression and decreasing OXPHOS capacity. However, the relative expression and subcellular enrichment of enzymes critical to lactate and pyruvate metabolism supported the observed extracellular acidification profiles. This analysis of metabolic dysfunction in cancer progression integrated with global protein expression and subcellular localization is a novel and useful technique for determining organelle-specific roles of proteins in disease. PMID:24086712

  20. Metabolic Reprograming of Mononuclear Phagocytes in Progressive Multiple Sclerosis

    PubMed Central

    Tannahill, Gillian Margaret; Iraci, Nunzio; Gaude, Edoardo; Frezza, Christian; Pluchino, Stefano

    2015-01-01

    Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system (CNS). Accumulation of brain damage in progressive MS is partly the result of mononuclear phagocytes (MPs) attacking myelin sheaths in the CNS. Although there is no cure yet for MS, significant advances have been made in the development of disease modifying agents. Unfortunately, most of these drugs fail to reverse established neurological deficits and can have adverse effects. Recent evidence suggests that MPs polarization is accompanied by profound metabolic changes, whereby pro-inflammatory MPs (M1) switch toward glycolysis, whereas anti-inflammatory MPs (M2) become more oxidative. It is therefore possible that reprograming MPs metabolism could affect their function and repress immune cell activation. This mini review describes the metabolic changes underpinning macrophages polarization and anticipates how metabolic re-education of MPs could be used for the treatment of MS. Key points: Inflammation in progressive MS is mediated primarily by MPs.Cell metabolism regulates the function of MPs.DMAs can re-educate the metabolism of MPs to promote healing. PMID:25814990

  1. Metabolic characterization of the natural progression of chronic hepatitis B.

    PubMed

    Schoeman, Johannes C; Hou, Jun; Harms, Amy C; Vreeken, Rob J; Berger, Ruud; Hankemeier, Thomas; Boonstra, Andre

    2016-06-10

    Worldwide, over 350 million people are chronically infected with the hepatitis B virus (HBV) and are at increased risk of developing progressive liver diseases. The confinement of HBV replication to the liver, which also acts as the central hub for metabolic and nutritional regulation, emphasizes the interlinked nature of host metabolism and the disease. Still, the metabolic processes operational during the distinct clinical phases of a chronic HBV infection-immune tolerant, immune active, inactive carrier, and HBeAg-negative hepatitis phases-remains unexplored. To investigate this, we conducted a targeted metabolomics approach on serum to determine the metabolic progression over the clinical phases of chronic HBV infection, using patient samples grouped based on their HBV DNA, alanine aminotransferase, and HBeAg serum levels. Our data illustrate the strength of metabolomics to provide insight into the metabolic dysregulation experienced during chronic HBV. The immune tolerant phase is characterized by the speculated viral hijacking of the glycerol-3-phosphate-NADH shuttle, explaining the reduced glycerophospholipid and increased plasmalogen species, indicating a strong link to HBV replication. The persisting impairment of the choline glycerophospholipids, even during the inactive carrier phase with minimal HBV activity, alludes to possible metabolic imprinting effects. The progression of chronic HBV is associated with increased concentrations of very long chain triglycerides together with citrulline and ornithine, reflective of a dysregulated urea cycle peaking in the HBV envelope antigen-negative phase. The work presented here will aid in future studies to (i) validate and understand the implication of these metabolic changes using a thorough systems biology approach, (ii) monitor and predict disease severity, as well as (iii) determine the therapeutic value of the glycerol-3-phosphate-NADH shuttle.

  2. Cancer progression by reprogrammed BCAA metabolism in myeloid leukaemia.

    PubMed

    Hattori, Ayuna; Tsunoda, Makoto; Konuma, Takaaki; Kobayashi, Masayuki; Nagy, Tamas; Glushka, John; Tayyari, Fariba; McSkimming, Daniel; Kannan, Natarajan; Tojo, Arinobu; Edison, Arthur S; Ito, Takahiro

    2017-05-25

    Reprogrammed cellular metabolism is a common characteristic observed in various cancers. However, whether metabolic changes directly regulate cancer development and progression remains poorly understood. Here we show that BCAT1, a cytosolic aminotransferase for branched-chain amino acids (BCAAs), is aberrantly activated and functionally required for chronic myeloid leukaemia (CML) in humans and in mouse models of CML. BCAT1 is upregulated during progression of CML and promotes BCAA production in leukaemia cells by aminating the branched-chain keto acids. Blocking BCAT1 gene expression or enzymatic activity induces cellular differentiation and impairs the propagation of blast crisis CML both in vitro and in vivo. Stable-isotope tracer experiments combined with nuclear magnetic resonance-based metabolic analysis demonstrate the intracellular production of BCAAs by BCAT1. Direct supplementation with BCAAs ameliorates the defects caused by BCAT1 knockdown, indicating that BCAT1 exerts its oncogenic function through BCAA production in blast crisis CML cells. Importantly, BCAT1 expression not only is activated in human blast crisis CML and de novo acute myeloid leukaemia, but also predicts disease outcome in patients. As an upstream regulator of BCAT1 expression, we identified Musashi2 (MSI2), an oncogenic RNA binding protein that is required for blast crisis CML. MSI2 is physically associated with the BCAT1 transcript and positively regulates its protein expression in leukaemia. Taken together, this work reveals that altered BCAA metabolism activated through the MSI2-BCAT1 axis drives cancer progression in myeloid leukaemia.

  3. Reprogramming of glucose metabolism in hepatocellular carcinoma: Progress and prospects

    PubMed Central

    Shang, Run-Ze; Qu, Shi-Bin; Wang, De-Sheng

    2016-01-01

    Hepatocellular carcinoma (HCC) is one of the most lethal cancers, and its rate of incidence is rising annually. Despite the progress in diagnosis and treatment, the overall prognoses of HCC patients remain dismal due to the difficulties in early diagnosis and the high level of tumor invasion, metastasis and recurrence. It is urgent to explore the underlying mechanism of HCC carcinogenesis and progression to find out the specific biomarkers for HCC early diagnosis and the promising target for HCC chemotherapy. Recently, the reprogramming of cancer metabolism has been identified as a hallmark of cancer. The shift from the oxidative phosphorylation metabolic pathway to the glycolysis pathway in HCC meets the demands of rapid cell proliferation and offers a favorable microenvironment for tumor progression. Such metabolic reprogramming could be considered as a critical link between the different HCC genotypes and phenotypes. The regulation of metabolic reprogramming in cancer is complex and may occur via genetic mutations and epigenetic modulations including oncogenes, tumor suppressor genes, signaling pathways, noncoding RNAs, and glycolytic enzymes etc. Understanding the regulatory mechanisms of glycolysis in HCC may enrich our knowledge of hepatocellular carcinogenesis and provide important foundations in the search for novel diagnostic biomarkers and promising therapeutic targets for HCC. PMID:28018100

  4. Reduced Renal Methylarginine Metabolism Protects against Progressive Kidney Damage

    PubMed Central

    Caplin, Ben; Boruc, Olga; Bruce-Cobbold, Claire; Cutillas, Pedro; Dormann, Dirk; Faull, Peter; Grossman, Rebecca C.; Khadayate, Sanjay; Mas, Valeria R.; Nitsch, Dorothea D.; Wang, Zhen; Norman, Jill T.; Wilcox, Christopher S.; Wheeler, David C.; Leiper, James

    2015-01-01

    Nitric oxide (NO) production is diminished in many patients with cardiovascular and renal disease. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthesis, and elevated plasma levels of ADMA are associated with poor outcomes. Dimethylarginine dimethylaminohydrolase-1 (DDAH1) is a methylarginine-metabolizing enzyme that reduces ADMA levels. We reported previously that a DDAH1 gene variant associated with increased renal DDAH1 mRNA transcription and lower plasma ADMA levels, but counterintuitively, a steeper rate of renal function decline. Here, we test the hypothesis that reduced renal-specific ADMA metabolism protects against progressive renal damage. Renal DDAH1 is expressed predominately within the proximal tubule. A novel proximal tubule–specific Ddah1 knockout (Ddah1PT−/−) mouse demonstrated tubular cell accumulation of ADMA and lower NO concentrations, but unaltered plasma ADMA concentrations. Ddah1PT−/− mice were protected from reduced kidney tissue mass, collagen deposition, and profibrotic cytokine expression in two independent renal injury models: folate nephropathy and unilateral ureteric obstruction. Furthermore, a study of two independent kidney transplant cohorts revealed higher levels of human renal allograft methylarginine-metabolizing enzyme gene expression associated with steeper function decline. We also report an association among DDAH1 expression, NO activity, and uromodulin expression supported by data from both animal and human studies, raising the possibility that kidney DDAH1 expression exacerbates renal injury through uromodulin-related mechanisms. Together, these data demonstrate that reduced renal tubular ADMA metabolism protects against progressive kidney function decline. Thus, circulating ADMA may be an imprecise marker of renal methylarginine metabolism, and therapeutic ADMA reduction may even be deleterious to kidney function. PMID:25855779

  5. Gender Differences in Adipocyte Metabolism and Liver Cancer Progression.

    PubMed

    Cheung, Otto K-W; Cheng, Alfred S-L

    2016-01-01

    Liver cancer is the third most common cancer type and the second leading cause of deaths in men. Large population studies have demonstrated remarkable gender disparities in the incidence and the cumulative risk of liver cancer. A number of emerging risk factors regarding metabolic alterations associated with obesity, diabetes and dyslipidemia have been ascribed to the progression of non-alcoholic fatty liver diseases (NAFLD) and ultimately liver cancer. The deregulation of fat metabolism derived from excessive insulin, glucose, and lipid promotes cancer-causing inflammatory signaling and oxidative stress, which eventually triggers the uncontrolled hepatocellular proliferation. This review presents the current standing on the gender differences in body fat compositions and their mechanistic linkage with the development of NAFLD-related liver cancer, with an emphasis on genetic, epigenetic and microRNA control. The potential roles of sex hormones in instructing adipocyte metabolic programs may help unravel the mechanisms underlying gender dimorphism in liver cancer and identify the metabolic targets for disease management.

  6. Gender Differences in Adipocyte Metabolism and Liver Cancer Progression

    PubMed Central

    Cheung, Otto K.-W.; Cheng, Alfred S.-L.

    2016-01-01

    Liver cancer is the third most common cancer type and the second leading cause of deaths in men. Large population studies have demonstrated remarkable gender disparities in the incidence and the cumulative risk of liver cancer. A number of emerging risk factors regarding metabolic alterations associated with obesity, diabetes and dyslipidemia have been ascribed to the progression of non-alcoholic fatty liver diseases (NAFLD) and ultimately liver cancer. The deregulation of fat metabolism derived from excessive insulin, glucose, and lipid promotes cancer-causing inflammatory signaling and oxidative stress, which eventually triggers the uncontrolled hepatocellular proliferation. This review presents the current standing on the gender differences in body fat compositions and their mechanistic linkage with the development of NAFLD-related liver cancer, with an emphasis on genetic, epigenetic and microRNA control. The potential roles of sex hormones in instructing adipocyte metabolic programs may help unravel the mechanisms underlying gender dimorphism in liver cancer and identify the metabolic targets for disease management. PMID:27703473

  7. Vitamin D, intermediary metabolism and prostate cancer tumor progression

    PubMed Central

    Wang, Wei-Lin W.; Tenniswood, Martin

    2014-01-01

    Epidemiological data have demonstrated an inverse association between serum vitamin D3 levels, cancer incidence and related mortality. However, the effects of vitamin D on prostate cancer biology and its utility for prevention of prostate cancer progression are not as well-defined. The data are often conflicting: some reports suggest that vitamin D3 induces apoptosis in androgen dependent prostate cancer cell lines, while others suggest that vitamin D3 only induces cell cycle arrest. Recent molecular studies have identified an extensive synergistic crosstalk between the vitamin D- and androgen-mediated mRNA and miRNA expression, adding an additional layer of post-transcriptional regulation to the known VDR- and AR-regulated gene activation. The Warburg effect, the inefficient metabolic pathway that converts glucose to lactate for rapid energy generation, is a phenomenon common to many different types of cancer. This process supports cell proliferation and promotes cancer progression via alteration of glucose, glutamine and lipid metabolism. Prostate cancer is a notable exception to this general process since the metabolic switch that occurs early during malignancy is the reverse of the Warburg effect. This “anti-Warburg effect” is due to the unique biology of normal prostate cells that harbor a truncated TCA cycle that is required to produce and secret citrate. In prostate cancer cells, the TCA cycle activity is restored and citrate oxidation is used to produce energy for cancer cell proliferation. 1,25(OH)2D3 and androgen together modulates the TCA cycle via transcriptional regulation of zinc transporters, suggesting that 1,25(OH)2D3 and androgen maintain normal prostate metabolism by blocking citrate oxidation. These data demonstrate the importance of androgens in the anti-proliferative effect of vitamin D in prostate cancer and highlight the importance of understanding the crosstalk between these two signaling pathways. PMID:24860512

  8. Hypermutation of DPYD Deregulates Pyrimidine Metabolism and Promotes Malignant Progression.

    PubMed

    Edwards, Lauren; Gupta, Rohit; Filipp, Fabian Volker

    2016-02-01

    New strategies are needed to diagnose and target human melanoma. To this end, genomic analyses was performed to assess somatic mutations and gene expression signatures using a large cohort of human skin cutaneous melanoma (SKCM) patients from The Cancer Genome Atlas (TCGA) project to identify critical differences between primary and metastatic tumors. Interestingly, pyrimidine metabolism is one of the major pathways to be significantly enriched and deregulated at the transcriptional level in melanoma progression. In addition, dihydropyrimidine dehydrogenase (DPYD) and other important pyrimidine-related genes: DPYS, AK9, CAD, CANT1, ENTPD1, NME6, NT5C1A, POLE, POLQ, POLR3B, PRIM2, REV3L, and UPP2 are significantly enriched in somatic mutations relative to the background mutation rate. Structural analysis of the DPYD protein dimer reveals a potential hotspot of recurring somatic mutations in the ligand-binding sites as well as the interfaces of protein domains that mediated electron transfer. Somatic mutations of DPYD are associated with upregulation of pyrimidine degradation, nucleotide synthesis, and nucleic acid processing while salvage and nucleotide conversion is downregulated in TCGA SKCM. At a systems biology level, somatic mutations of DPYD cause a switch in pyrimidine metabolism and promote gene expression of pyrimidine enzymes toward malignant progression. ©2015 American Association for Cancer Research.

  9. Progressive cardiovascular autonomic dysfunction in rats with evolving metabolic syndrome.

    PubMed

    Lehnen, A M; Leguisamo, N M; Casali, K R; Schaan, B D

    2013-06-01

    Metabolic syndrome is linked to increased cardiovascular mortality, which may be partially attributed to cardiac sympatho-vagal imbalance. However, autonomic changes were not evaluated during the metabolic syndrome development in a monosodium glutamate-induced animal model. We evaluate temporal changes in cardiovascular autonomic modulation in an animal model of metabolic syndrome. Eighteen neonate male spontaneously hypertensive rats (SHR) were treated with monosodium glutamate (MetS), and compared with Wistar-Kyoto (C) and saline-treated SHR (H). Lee index, insulin resistance and autonomic control (spectral analysis) were evaluated at 3 (3-mo), 6 (6-mo) and 9 (9-mo) months of age (compared by two-way ANOVA, p<0.05). Weight of visceral fat, Lee index and arterial pressure were higher in the MetS vs. C and H groups (p<0.001) at all ages. Heart rate variability (HRV) was decreased in the MetS and H groups at 3-mo and 9-mo vs. C. The LF component of HRV was reduced in the MetS group at 3-mo vs. C (p=0.032), and higher vs. C and H at 9-mo (p<0.001, all comparisons). H and MetS rats had a higher LF/HF index vs. C at 9-mo (p=0.001, all comparisons). The VLF component of systolic arterial pressure variability of the MetS was higher earlier (6-mo) than that of the H group. A reduction of 70%, 98% and 54% in αLF index of H and MetS rats vs. C, was observed at 3, 6 and 9 months, respectively. Metabolic syndrome and hypertension in rats evolve with progressive autonomic dysfunction (worst at 9 months), with specific derangements occurring very early.

  10. Comparative Analysis of Yeast Metabolic Network Models Highlights Progress, Opportunities for Metabolic Reconstruction

    PubMed Central

    Heavner, Benjamin D.; Price, Nathan D.

    2015-01-01

    We have compared 12 genome-scale models of the Saccharomyces cerevisiae metabolic network published since 2003 to evaluate progress in reconstruction of the yeast metabolic network. We compared the genomic coverage, overlap of annotated metabolites, predictive ability for single gene essentiality with a selection of model parameters, and biomass production predictions in simulated nutrient-limited conditions. We have also compared pairwise gene knockout essentiality predictions for 10 of these models. We found that varying approaches to model scope and annotation reflected the involvement of multiple research groups in model development; that single-gene essentiality predictions were affected by simulated medium, objective function, and the reference list of essential genes; and that predictive ability for single-gene essentiality did not correlate well with predictive ability for our reference list of synthetic lethal gene interactions (R = 0.159). We conclude that the reconstruction of the yeast metabolic network is indeed gradually improving through the iterative process of model development, and there remains great opportunity for advancing our understanding of biology through continued efforts to reconstruct the full biochemical reaction network that constitutes yeast metabolism. Additionally, we suggest that there is opportunity for refining the process of deriving a metabolic model from a metabolic network reconstruction to facilitate mechanistic investigation and discovery. This comparative study lays the groundwork for developing improved tools and formalized methods to quantitatively assess metabolic network reconstructions independently of any particular model application, which will facilitate ongoing efforts to advance our understanding of the relationship between genotype and cellular phenotype. PMID:26566239

  11. Fatty liver as a risk factor for progression from metabolically healthy to metabolically abnormal in non-overweight individuals.

    PubMed

    Hashimoto, Yoshitaka; Hamaguchi, Masahide; Fukuda, Takuya; Ohbora, Akihiro; Kojima, Takao; Fukui, Michiaki

    2017-07-01

    Recent studies identified that metabolically abnormal non-obese phenotype is a risk factor for cardiovascular diseases. However, little is known about risk factor for progression from metabolically healthy non-overweight to metabolically abnormal phenotype. We hypothesized that fatty liver had a clinical impact on progression from metabolically healthy non-overweight to metabolically abnormal phenotype. In this retrospective cohort study, 14,093 Japanese (7557 men and 6736 women), who received the health-checkup program from 2004 to 2012, were enrolled. Overweight and obesity were defined as body mass index 23.0-25.0 and ≥25.0 kg/m(2). Four metabolic factors (impaired fasting glucose, hypertension, hypertriglyceridemia and low high density lipoprotein-cholesterol concentration) were used for definition of metabolically healthy (less than two factors) or metabolically abnormal (two or more). We divided the participants into three groups: metabolically healthy non-overweight (9755 individuals, men/women = 4290/5465), metabolically healthy overweight (2547 individuals, 1800/747) and metabolically healthy obesity (1791 individuals, 1267/524). Fatty liver was diagnosed by ultrasonography. Over the median follow-up period of 5.3 years, 873 metabolically healthy non-overweight, 512 metabolically healthy overweight and 536 metabolically healthy obesity individuals progressed to metabolically abnormal. The adjusted hazard risks of fatty liver on progression were 1.49 (95% confidence interval 1.20-1.83, p = 0.005) in metabolically healthy non-overweight, 1.37 (1.12-1.66, p = 0.002) in metabolically healthy overweight and 1.38 (1.15-1.66, p < 0.001) in metabolically healthy obesity, after adjusting for age, sex, alcohol, smoking, exercise, impaired fasting glucose, hypertension, hypertriglyceridemia, low high density lipoprotein-cholesterol concentration, and abdominal obesity. Fatty liver is an independent risk factor for progression from metabolically

  12. Extra focal convective suppressing solar collector. Final technical progress report

    SciTech Connect

    1996-05-01

    This progress report describes work done on the Extra Focal Convective Suppressing Solar Collector. The topics of the report include sensor refinement for the tracking electronics, tracking controller refinement, system optics evaluation, absorber system material evaluation and performance, tracking hardware evaluation and refinement, and full scale prototype construction and testing.

  13. Hypermutation of DPYD Deregulates Pyrimidine Metabolism and Promotes Malignant Progression

    PubMed Central

    Edwards, Lauren; Gupta, Rohit; Filipp, Fabian V.

    2016-01-01

    New strategies are needed to diagnose and target human melanoma. To this end, genomic analyses was performed to assess somatic mutations and gene expression signatures using a large cohort of human skin cutaneous melanoma (SKCM) patients from The Cancer Genome Atlas (TCGA) project to identify critical differences between primary and metastatic tumors. Interestingly, pyrimidine metabolism is one of the major pathways to be significantly enriched and deregulated at the transcriptional level in melanoma progression. In addition, dihydropyrimidine dehydrogenase (DPYD) and other important pyrimidine-related genes: DPYS, AK9, CAD, CANT1, ENTPD1, NME6, NT5C1A, POLE, POLQ, POLR3B, PRIM2, REV3L, and UPP2 are significantly enriched in somatic mutations relative to the background mutation rate. Structural analysis of the DPYD protein dimer reveals a potential hotspot of recurring somatic mutations in the ligand binding sites as well as the interfaces of protein domains that mediated electron transfer. Somatic mutations of DPYD are associated with upregulation of pyrimidine degradation, nucleotide synthesis, and nucleic acid processing while salvage and nucleotide conversion is downregulated in TCGA SKCM. PMID:26609109

  14. Nuclear Physics Laboratory, University of Colorado, Final Progress Report

    SciTech Connect

    Kinney, E.R., ed.

    2004-05-12

    OAK-B135 The results and progress of research funded by DOE grant number DOE-FG03-95ER40913 at the University of Colorado at Boulder is described. Includes work performed at the HERMES experiment at DESY to study the quark structure of the nucleon and the hadronization process in nuclei, as well as hadronic reactions studied at LAMPF, KEK, and Fermilab.

  15. Effect of Pantethine on Ovarian Tumor Progression and Choline Metabolism

    PubMed Central

    Penet, Marie-France; Krishnamachary, Balaji; Wildes, Flonne; Mironchik, Yelena; Mezzanzanica, Delia; Podo, Franca; de Reggi, Max; Gharib, Bouchra; Bhujwalla, Zaver M.

    2016-01-01

    Epithelial ovarian cancer remains the leading cause of death from gynecologic malignancy among women in developed countries. New therapeutic strategies evaluated with relevant preclinical models are urgently needed to improve survival rates. Here, we have assessed the effect of pantethine on tumor growth and metabolism using magnetic resonance imaging and high-resolution proton magnetic resonance spectroscopy (MRS) in a model of ovarian cancer. To evaluate treatment strategies, it is important to use models that closely mimic tumor growth in humans. Therefore, we used an orthotopic model of ovarian cancer where a piece of tumor tissue, derived from an ovarian tumor xenograft, is engrafted directly onto the ovary of female mice, to maintain the tumor physiological environment. Treatment with pantethine, the precursor of vitamin B5 and active moiety of coenzyme A, was started when tumors were ~100 mm3 and consisted of a daily i.p. injection of 750 mg/kg in saline. Under these conditions, no side effects were observed. High-resolution 1H MRS was performed on treated and control tumor extracts. A dual-phase extraction method based on methanol/chloroform/water was used to obtain lipid and water-soluble fractions from the tumors. We also investigated effects on metastases and ascites formation. Pantethine treatment resulted in slower tumor progression, decreased levels of phosphocholine and phosphatidylcholine, and reduced metastases and ascites occurrence. In conclusion, pantethine represents a novel potential, well-tolerated, therapeutic tool in patients with ovarian cancer. Further in vivo preclinical studies are needed to confirm the beneficial role of pantethine and to better understand its mechanism of action. PMID:27900284

  16. The progress and challenges in metabolic research in China.

    PubMed

    Xu, Li; Ren, Hao; Gao, Guangang; Zhou, Linkang; Malik, Muhammad Arshad; Li, Peng

    2016-11-01

    Metabolism refers to a chain of chemical reactions converting food/fuel into energy to conduct cellular processes, including the synthesis of the building blocks of the body, such as proteins, lipids, nucleic acids, and carbohydrates, and the elimination of nitrogenous wastes. Metabolic chain reactions are catalyzed by various enzymes that are orchestrated in specific pathways. Metabolic pathways are important for organisms to grow and reproduce, maintain their structures, and respond to their environments. The coordinated regulation of metabolic pathways is important for maintaining metabolic homeostasis. The key steps and crucial enzymes in these pathways have been well investigated. However, the crucial regulatory factors and feedback (or feedforward) mechanisms of nutrients and intermediate metabolites of these biochemical processes remain to be fully elucidated. In addition, the roles of these enzymes and regulatory factors in controlling metabolism under physiological and pathological conditions are largely unknown. In particular, metabolic dysregulation is closely linked to the development of many diseases, including obesity, fatty liver, diabetes, cancer, cardiovascular, cerebrovascular, and neurodegenerative diseases. Therefore, metabolism, an old area of biochemistry, has attracted much attention in the last decade. With substantially increased government funding, the involvement of talented researchers, an improved infrastructure and scientific environment over the last ten years, the basic research in the field of metabolism in China has dramatically advanced. Here, we have summarized the major discoveries of scientists in China in the last decade in the area of metabolism. Due to the vast amount of information, we focused this review on specific aspects of metabolism, particularly metabolic regulation and lipid metabolism in vertebrates. © 2016 IUBMB Life, 68(11):847-853, 2016. © 2016 International Union of Biochemistry and Molecular Biology.

  17. Studies of high energy phenomena using muons. Final progress report

    SciTech Connect

    Hedin, D.; Kaplan, D.; Green, J.

    1993-05-01

    This report covers the activities of the NIU high energy physics group as supported by DOE contract AC02-87ER40368 during the period from July of 1990 to June of 1991 and from February to March 1992. Our group has three main efforts which will be discussed in this paper. The first is the D0 experiment at the Fermilab proton-antiproton collider, with major emphasis on its muon system. The second is the involvement of a portion of the group in Fermilab Experiment 789 which involved detection of meson decays. Finally, we discuss our work with the SDC collaboration at the SSC.

  18. Nuclear research with the electromagnetic probe. Final progress report

    SciTech Connect

    Meziani, Z.E.

    1994-10-01

    This is the final report on the research carried at Stanford University under contract DE-FG03-88ER40439. All the work accomplished under this grant is reported in the publications listed as part of the Principal Investigator bibliography at the end of this report. In the last few years our research was directed at some of the forefront questions in nuclear physics. We investigated the nuclear medium effects on the intrinsic properties of bound nucleons, specifically the ectromagnetic form factors. For these studies we performed a number of specialized electron scattering experiments with specific sensitivity to nuclear medium effects. At the next level of structure, elementary constituents of matter are quarks and gluons. Defining the energy regime where the quark-gluon description of nuclear systems becomes more relevant than the nucleon-meson description is of great importance in thoroughly understanding the nuclear structure. To explore this transition region, we studied the scaling region in the disintegration of the deuteron, the simplest nuclear system with high energy photons. Finally we focused on the investigation of the nucleon internal spin structure along with the test of the Bjoerken sum rule a fundamental sum rule of QCD.

  19. Energy efficient louver and blind. Final technical progress report

    SciTech Connect

    Khajavi, S.

    1996-10-14

    In the month of July, the authors completed the energy testing at Lawrence Berkeley Labs. The final testing was done with blinds in 15 degree position. This is a comfortable blind angle that allows for view of the outside while allowing for natural light to enter the room. It was found that the energy savings are much higher at this angle. At zero degree blind angle the savings were 150 W/sq. meter, in the 15 degree the heat gain is cut by 225 W/sq. meter. During the same period the heat gain in control chamber was 500 W. The heat gain reduction achieved in tests if used in commercial blinds, would result in an energy pay back period or one year and nine months.

  20. Alcohol fuels technology program: Byng public school. Final progress report

    SciTech Connect

    Not Available

    1982-04-01

    This is the final report for the Energy Grant awarded to Byng School for the purpose of building a distillery and producing fuel alcohol to be used in the school vehicles. The distillery has been built and alcohol has been produced and tested. At the time of the grant award, it was feared gasoline would soon retail for $4 per gallon. Fortunately, this has not been the case and the school is able to purchase gasoline for about 97 cents. As it cost 93 cents per gallon to produce alcohol in the distillery, the plan to produce alcohol for use in the busses has temporarily been set aside. We are holding the distillery ready for production as insurance against an increase in gasoline price. The plant and process are described.

  1. Final Progress Report for FG02-89ER14030

    SciTech Connect

    Hanson, Maureen R

    2011-10-26

    have provided more information on stromule formation and function and the actin-myosin machinery that mediates the intracellular trafficking that is required for photosynthesis and metabolism to operate efficiently within the plant cell.

  2. 1993 annual final progress report: July 1992 through June 1993

    SciTech Connect

    Rohatgi, A.; Crotty, G.; Chen, Z.; Sana, P.; Salami, J.; Doolittle, A.; Pang, A.; Pham, T.

    1994-11-01

    This is the first annual report since the Inauguration of the University Center of Excellence for Photovoltaics Research and Development (UCEP) at Georgia Tech. The essential objective of the Center is to improve the fundamental understanding of the science and technology of advanced PV devices and materials, to provide training and enrich the educational experience of students in the field, and to increase US competitiveness by providing guidelines to industry and DOE for achieving cost-effective and high efficiency PV devices. These objectives are to be accomplished through a combination of research and education. This report summarizes the technical accomplishments, including modeling, processing, and characterization of cast multicrystalline silicon solar cells; use of modeling and PCD measurements to develop a road map for progressing toward 20% multicrystalline and 25% single crystalline cells; the development of a novel PECVD SiN/SiO{sub 2} AR coating that also provides good surface passivation; PECVD deposited SiO{sub 2} films with record low S and D{sub it} at the SiO{sub 2}/Si interface; and educational activities and accomplishments.

  3. Mitochondrial metabolism and energy sensing in tumor progression.

    PubMed

    Iommarini, Luisa; Ghelli, Anna; Gasparre, Giuseppe; Porcelli, Anna Maria

    2017-02-14

    Energy homeostasis is pivotal for cell fate since metabolic regulation, cell proliferation and death are strongly dependent on the balance between catabolic and anabolic pathways. In particular, metabolic and energetic changes have been observed in cancer cells even before the discovery of oncogenes and tumor suppressors, but have been neglected for a long time. Instead, during the past 20years a renaissance of the study of tumor metabolism has led to a revised and more accurate sight of the metabolic landscape of cancer cells. In this scenario, genetic, biochemical and clinical evidences place mitochondria as key actors in cancer metabolic restructuring, not only because there are energy and biosynthetic intermediates manufacturers, but also because occurrence of mutations in metabolic enzymes encoded by both nuclear and mitochondrial DNA has been associated to different types of cancer. Here we provide an overview of the possible mechanisms modulating mitochondrial energy production and homeostasis in the intriguing scenario of neoplastic cells, focusing on the double-edged role of 5'-AMP activated protein kinase in cancer metabolism. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.

  4. Verification of Steelmaking Slags Iron Content Final Technical Progress Report

    SciTech Connect

    J.Y. Hwang

    2006-10-04

    The steel industry in the United States generates about 30 million tons of by-products each year, including 6 million tons of desulfurization and BOF/BOP slag. The recycling of BF (blast furnace) slag has made significant progress in past years with much of the material being utilized as construction aggregate and in cementitious applications. However, the recycling of desulfurization and BOF/BOP slags still faces many technical, economic, and environmental challenges. Previous efforts have focused on in-plant recycling of the by-products, achieving only limited success. As a result, large amounts of by-products of various qualities have been stockpiled at steel mills or disposed into landfills. After more than 50 years of stockpiling and landfilling, available mill site space has diminished and environmental constraints have increased. The prospect of conventionally landfilling of the material is a high cost option, a waste of true national resources, and an eternal material liability issue. The research effort has demonstrated that major inroads have been made in establishing the viability of recycling and reuse of the steelmaking slags. The research identified key components in the slags, developed technologies to separate the iron units and produce marketable products from the separation processes. Three products are generated from the technology developed in this research, including a high grade iron product containing about 90%Fe, a medium grade iron product containing about 60% Fe, and a low grade iron product containing less than 10% Fe. The high grade iron product contains primarily metallic iron and can be marketed as a replacement of pig iron or DRI (Direct Reduced Iron) for steel mills. The medium grade iron product contains both iron oxide and metallic iron and can be utilized as a substitute for the iron ore in the blast furnace. The low grade iron product is rich in calcium, magnesium and iron oxides and silicates. It has a sufficient lime value and

  5. Final Progress Report for Ionospheric Dusty Plasma In the Laboratory [Smokey Plasma

    SciTech Connect

    Robertson, Scott

    2010-07-31

    “Ionospheric Dusty Plasma in the Laboratory” is a research project with the purpose of finding and reproducing the characteristics of plasma in the polar mesosphere that is unusually cold (down to 140 K) and contains nanometer-sized dust particles. This final progress report summarizes results from four years of effort that include a final year with a no-cost extension.

  6. Kidney cancer progression linked to shifts in tumor metabolism

    Cancer.gov

    Investigators in The Cancer Genome Atlas Research Network have uncovered a connection between how tumor cells use energy from metabolic processes and the aggressiveness of the most common form of kidney cancer, clear cell renal cell carcinoma.

  7. [Regulation of terpene metabolism]. Annual progress report, March 15, 1988--March 14, 1989

    SciTech Connect

    Croteau, R.

    1989-12-31

    Progress in understanding of the metabolism of monoterpenes by peppermint and spearmint is recorded including the actions of two key enzymes, geranyl pyrophosphate:limonene cyclase and a UDP-glucose dependent glucosyl transferase; concerning the ultrastructure of oil gland senescence; enzyme subcellular localization; regulation of metabolism; and tissue culture systems.

  8. Glucose Metabolism in the Progression of Prostate Cancer

    PubMed Central

    Cutruzzolà, Francesca; Giardina, Giorgio; Marani, Marina; Macone, Alberto; Paiardini, Alessandro; Rinaldo, Serena; Paone, Alessio

    2017-01-01

    Prostate cancer is one of the most common types of cancer in western country males but the mechanisms involved in the transformation processes have not been clearly elucidated. Alteration in cellular metabolism in cancer cells is recognized as a hallmark of malignant transformation, although it is becoming clear that the biological features of metabolic reprogramming not only differ in different cancers, but also among different cells in a type of cancer. Normal prostate epithelial cells have a peculiar and very inefficient energy metabolism as they use glucose to synthesize citrate that is secreted as part of the seminal liquid. During the transformation process, prostate cancer cells modify their energy metabolism from inefficient to highly efficient, often taking advantage of the interaction with other cell types in the tumor microenvironment that are corrupted to produce and secrete metabolic intermediates used by cancer cells in catabolic and anabolic processes. We recapitulate the metabolic transformations occurring in the prostate from the normal cell to the metastasis, highlighting the role of the microenvironment and summarizing what is known on the molecular mechanisms involved in the process. PMID:28270771

  9. Studies in iodine metabolism: Progress report, July 1968-July 1969

    SciTech Connect

    Van Middlesworth, L.

    1987-01-01

    This document describes research on iodine metabolism conducted at the University of Tennessee, Memphis between July 1968 and July 1969. The author and his research team prepared autoradiographs of rat thyroids from individuals exposed to Iodine 125 in utero. Additional studies were conducted to determine the effect on hypothalamic lesions on iodide metabolism in rats; to evaluate an iodide-specific electrode for measuring iodide levels in blood or urine; and to study the amount of thyroxine absorption from the intestine. An analysis of bovine and sheep thyroids from eight locations provided additional information on global fallout levels. 21 figs., 2 tabs.

  10. Obesity and Cancer Progression: Is There a Role of Fatty Acid Metabolism?

    PubMed Central

    Balaban, Seher; Lee, Lisa S.; Schreuder, Mark; Hoy, Andrew J.

    2015-01-01

    Currently, there is renewed interest in elucidating the metabolic characteristics of cancer and how these characteristics may be exploited as therapeutic targets. Much attention has centered on glucose, glutamine and de novo lipogenesis, yet the metabolism of fatty acids that arise from extracellular, as well as intracellular, stores as triacylglycerol has received much less attention. This review focuses on the key pathways of fatty acid metabolism, including uptake, esterification, lipolysis, and mitochondrial oxidation, and how the regulators of these pathways are altered in cancer. Additionally, we discuss the potential link that fatty acid metabolism may serve between obesity and changes in cancer progression. PMID:25866768

  11. The Role of Central Metabolism in Prostate Cancer Progression

    DTIC Science & Technology

    2009-10-01

    polyunsaturated fatty acids ( PUFAs ) decreases PCa risk while ω- 6 intake increases risk. Work from our laboratories and others suggests that the...catabolic fatty acid pathways as well as possibly other pathways, modulate PCa. We hypothesize that by enriching the diet with ω-3 PUFAs PCa tumor...metabolites of dietary ω-3 and -6 PUFAs directly affect PCa and the ability to do so depends on intake and metabolic enzyme expression. Omega -3 and -6

  12. Androgen Metabolism in Progression to Androgen-Independent Prostate Cancer

    DTIC Science & Technology

    2011-06-01

    by research staff. Dose modifications for toxicity were outlined in the protocol. As mifepristone is metabolized by CYP4503A4, concomitant...phase II study of mifepristone (RU-486) in castration- resistant prostate cancer, with a correlative assessment of androgen-related hormones. BJU. Int...due to CYP17A1 blockade and not a toxic effect (Figure 2B). Abiraterone, a more specific CYP17A1 inhibitor, similarly decreased basal PSA and ERG

  13. Studies in iodine metabolism. Progress report, 1982-1983

    SciTech Connect

    Van Middlesworth, L.

    1983-01-01

    Research progress is reported for the period 1982 to 1983 in the following areas: (1) monitoring of animal thyroids for /sup 129/I, /sup 125/I, /sup 131/I, /sup 226/Ra, and /sup 228/Ra; and (2) neonatal hypo-l thyroidism in laboratory rats. (ACR)

  14. Measuring cell cycle progression kinetics with metabolic labeling and flow cytometry.

    PubMed

    Fleisig, Helen; Wong, Judy

    2012-05-22

    metabolic processes for each cell cycle stage are useful in blocking the progression of the cell cycle to the next stage. For example, the ribonucleotide reductase inhibitor hydroxyurea halts cells at the G1/S juncture by limiting the supply of deoxynucleotides, the building blocks of DNA. Other notable chemicals include treatment with aphidicolin, a polymerase alpha inhibitor for G1 arrest, treatment with colchicine and nocodazole, both of which interfere with mitotic spindle formation to halt cells in M phase and finally, treatment with the DNA chain terminator 5-fluorodeoxyridine to initiate S phase arrest. Treatment with these chemicals is an effective means of synchronizing an entire population of cells at a particular phase. With removal of the chemical, cells rejoin the cell cycle in unison. Treatment of the test agent following release from the cell cycle blocking chemical ensures that the drug response elicited is from a uniform, cell cycle stage-specific population. However, since many of the chemical synchronizers are known genotoxic compounds, teasing apart the participation of various response pathways (to the synchronizers vs. the test agents) is challenging. Here we describe a metabolic labeling method for following a subpopulation of actively cycling cells through their progression from the DNA replication phase, through to the division and separation of their daughter cells. Coupled with flow cytometry quantification, this protocol enables for measurement of kinetic progression of the cell cycle in the absence of either mechanically- or chemically- induced cellular stresses commonly associated with other cell cycle synchronization methodologies. In the following sections we will discuss the methodology, as well as some of its applications in biomedical research.

  15. 77 FR 26316 - Progress Energy Florida; Final Environmental Impact Statement for Combined Licenses for Levy...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-05-03

    ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Progress Energy Florida; Final Environmental Impact Statement for Combined Licenses for Levy Nuclear Plant Units 1 and 2 Notice is hereby given that the U.S. Nuclear Regulatory Commission (NRC or the Commission) and the U.S. Army Corps of Engineer...

  16. Energy integrated farm, including a solar methane digestor and alcohol plant. Final progress report

    SciTech Connect

    Meier, O.

    1982-01-01

    This final progress report summarizes the authors success in running an alcohol still. The still was to produce over 20,000 gallons of alcohol per year, the waste hot water would be used to heat a methane digestion system and for domestic space and water heating. Many problems were encountered and solutions were noted.

  17. Twin Owls Mountain Camp, A Summer Workshop for Colorado Young People. Final Report and Progress Report.

    ERIC Educational Resources Information Center

    Rocchio, Richard

    A progress report and final evaluation of the Twin Owls Mountain Camp - Summer Workshop for Colorado Young People are contained in this two-volume publication. Involved in the project was the operation of a summer camp for governmental/ecological education using a participative approach to the learning/teaching process. Also, it was to be…

  18. Operation Breakthrough, 1973-1974. Final Evaluation Report. And: Fourth Quarterly Progress Report for Operation Breakthrough.

    ERIC Educational Resources Information Center

    EDCON Associates, Willow Grove, PA.

    The document comprises the final evaluation report and the fourth quarterly progress report of Operation Breakthrough, an experimental demonstration project to upgrade Spanish-speaking workers in entry-level factory jobs. Ten classes at six sites with a total of 133 students were held; 53 attended at least 50 of the total 150 hours. Classes were…

  19. Metabolically Derived Human Ventilation Rates: A Revised Approach Based Upon Oxygen Consumption Rates (Final Report, 2009)

    EPA Science Inventory

    EPA announced the availability of the final report, Metabolically Derived Human Ventilation Rates: A Revised Approach Based Upon Oxygen Consumption Rates. This report provides a revised approach for calculating an individual's ventilation rate directly from their oxygen c...

  20. Metabolically Derived Human Ventilation Rates: A Revised Approach Based Upon Oxygen Consumption Rates (Final Report, 2009)

    EPA Science Inventory

    EPA announced the availability of the final report, Metabolically Derived Human Ventilation Rates: A Revised Approach Based Upon Oxygen Consumption Rates. This report provides a revised approach for calculating an individual's ventilation rate directly from their oxygen c...

  1. (Regulation of terpene metabolism). Progress report. [Mentha piperita

    SciTech Connect

    Croteau, R.

    1986-01-01

    Studies on the regulation of monoterpene metabolism in M. piperita were conducted. All of the steps from the acyclic precursor geranyl pyrophosphate to the various menthol isomers have been demonstrated. The first intermediate to accumulate in vivo is d-pulegone. The emphasis has been on the demonstration, partial purification and characterization of the relevant enzymes in the pathway. The studies on the isopiperitenol dehydrogenase and isopiperitenone isomerase have been completed. We are not studying the endocyclic double-bond reductase (NADPH-dependent) and, based on substrate specificity studies and the previously demonstrated isomerization of cis- isopulegone to pulegone, are now virtually convinced that the major pathway to menthol(s) in peppermint involves reduction of isopiperitenone to isopulegone and isomerication of isopulegone to pulegone. 16 refs., 1 fig.

  2. BCAT1 expression associates with ovarian cancer progression: possible implications in altered disease metabolism

    PubMed Central

    Wang, Zhi-Qiang; Faddaoui, Adnen; Bachvarova, Magdalena; Plante, Marie; Gregoire, Jean; Renaud, Marie-Claude; Sebastianelli, Alexandra; Guillemette, Chantal; Gobeil, Stéphane; Macdonald, Elizabeth; Vanderhyden, Barbara; Bachvarov, Dimcho

    2015-01-01

    Previously, we have identified the branched chain amino-acid transaminase 1 (BCAT1) gene as notably hypomethylated in low-malignant potential (LMP) and high-grade (HG) serous epithelial ovarian tumors, compared to normal ovarian tissues. Here we show that BCAT1 is strongly overexpressed in both LMP and HG serous epithelial ovarian tumors, which probably correlates with its hypomethylated status. Knockdown of the BCAT1 expression in epithelial ovarian cancer (EOC) cells led to sharp decrease of cell proliferation, migration and invasion and inhibited cell cycle progression. BCAT1 silencing was associated with the suppression of numerous genes and pathways known previously to be implicated in ovarian tumorigenesis, and the induction of some tumor suppressor genes (TSGs). Moreover, BCAT1 suppression resulted in downregulation of numerous genes implicated in lipid production and protein synthesis, suggesting its important role in controlling EOC metabolism. Further metabolomic analyses were indicative for significant depletion of most amino acids and different phospho- and sphingolipids following BCAT1 knockdown. Finally, BCAT1 suppression led to significantly prolonged survival time in xenograft model of advanced peritoneal EOC. Taken together, our findings provide new insights about the functional role of BCAT1 in ovarian carcinogenesis and identify this transaminase as a novel EOC biomarker and putative EOC therapeutic target. PMID:26372729

  3. BCAT1 expression associates with ovarian cancer progression: possible implications in altered disease metabolism.

    PubMed

    Wang, Zhi-Qiang; Faddaoui, Adnen; Bachvarova, Magdalena; Plante, Marie; Gregoire, Jean; Renaud, Marie-Claude; Sebastianelli, Alexandra; Guillemette, Chantal; Gobeil, Stéphane; Macdonald, Elizabeth; Vanderhyden, Barbara; Bachvarov, Dimcho

    2015-10-13

    Previously, we have identified the branched chain amino-acid transaminase 1 (BCAT1) gene as notably hypomethylated in low-malignant potential (LMP) and high-grade (HG) serous epithelial ovarian tumors, compared to normal ovarian tissues. Here we show that BCAT1 is strongly overexpressed in both LMP and HG serous epithelial ovarian tumors, which probably correlates with its hypomethylated status. Knockdown of the BCAT1 expression in epithelial ovarian cancer (EOC) cells led to sharp decrease of cell proliferation, migration and invasion and inhibited cell cycle progression. BCAT1 silencing was associated with the suppression of numerous genes and pathways known previously to be implicated in ovarian tumorigenesis, and the induction of some tumor suppressor genes (TSGs). Moreover, BCAT1 suppression resulted in downregulation of numerous genes implicated in lipid production and protein synthesis, suggesting its important role in controlling EOC metabolism. Further metabolomic analyses were indicative for significant depletion of most amino acids and different phospho- and sphingolipids following BCAT1 knockdown. Finally, BCAT1 suppression led to significantly prolonged survival time in xenograft model of advanced peritoneal EOC. Taken together, our findings provide new insights about the functional role of BCAT1 in ovarian carcinogenesis and identify this transaminase as a novel EOC biomarker and putative EOC therapeutic target.

  4. Systemic autophagy insufficiency compromises adaptation to metabolic stress and facilitates progression from obesity to diabetes.

    PubMed

    Lim, Yu-Mi; Lim, Hyejin; Hur, Kyu Yeon; Quan, Wenying; Lee, Hae-Youn; Cheon, Hwanju; Ryu, Dongryeol; Koo, Seung-Hoi; Kim, Hong Lim; Kim, Jin; Komatsu, Masaaki; Lee, Myung-Shik

    2014-09-26

    Despite growing interest in the relationship between autophagy and systemic metabolism, how global changes in autophagy affect metabolism remains unclear. Here we show that mice with global haploinsufficiency of an essential autophagy gene (Atg7(+/-) mice) do not show metabolic abnormalities but develop diabetes when crossed with ob/ob mice. Atg7(+/-)-ob/ob mice show aggravated insulin resistance with increased lipid content and inflammatory changes, suggesting that autophagy haploinsufficiency impairs the adaptive response to metabolic stress. We further demonstrate that intracellular lipid content and insulin resistance after lipid loading are increased as a result of autophagy insufficiency, and provide evidence for increased inflammasome activation in Atg7(+/-)-ob/ob mice. Imatinib or trehalose improves metabolic parameters of Atg7(+/-)-ob/ob mice and enhances autophagic flux. These results suggest that systemic autophagy insufficiency could be a factor in the progression from obesity to diabetes, and autophagy modulators have therapeutic potential against diabetes associated with obesity and inflammation.

  5. Mitochondrial-associated metabolic disorders: foundations, pathologies and recent progress.

    PubMed

    McInnes, Joseph

    2013-10-12

    Research in the last decade has revolutionized the way in which we view mitochondria. Mitochondria are no longer viewed solely as cellular powerhouses; rather, mitochondria are now understood to be vibrant, mobile structures, constantly undergoing fusion and fission, and engaging in intimate interactions with other cellular compartments and structures. Findings have implicated mitochondria in a wide variety of cellular processes and molecular interactions, such as calcium buffering, lipid flux, and intracellular signaling. As such, it does not come as a surprise that an increasing number of human pathologies have been associated with functional defects in mitochondria. The difficulty in understanding and treating human pathologies caused by mitochondrial dysfunction arises from the complex relationships between mitochondria and other cellular processes, as well as the genetic background of such diseases. This review attempts to provide a summary of the background knowledge and recent developments in mitochondrial processes relating to mitochondrial-associated metabolic diseases arising from defects or deficiencies in mitochondrial function, as well as insights into current and future avenues for investigation.

  6. Adipose Tissue in Metabolic Syndrome: Onset and Progression of Atherosclerosis.

    PubMed

    Luna-Luna, María; Medina-Urrutia, Aida; Vargas-Alarcón, Gilberto; Coss-Rovirosa, Fernanda; Vargas-Barrón, Jesús; Pérez-Méndez, Óscar

    2015-07-01

    Metabolic syndrome (MetS) should be considered a clinical entity when its different symptoms share a common etiology: obesity/insulin resistance as a result of a multi-organ dysfunction. The main interest in treating MetS as a clinical entity is that the addition of its components drastically increases the risk of atherosclerosis. In MetS, the adipose tissue plays a central role along with an unbalanced gut microbiome, which has become relevant in recent years. Once visceral adipose tissue (VAT) increases, dyslipidemia and endothelial dysfunction follow as additive risk factors. However, when the nonalcoholic fatty liver is present, risk of a cardiovascular event is highly augmented. Epicardial adipose tissue (EAT) seems to increase simultaneously with the VAT. In this context, the former may play a more important role in the development of the atherosclerotic plaque than the latter. Hence, EAT may act as a paracrine tissue vis-à-vis the coronary arteries favoring the local inflammation and the atheroma calcification.

  7. Metabolism of fatty acids by Syntrophomonas wolfei. Progress report, March 15, 1983-July 15, 1984

    SciTech Connect

    McInerney, M.J.

    1984-01-01

    Progress is reported in the following research areas: (1) metabolic studies of Syntrophomonas wolfei; (2) evidence for a carrier-mediated system for the electrogenic excretion of acetate in Desulfovibrio desulfurecans; and (3) development of a method to positively select for nitrous oxide producing bacteria. (ACR)

  8. Mutations in mitochondrial enzyme GPT2 cause metabolic dysfunction and neurological disease with developmental and progressive features

    PubMed Central

    Ouyang, Qing; Nakayama, Tojo; Baytas, Ozan; Davidson, Shawn M.; Yang, Chendong; Schmidt, Michael; Lizarraga, Sofia B.; Mishra, Sasmita; EI-Quessny, Malak; Niaz, Saima; Gul Butt, Mirrat; Imran Murtaza, Syed; Javed, Afzal; Chaudhry, Haroon Rashid; Vaughan, Dylan J.; Hill, R. Sean; Partlow, Jennifer N.; Yoo, Seung-Yun; Lam, Anh-Thu N.; Nasir, Ramzi; Al-Saffar, Muna; Barkovich, A. James; Schwede, Matthew; Nagpal, Shailender; Rajab, Anna; DeBerardinis, Ralph J.; Housman, David E.; Mochida, Ganeshwaran H.; Morrow, Eric M.

    2016-01-01

    Mutations that cause neurological phenotypes are highly informative with regard to mechanisms governing human brain function and disease. We report autosomal recessive mutations in the enzyme glutamate pyruvate transaminase 2 (GPT2) in large kindreds initially ascertained for intellectual and developmental disability (IDD). GPT2 [also known as alanine transaminase 2 (ALT2)] is one of two related transaminases that catalyze the reversible addition of an amino group from glutamate to pyruvate, yielding alanine and α-ketoglutarate. In addition to IDD, all affected individuals show postnatal microcephaly and ∼80% of those followed over time show progressive motor symptoms, a spastic paraplegia. Homozygous nonsense p.Arg404* and missense p.Pro272Leu mutations are shown biochemically to be loss of function. The GPT2 gene demonstrates increasing expression in brain in the early postnatal period, and GPT2 protein localizes to mitochondria. Akin to the human phenotype, Gpt2-null mice exhibit reduced brain growth. Through metabolomics and direct isotope tracing experiments, we find a number of metabolic abnormalities associated with loss of Gpt2. These include defects in amino acid metabolism such as low alanine levels and elevated essential amino acids. Also, we find defects in anaplerosis, the metabolic process involved in replenishing TCA cycle intermediates. Finally, mutant brains demonstrate misregulated metabolites in pathways implicated in neuroprotective mechanisms previously associated with neurodegenerative disorders. Overall, our data reveal an important role for the GPT2 enzyme in mitochondrial metabolism with relevance to developmental as well as potentially to neurodegenerative mechanisms. PMID:27601654

  9. Progression of Cardio-Metabolic Risk Factors in Subjects Born Small and Large for Gestational Age

    PubMed Central

    Chiavaroli, Valentina; Marcovecchio, Maria Loredana; de Giorgis, Tommaso; Diesse, Laura; Chiarelli, Francesco; Mohn, Angelika

    2014-01-01

    Background Subjects born small (SGA) and large (LGA) for gestational age have an increased risk of cardio-metabolic alterations already during prepuberty. Nevertheless, the progression of their cardio-metabolic profile from childhood to adolescence has not been fully explored. Our aim was to assess potential changes in the cardio-metabolic profile from childhood to adolescence in subjects born SGA and LGA compared to those born appropriate (AGA) for gestational age. Methods This longitudinal study included 35 AGA, 24 SGA and 31 LGA subjects evaluated during childhood (mean age (±SD) 8.4±1.4 yr) and then re-assessed during adolescence (mean age 13.3±1.8 yr). BMI, blood pressure, insulin resistance (fasting insulin, HOMA-IR) and lipids were assessed. A cardio-metabolic risk z-score was applied and this consisted in calculating the sum of sex-specific z-scores for BMI, blood pressure, HOMA-IR, triglycerides and triglycerides:high-density lipoprotein cholesterol ratio. Results Fasting insulin and HOMA-IR were higher in SGA and LGA than AGA subjects both during childhood (all P<0.01) and adolescence (all P<0.01). Similarly, the clustered cardio-metabolic risk score was higher in SGA and LGA than AGA children (both P<0.05), and these differences among groups increased during adolescence (both P<0.05). Of note, a progression of the clustered cardio-metabolic risk score was observed from childhood to adolescence within SGA and within LGA subjects (both P<0.05). Conclusions SGA and LGA subjects showed an adverse cardio-metabolic profile during childhood when compared to AGA peers, with a worsening of this profile during adolescence. These findings indicate an overtime progression of insulin resistance and overall estimated cardiovascular risk from childhood to adolescence in SGA and LGA populations. PMID:25117750

  10. Role of abnormal lipid metabolism in development, progression, diagnosis and therapy of pancreatic cancer

    PubMed Central

    Swierczynski, Julian; Hebanowska, Areta; Sledzinski, Tomasz

    2014-01-01

    There is growing evidence that metabolic alterations play an important role in cancer development and progression. The metabolism of cancer cells is reprogrammed in order to support their rapid proliferation. Elevated fatty acid synthesis is one of the most important aberrations of cancer cell metabolism. An enhancement of fatty acids synthesis is required both for carcinogenesis and cancer cell survival, as inhibition of key lipogenic enzymes slows down the growth of tumor cells and impairs their survival. Based on the data that serum fatty acid synthase (FASN), also known as oncoantigen 519, is elevated in patients with certain types of cancer, its serum level was proposed as a marker of neoplasia. This review aims to demonstrate the changes in lipid metabolism and other metabolic processes associated with lipid metabolism in pancreatic ductal adenocarcinoma (PDAC), the most common pancreatic neoplasm, characterized by high mortality. We also addressed the influence of some oncogenic factors and tumor suppressors on pancreatic cancer cell metabolism. Additionally the review discusses the potential role of elevated lipid synthesis in diagnosis and treatment of pancreatic cancer. In particular, FASN is a viable candidate for indicator of pathologic state, marker of neoplasia, as well as, pharmacological treatment target in pancreatic cancer. Recent research showed that, in addition to lipogenesis, certain cancer cells can use fatty acids from circulation, derived from diet (chylomicrons), synthesized in liver, or released from adipose tissue for their growth. Thus, the interactions between de novo lipogenesis and uptake of fatty acids from circulation by PDAC cells require further investigation. PMID:24605027

  11. The Role of Mitochondria in Cancer Induction, Progression and Changes in Metabolism.

    PubMed

    Rogalinska, Malgorzata

    2016-01-01

    Mitochondria play important roles as energetic centers. Mutations in mitochondrial DNA (mtDNA) were found in several diseases, including cancers. Studies on cytoplasmic hybrids (cybrids) confirm that directed mutation introduced into mtDNA could be a reason for cancer induction. Mitochondria could also be a factor linking cancer transformation and progression. The importance of mitochondria in cancer also confirms their involvement in the resistance to treatment. Resistance to treatment of cancer cells can frequently be a reason for glycolysis acceleration. It could be explained by cancer cells' high proliferation index and high energy request. The involvement of mitochondria in metabolic disturbances of several metabolic diseases, including cancers, was reported. These data confirm that cancer induction, as well as cancer progression, could have metabolic roots. The aberrant products observed in prostate cells involved in the Krebs cycle could promote cancer progression. These multiple relationships between alterations on a genetic level translated into disturbances in cellular metabolism and their potential relation with epigenetic control of gene expression make cancerogenesis more complicated and prognoses' success in studies on cancer etiology more distant in time.

  12. Control of sugar transport and metabolism in Zymomonas mobilis. Final report

    SciTech Connect

    Conway, T.

    1995-09-01

    This research deals with the physiology and genetics of sugar transport and metabolic control in Zymomonas mobilis. The specific objectives of the grant as as follows: First, the complex interactions of transcriptional, post-transcriptional and translational control mechanisms on regulation of the glf operon will be investigated. Second, the structure and function of the unique glucose facilitator will be examined by a combination of in vitro and in vivo approaches, making use of the genetically reconstituted system in E. coli. Third, the possibility that physical association or indirect interactions between the glucose facilitator and glucokinase are involved in metabolic control will be analyzed. Fourth, the Z. mobilis glucose transport and phosphorylation system will be utilized to metabolically engineer recombinant E. coli with altered cell pool metabolite profiles. Work on the third and fourth objectives is complete, work on the first and second objectives is progressing nicely. Publication of this work has been admittedly slow, due primarily to a change n location of the research program from the University of Nebraska to The Ohio State University. However, it should be noted that much of the unpublished data outlined below represented completed studies, and are contained in graduate student theses which are being prepared for submission this summer. Since a full year remains in the current funding period, and the new laboratory is now up and running, we fully expect to make reasonable progress on the remaining objectives and to publish the results in a timely fashion.

  13. Fiber-optic, anti-cycling, high pressure sodium street light control. Final technical progress report

    SciTech Connect

    1995-05-01

    This is the Final Technical Progress Report on a project to develop and market a Fiber-Optic Anti-Cycling High Pressure Sodium Street Light Control. The field test units are now being made with a single vertical PC board design and contains a computer-on-a-chip or PROM IC to take the place of the majority of the components previously contained on the upper logic board. This will reduce the final costs of the unit when it is in production and increase the control`s flexibility. The authors have finished the soft tooling and have made the 400 plastic cases for the field test units. The new configuration of the cases entails a simplified design of the control shell which will have the lenses cast in place. The shell and base plastics are now finished and in final assembly awaiting the completion of the PC boards.

  14. The Warburg effect in tumor progression: Mitochondrial oxidative metabolism as an anti-metastasis mechanism

    PubMed Central

    Lu, Jianrong; Tan, Ming; Cai, Qingsong

    2014-01-01

    Compared to normal cells, cancer cells strongly upregulate glucose uptake and glycolysis to give rise to increased yield of intermediate glycolytic metabolites and the end product pyruvate. Moreover, glycolysis is uncoupled from the mitochondrial tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) in cancer cells. Consequently, the majority of glycolysis-derived pyruvate is diverted to lactate fermentation and kept away from mitochondrial oxidative metabolism. This metabolic phenotype is known as the Warburg effect. While it has become widely accepted that the glycolytic intermediates provide essential anabolic support for cell proliferation and tumor growth, it remains largely elusive whether and how the Warburg metabolic phenotype may play a role in tumor progression. We hereby review the cause and consequence of the restrained oxidative metabolism, in particular in tumor metastasis. Cells change or lose their extracellular matrix during the metastatic process. Inadequate/inappropriate matrix attachment generates reactive oxygen species (ROS) and causes a specific type of cell death, termed anoikis, in normal cells. Although anoikis is a barrier to metastasis, cancer cells have often acquired elevated threshold for anoikis and hence heightened metastatic potential. As ROS are inherent byproducts of oxidative metabolism, forced stimulation of glucose oxidation in cancer cells raises oxidative stress and restores cells’ sensitivity to anoikis. Therefore, by limiting the pyruvate flux into mitochondrial oxidative metabolism, the Warburg effect enables cancer cells to avoid excess ROS generation from mitochondrial respiration and thus gain increased anoikis resistance and survival advantage for metastasis. Consistent with this notion, pro-metastatic transcription factors HIF and Snail attenuate oxidative metabolism, whereas tumor suppressor p53 and metastasis suppressor KISS1 promote mitochondrial oxidation. Collectively, these findings reveal

  15. The Warburg effect in tumor progression: mitochondrial oxidative metabolism as an anti-metastasis mechanism.

    PubMed

    Lu, Jianrong; Tan, Ming; Cai, Qingsong

    2015-01-28

    Compared to normal cells, cancer cells strongly upregulate glucose uptake and glycolysis to give rise to increased yield of intermediate glycolytic metabolites and the end product pyruvate. Moreover, glycolysis is uncoupled from the mitochondrial tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) in cancer cells. Consequently, the majority of glycolysis-derived pyruvate is diverted to lactate fermentation and kept away from mitochondrial oxidative metabolism. This metabolic phenotype is known as the Warburg effect. While it has become widely accepted that the glycolytic intermediates provide essential anabolic support for cell proliferation and tumor growth, it remains largely elusive whether and how the Warburg metabolic phenotype may play a role in tumor progression. We hereby review the cause and consequence of the restrained oxidative metabolism, in particular in the context of tumor metastasis. Cells change or lose their extracellular matrix during the metastatic process. Inadequate/inappropriate matrix attachment generates reactive oxygen species (ROS) and causes a specific type of cell death, termed anoikis, in normal cells. Although anoikis is a barrier to metastasis, cancer cells have often acquired elevated threshold for anoikis and hence heightened metastatic potential. As ROS are inherent byproducts of oxidative metabolism, forced stimulation of glucose oxidation in cancer cells raises oxidative stress and restores cells' sensitivity to anoikis. Therefore, by limiting the pyruvate flux into mitochondrial oxidative metabolism, the Warburg effect enables cancer cells to avoid excess ROS generation from mitochondrial respiration and thus gain increased anoikis resistance and survival advantage for metastasis. Consistent with this notion, pro-metastatic transcription factors HIF and Snail attenuate oxidative metabolism, whereas tumor suppressor p53 and metastasis suppressor KISS1 promote mitochondrial oxidation. Collectively, these

  16. Hippocampus neuronal metabolic gene expression outperforms whole tissue data in accurately predicting Alzheimer's disease progression.

    PubMed

    Stempler, Shiri; Waldman, Yedael Y; Wolf, Lior; Ruppin, Eytan

    2012-09-01

    Numerous metabolic alterations are associated with the impairment of brain cells in Alzheimer's disease (AD). Here we use gene expression microarrays of both whole hippocampus tissue and hippocampal neurons of AD patients to investigate the ability of metabolic gene expression to predict AD progression and its cognitive decline. We find that the prediction accuracy of different AD stages is markedly higher when using neuronal expression data (0.9) than when using whole tissue expression (0.76). Furthermore, the metabolic genes' expression is shown to be as effective in predicting AD severity as the entire gene list. Remarkably, a regression model from hippocampal metabolic gene expression leads to a marked correlation of 0.57 with the Mini-Mental State Examination cognitive score. Notably, the expression of top predictive neuronal genes in AD is significantly higher than that of other metabolic genes in the brains of healthy subjects. All together, the analyses point to a subset of metabolic genes that is strongly associated with normal brain functioning and whose disruption plays a major role in AD.

  17. 40 CFR 60.1630 - How do I comply with the increment of progress for achieving final compliance?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... final control plan. (b) Connect the air pollution control equipment with the municipal waste combustion unit identified in the final control plan and complete process changes to the municipal waste... progress for achieving final compliance? 60.1630 Section 60.1630 Protection of Environment ENVIRONMENTAL...

  18. Nonlinear and Nonideal MHD. Final annual progress report, January 1, 2003 through December 31, 2003

    SciTech Connect

    Callen, James D

    2003-04-30

    This is the third and final annual progress report on the current 3-year ''Nonlinear and Nonideal MHD'' DoE grand DE-FG02-86ER53218 for the six months since the November 2002 progress report. During this grant year the funding level was $309k. The participating personnel and their approximate degree of funded involvement in this research project this grant year has been as follows: Professor J. D. Callen (PI, 1.8 months during academic year, 2.2 summer months); Professor C.C. Hegna (Co-PI: 2.3 months during academic year, 1.5 summer months); postdoc Dr. S. Gupta (100%); and graduate students A.L. Garcia-Perciante (50% RA) and X. Liu (50% RA).

  19. Extreme Performance Scalable Operating Systems Final Progress Report (July 1, 2008 - October 31, 2011)

    SciTech Connect

    Malony, Allen D; Shende, Sameer

    2011-10-31

    This is the final progress report for the FastOS (Phase 2) (FastOS-2) project with Argonne National Laboratory and the University of Oregon (UO). The project started at UO on July 1, 2008 and ran until April 30, 2010, at which time a six-month no-cost extension began. The FastOS-2 work at UO delivered excellent results in all research work areas: * scalable parallel monitoring * kernel-level performance measurement * parallel I/0 system measurement * large-scale and hybrid application performance measurement * onlne scalable performance data reduction and analysis * binary instrumentation

  20. 40 CFR 62.15065 - How do I comply with the increment of progress for submittal of a final control plan?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... progress for submittal of a final control plan? 62.15065 Section 62.15065 Protection of Environment....15065 How do I comply with the increment of progress for submittal of a final control plan? For your final control plan increment of progress, you must complete two items: (a) Submit the final control...

  1. 40 CFR 62.15065 - How do I comply with the increment of progress for submittal of a final control plan?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... progress for submittal of a final control plan? 62.15065 Section 62.15065 Protection of Environment....15065 How do I comply with the increment of progress for submittal of a final control plan? For your final control plan increment of progress, you must complete two items: (a) Submit the final control...

  2. Liver inflammation and metabolic signaling in ApcMin/+ mice: the role of cachexia progression.

    PubMed

    Narsale, Aditi A; Enos, Reilly T; Puppa, Melissa J; Chatterjee, Saurabh; Murphy, E Angela; Fayad, Raja; Pena, Majorette O'; Durstine, J Larry; Carson, James A

    2015-01-01

    The ApcMin/+ mouse exhibits an intestinal tumor associated loss of muscle and fat that is accompanied by chronic inflammation, insulin resistance and hyperlipidemia. Since the liver governs systemic energy demands through regulation of glucose and lipid metabolism, it is likely that the liver is a pathological target of cachexia progression in the ApcMin/+ mouse. The purpose of this study was to determine if cancer and the progression of cachexia affected liver endoplasmic reticulum (ER)-stress, inflammation, metabolism, and protein synthesis signaling. The effect of cancer (without cachexia) was examined in wild-type and weight-stable ApcMin/+ mice. Cachexia progression was examined in weight-stable, pre-cachectic, and severely-cachectic ApcMin/+ mice. Livers were analyzed for morphology, glycogen content, ER-stress, inflammation, and metabolic changes. Cancer induced hepatic expression of ER-stress markers BiP (binding immunoglobulin protein), IRE-1α (endoplasmic reticulum to nucleus signaling 1), and inflammatory intermediate STAT-3 (signal transducer and activator of transcription 3). While gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression was suppressed by cancer, glycogen content or protein synthesis signaling remained unaffected. Cachexia progression depleted liver glycogen content and increased mRNA expression of glycolytic enzyme PFK (phosphofrucktokinase) and gluconeogenic enzyme PEPCK. Cachexia progression further increased pSTAT-3 but suppressed p-65 and JNK (c-Jun NH2-terminal kinase) activation. Interestingly, progression of cachexia suppressed upstream ER-stress markers BiP and IRE-1α, while inducing its downstream target CHOP (DNA-damage inducible transcript 3). Cachectic mice exhibited a dysregulation of protein synthesis signaling, with an induction of p-mTOR (mechanistic target of rapamycin), despite a suppression of Akt (thymoma viral proto-oncogene 1) and S6 (ribosomal protein S6) phosphorylation. Thus, cancer

  3. Effect of SO/sub 2/ on light modulation of plant metabolism. Progress report, June 1, 1982-May 31, 1983

    SciTech Connect

    Anderson, L.E.

    1983-01-01

    Research progress is reported on investigations into the effect of light on the activity of enzymes involved in stomatal metabolism. The effects of sulfite, arsenite, and SO/sub 2/ on this light-mediated system have been studied. (ACR)

  4. Targeting metabolic flexibility by simultaneously inhibiting respiratory complex I and lactate generation retards melanoma progression

    PubMed Central

    Chaube, Balkrishna; Malvi, Parmanand; Singh, Shivendra Vikram; Mohammad, Naoshad; Meena, Avtar Singh; Bhat, Manoj Kumar

    2015-01-01

    Melanoma is a largely incurable skin malignancy owing to the underlying molecular and metabolic heterogeneity confounded by the development of resistance. Cancer cells have metabolic flexibility in choosing either oxidative phosphorylation (OXPHOS) or glycolysis for ATP generation depending upon the nutrient availability in tumor microenvironment. In this study, we investigated the involvement of respiratory complex I and lactate dehydrogenase (LDH) in melanoma progression. We show that inhibition of complex I by metformin promotes melanoma growth in mice via elevating lactate and VEGF levels. In contrast, it leads to the growth arrest in vitro because of enhanced extracellular acidification as a result of increased glycolysis. Inhibition of LDH or lactate generation causes decrease in glycolysis with concomitant growth arrest both in vitro and in vivo. Blocking lactate generation in metformin-treated melanoma cells results in diminished cell proliferation and tumor progression in mice. Interestingly, inhibition of either LDH or complex I alone does not induce apoptosis, whereas inhibiting both together causes depletion in cellular ATP pool resulting in metabolic catastrophe induced apoptosis. Overall, our study suggests that LDH and complex I play distinct roles in regulating glycolysis and cell proliferation. Inhibition of these two augments synthetic lethality in melanoma. PMID:26484566

  5. Metabolic genes in cancer: their roles in tumor progression and clinical implications

    PubMed Central

    Furuta, Eiji; Okuda, Hiroshi; Kobayashi, Aya; Watabe, Kounosuke

    2010-01-01

    Re-programming of metabolic pathways is a hallmark of physiological changes in cancer cells. The expression of certain genes that directly control the rate of key metabolic pathways including glycolysis, lipogenesis and nucleotide synthesis are drastically altered at different stages of tumor progression. These alterations are generally considered as an adaptation of tumor cells; however, they also contribute to the progression of tumor cells to become more aggressive phenotypes. This review summarizes the recent information about the mechanistic link of these genes to oncogenesis and their potential utility as diagnostic markers as well as for therapeutic targets. We particularly focus on three groups of genes; GLUT1, G6PD, TKTL1 and PGI/AMF in glycolytic pathway, ACLY, ACC1 and FAS in lipogenesis and RRM1, RRM2 and TYMS for nucleotide synthesis. All these genes are highly up-regulated in a variety of tumor cells in cancer patients, and they play active roles in tumor progression rather than expressing merely as a consequence of phenotypic change of the cancer cells. Molecular dissection of their orchestrated networks and understanding the exact mechanism of their expression will provide a window of opportunity to target these genes for specific cancer therapy. We also reviewed existing database of gene microarray to validate the utility of these genes for cancer diagnosis. PMID:20122995

  6. Microbial Regulation of Glucose Metabolism and Cell-Cycle Progression in Mammalian Colonocytes

    PubMed Central

    Donohoe, Dallas R.; Wali, Aminah; Brylawski, Bruna P.; Bultman, Scott J.

    2012-01-01

    A prodigious number of microbes inhabit the human body, especially in the lumen of the gastrointestinal (GI) tract, yet our knowledge of how they regulate metabolic pathways within our cells is rather limited. To investigate the role of microbiota in host energy metabolism, we analyzed ATP levels and AMPK phosphorylation in tissues isolated from germfree and conventionally-raised C57BL/6 mice. These experiments demonstrated that microbiota are required for energy homeostasis in the proximal colon to a greater extent than other segments of the GI tract that also harbor high densities of bacteria. This tissue-specific effect is consistent with colonocytes utilizing bacterially-produced butyrate as their primary energy source, whereas most other cell types utilize glucose. However, it was surprising that glucose did not compensate for butyrate deficiency. We measured a 3.5-fold increase in glucose uptake in germfree colonocytes. However, 13C-glucose metabolic-flux experiments and biochemical assays demonstrated that they shifted their glucose metabolism away from mitochondrial oxidation/CO2 production and toward increased glycolysis/lactate production, which does not yield enough ATPs to compensate. The mechanism responsible for this metabolic shift is diminished pyruvate dehydrogenase (PDH) levels and activity. Consistent with perturbed PDH function, the addition of butyrate, but not glucose, to germfree colonocytes ex vivo stimulated oxidative metabolism. As a result of this energetic defect, germfree colonocytes exhibited a partial block in the G1-to-S-phase transition that was rescued by a butyrate-fortified diet. These data reveal a mechanism by which microbiota regulate glucose utilization to influence energy homeostasis and cell-cycle progression of mammalian host cells. PMID:23029553

  7. The Role of Single-Subject Brain Metabolic Patterns in the Early Differential Diagnosis of Primary Progressive Aphasias and in Prediction of Progression to Dementia

    PubMed Central

    Cerami, Chiara; Dodich, Alessandra; Greco, Lucia; Iannaccone, Sandro; Magnani, Giuseppe; Marcone, Alessandra; Pelagallo, Elisabetta; Santangelo, Roberto; Cappa, Stefano F.; Perani, Daniela

    2016-01-01

    Background and Objective: Primary progressive aphasia (PPA) is a clinical syndrome due to different neurodegenerative conditions in which an accurate early diagnosis needs to be supported by a reliable diagnostic tool at the individual level. In this study, we investigated in PPA the FDG-PET brain metabolic patterns at the single-subject level, in order to assess the case-to-case variability and its relationship with clinical-neuropsychological findings. Material and Methods: 55 patients (i.e., 11 semantic variant/sv-PPA, 19 non fluent variant/nfv-PPA, 17 logopenic variant/lv-PPA, 3 slowly progressive anarthria/SPA, and 5 mixed PPA/m-PPA) were included. Clinical-neuropsychological information and FDG-PET data were acquired at baseline. A follow-up of 27.4±12.55 months evaluated the clinical progression. Brain metabolism was analyzed using an optimized and validated voxel-based SPM method at the single-subject level. Results: FDG-PET voxel-wise metabolic assessment revealed specific metabolic signatures characterizing each PPA variant at the individual level, reflecting the underlying neurodegeneration in language networks. Notably, additional dysfunctional patterns predicted clinical progression to specific dementia conditions. In the case of nfv-PPA, a metabolic pattern characterized by involvement of parietal, subcortical and brainstem structures predicted progression to a corticobasal degeneration syndrome or to progressive supranuclear palsy. lv-PPA and sv-PPA cases who progressed to Alzheimer’s disease and frontotemporal dementia at the follow-up presented with extended bilateral patterns at baseline. Discussion: Our results indicate that FDG-PET voxel-wise imaging is a valid biomarker for the early differential diagnosis of PPAs and for the prediction of progression to specific dementia condition. This study supports the use of FDG-PET imaging quantitative assessment in clinical settings for a better characterization of PPA individuals and prognostic

  8. Increase in serum albumin concentration is associated with prediabetes development and progression to overt diabetes independently of metabolic syndrome.

    PubMed

    Jun, Ji Eun; Lee, Seung-Eun; Lee, You-Bin; Jee, Jae Hwan; Bae, Ji Cheol; Jin, Sang-Man; Hur, Kyu Yeon; Lee, Moon-Kyu; Kim, Jae Hyeon

    2017-01-01

    Serum albumin concentration is associated with both type 2 diabetes and metabolic syndrome (MetS). We sought to investigate whether baseline serum albumin and change in serum albumin could be independent risk factors for prediabetes in subjects without MetS. We further examined the effect of serum albumin on progression to overt diabetes in subjects who developed prediabetes. Among 10,792 participants without diabetes and MetS who consecutively underwent yearly health check-ups over six years, 9,807 subjects without incident MetS were enrolled in this longitudinal retrospective study. The risk of developing prediabetes (impared fasting glucose or hemoglobin A1c) was analyzed according to baseline and percent change in serum albumin concentration using Cox regression analysis. Serial changes in serum albumin concentration were measured from baseline to one year before prediabetes diagnosis, and then from the time of prediabetes diagnosis to progression to overt diabetes or final follow-up. A total of 4,398 incident cases of prediabetes developed during 35,807 person-years (median 3.8 years). The hazard ratio for incident prediabetes decreased as percent change in serum albumin concentration (quartiles and per 1%) increased in a crude and fully adjusted model. However, baseline serum albumin concentration itself was not associated with prediabetic risk. Serum albumin levels kept increasing until the end of follow-up in prediabetic subjects who returned to normal glycemic status, whereas these measures did not change in prediabetic subjects who developed type 2 diabetes. Serum albumin concentration measured at the end of follow-up was the highest in the regression group, compared to the stationary (p = 0.014) or progression groups (p = 0.009). Increase in serum albumin concentration might protect against early glycemic deterioration and progression to type 2 diabetes even in subjects without MetS.

  9. Increase in serum albumin concentration is associated with prediabetes development and progression to overt diabetes independently of metabolic syndrome

    PubMed Central

    Jun, Ji Eun; Lee, Seung-Eun; Lee, You-Bin; Jee, Jae Hwan; Bae, Ji Cheol; Jin, Sang-Man; Hur, Kyu Yeon; Lee, Moon-Kyu

    2017-01-01

    Aim Serum albumin concentration is associated with both type 2 diabetes and metabolic syndrome (MetS). We sought to investigate whether baseline serum albumin and change in serum albumin could be independent risk factors for prediabetes in subjects without MetS. We further examined the effect of serum albumin on progression to overt diabetes in subjects who developed prediabetes. Methods Among 10,792 participants without diabetes and MetS who consecutively underwent yearly health check-ups over six years, 9,807 subjects without incident MetS were enrolled in this longitudinal retrospective study. The risk of developing prediabetes (impared fasting glucose or hemoglobin A1c) was analyzed according to baseline and percent change in serum albumin concentration using Cox regression analysis. Serial changes in serum albumin concentration were measured from baseline to one year before prediabetes diagnosis, and then from the time of prediabetes diagnosis to progression to overt diabetes or final follow-up. Results A total of 4,398 incident cases of prediabetes developed during 35,807 person-years (median 3.8 years). The hazard ratio for incident prediabetes decreased as percent change in serum albumin concentration (quartiles and per 1%) increased in a crude and fully adjusted model. However, baseline serum albumin concentration itself was not associated with prediabetic risk. Serum albumin levels kept increasing until the end of follow-up in prediabetic subjects who returned to normal glycemic status, whereas these measures did not change in prediabetic subjects who developed type 2 diabetes. Serum albumin concentration measured at the end of follow-up was the highest in the regression group, compared to the stationary (p = 0.014) or progression groups (p = 0.009). Conclusions Increase in serum albumin concentration might protect against early glycemic deterioration and progression to type 2 diabetes even in subjects without MetS. PMID:28430803

  10. Altered Metabolic Homeostasis in Amyotrophic Lateral Sclerosis: Mechanisms of Energy Imbalance and Contribution to Disease Progression.

    PubMed

    Ioannides, Zara A; Ngo, Shyuan T; Henderson, Robert D; McCombe, Pamela A; Steyn, Frederik J

    2016-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the death of motor neurones, which leads to paralysis and death in an average of 3 years following diagnosis. The cause of ALS is unknown, but there is substantial evidence that metabolic factors, including nutritional state and body weight, affect disease progression and survival. This review provides an overview of the characteristics of metabolic dysregulation in ALS focusing on mechanisms that lead to disrupted energy supply (at a whole-body and cellular level) and altered energy expenditure. We discuss how a decrease in energy supply occurs in parallel with an increase in energy demand and leads to a state of chronic energy deficit which has a negative impact on disease outcome in ALS. We conclude by presenting potential and tested strategies to compensate for, or correct this energy imbalance, and speculate on promising areas for further research. © 2016 S. Karger AG, Basel.

  11. Progress and challenges in developing metabolic footprints from diet in human gut microbial cometabolism.

    PubMed

    Duffy, Linda C; Raiten, Daniel J; Hubbard, Van S; Starke-Reed, Pamela

    2015-05-01

    Homo sapiens harbor trillions of microbes, whose microbial metagenome (collective genome of a microbial community) using omic validation interrogation tools is estimated to be at least 100-fold that of human cells, which comprise 23,000 genes. This article highlights some of the current progress and open questions in nutrition-related areas of microbiome research. It also underscores the metabolic capabilities of microbial fermentation on nutritional substrates that require further mechanistic understanding and systems biology approaches of studying functional interactions between diet composition, gut microbiota, and host metabolism. Questions surrounding bacterial fermentation and degradation of dietary constituents (particularly by Firmicutes and Bacteroidetes) and deciphering how microbial encoding of enzymes and derived metabolites affect recovery of dietary energy by the host are more complex than previously thought. Moreover, it is essential to understand to what extent the intestinal microbiota is subject to dietary control and to integrate these data with functional metabolic signatures and biomarkers. Many lines of research have demonstrated the significant role of the gut microbiota in human physiology and disease. Probiotic and prebiotic products are proliferating in the market in response to consumer demand, and the science and technology around these products are progressing rapidly. With high-throughput molecular technologies driving the science, studying the bidirectional interactions of host-microbial cometabolism, epithelial cell maturation, shaping of innate immune development, normal vs. dysfunctional nutrient absorption and processing, and the complex signaling pathways involved is now possible. Substantiating the safety and mechanisms of action of probiotic/prebiotic formulations is critical. Beneficial modulation of the human microbiota by using these nutritional and biotherapeutic strategies holds considerable promise as next

  12. Progress and Challenges in Developing Metabolic Footprints from Diet in Human Gut Microbial Cometabolism12

    PubMed Central

    Duffy, Linda C; Raiten, Daniel J; Hubbard, Van S; Starke-Reed, Pamela

    2015-01-01

    Homo sapiens harbor trillions of microbes, whose microbial metagenome (collective genome of a microbial community) using omic validation interrogation tools is estimated to be at least 100-fold that of human cells, which comprise 23,000 genes. This article highlights some of the current progress and open questions in nutrition-related areas of microbiome research. It also underscores the metabolic capabilities of microbial fermentation on nutritional substrates that require further mechanistic understanding and systems biology approaches of studying functional interactions between diet composition, gut microbiota, and host metabolism. Questions surrounding bacterial fermentation and degradation of dietary constituents (particularly by Firmicutes and Bacteroidetes) and deciphering how microbial encoding of enzymes and derived metabolites affect recovery of dietary energy by the host are more complex than previously thought. Moreover, it is essential to understand to what extent the intestinal microbiota is subject to dietary control and to integrate these data with functional metabolic signatures and biomarkers. Many lines of research have demonstrated the significant role of the gut microbiota in human physiology and disease. Probiotic and prebiotic products are proliferating in the market in response to consumer demand, and the science and technology around these products are progressing rapidly. With high-throughput molecular technologies driving the science, studying the bidirectional interactions of host-microbial cometabolism, epithelial cell maturation, shaping of innate immune development, normal vs. dysfunctional nutrient absorption and processing, and the complex signaling pathways involved is now possible. Substantiating the safety and mechanisms of action of probiotic/prebiotic formulations is critical. Beneficial modulation of the human microbiota by using these nutritional and biotherapeutic strategies holds considerable promise as next

  13. Effect of SO/sub 2/ on light modulation of plant metabolism. Progress report

    SciTech Connect

    Anderson, L.E.

    1985-01-01

    This progress report briefly notes conclusions of work done on SO/sub 2/ effect on light modulation of plant metabolism. Conclusions include: effect of light activation on kinetic parameters of fructosebisphosphatase - for this enzyme K/sub m/ decreases and V/sub max/ increases as a result of light activation; and the effect of sulfite and arsenite on light activation in 2 Pisum cultivars - the differences in sensitivity to SO/sub 2/ is directly reflected in differences in a thylakoid bound factor (LEM) to SO/sub 2/.

  14. Cell cycle progression is an essential regulatory component of phospholipid metabolism and membrane homeostasis

    PubMed Central

    Sanchez-Alvarez, Miguel; Zhang, Qifeng; Finger, Fabian; Wakelam, Michael J. O.; Bakal, Chris

    2015-01-01

    We show that phospholipid anabolism does not occur uniformly during the metazoan cell cycle. Transition to S-phase is required for optimal mobilization of lipid precursors, synthesis of specific phospholipid species and endoplasmic reticulum (ER) homeostasis. Average changes observed in whole-cell phospholipid composition, and total ER lipid content, upon stimulation of cell growth can be explained by the cell cycle distribution of the population. TORC1 promotes phospholipid anabolism by slowing S/G2 progression. The cell cycle stage-specific nature of lipid biogenesis is dependent on p53. We propose that coupling lipid metabolism to cell cycle progression is a means by which cells have evolved to coordinate proliferation with cell and organelle growth. PMID:26333836

  15. Mechanisms Linking Glucose Homeostasis and Iron Metabolism Toward the Onset and Progression of Type 2 Diabetes.

    PubMed

    Fernández-Real, José Manuel; McClain, Donald; Manco, Melania

    2015-11-01

    The bidirectional relationship between iron metabolism and glucose homeostasis is increasingly recognized. Several pathways of iron metabolism are modified according to systemic glucose levels, whereas insulin action and secretion are influenced by changes in relative iron excess. We aimed to update the possible influence of iron on insulin action and secretion and vice versa. The mechanisms that link iron metabolism and glucose homeostasis in the main insulin-sensitive tissues and insulin-producing β-cells were revised according to their possible influence on the development of type 2 diabetes (T2D). The mechanisms leading to dysmetabolic hyperferritinemia and hepatic overload syndrome were diverse, including diet-induced alterations in iron absorption, modulation of gluconeogenesis, heme-mediated disruption of circadian glucose rhythm, impaired hepcidin secretion and action, and reduced copper availability. Glucose metabolism in adipose tissue seems to be affected by both iron deficiency and excess through interaction with adipocyte differentiation, tissue hyperplasia and hypertrophy, release of adipokines, lipid synthesis, and lipolysis. Reduced heme synthesis and dysregulated iron uptake or export could also be contributing factors affecting glucose metabolism in the senescent muscle, whereas exercise is known to affect iron and glucose status. Finally, iron also seems to modulate β-cells and insulin secretion, although this has been scarcely studied. Iron is increasingly recognized to influence glucose metabolism at multiple levels. Body iron stores should be considered as a potential target for therapy in subjects with T2D or those at risk for developing T2D. Further research is warranted. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  16. Metabolic Tumor Burden Predicts for Disease Progression and Death in Lung Cancer

    SciTech Connect

    Lee, Percy; Weerasuriya, Dilani K.; Lavori, Philip W.; Quon, Andrew; Hara, Wendy; Maxim, Peter G.; Le, Quynh-Thu; Wakelee, Heather A.; Donington, Jessica S.; Graves, Edward E.; Loo, Billy W.

    2007-10-01

    Purpose: In lung cancer, stage is an important prognostic factor for disease progression and survival. However, stage may be simply a surrogate for underlying tumor burden. Our purpose was to assess the prognostic value of tumor burden measured by {sup 18}F-fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging. Patients and Methods: We identified 19 patients with lung cancer who had staging PET-CT scans before any therapy, and adequate follow-up (complete to time of progression for 18, and death for 15 of 19). Metabolically active tumor regions were segmented on pretreatment PET scans semi-automatically using custom software. We determined the relationship between times to progression (TTP) and death (OS) and two PET parameters: total metabolic tumor volume (MTV), and standardized uptake value (SUV). Results: The estimated median TTP and OS for the cohort were 9.3 months and 14.8 months. On multivariate Cox proportional hazards regression analysis, an increase in MTV of 25 ml (difference between the 75th and 25th percentiles) was associated with increased hazard of progression and of death (5.4-fold and 7.6-fold), statistically significant (p = 0.0014 and p = 0.001) after controlling for stage, treatment intent (definitive or palliative), age, Karnofsky performance status, and weight loss. We did not find a significant relationship between SUV and TTP or OS. Conclusions: In this study, high tumor burden assessed by PET MTV is an independent poor prognostic feature in lung cancer, promising for stratifying patients in randomized trials and ultimately for selecting risk-adapted therapies. These results will need to be validated in larger cohorts with longer follow-up, and evaluated prospectively.

  17. Regulation of terpene metabolism. Final technical report, March 15, 1988--March 14, 1996

    SciTech Connect

    Croteau, R.

    1996-12-31

    This research focuses on the following topics: the biosynthesis and catabolism of monoterpenes; the organization of monoterpene metabolism; the developmental regulation of monoterpene metabolism; the flux control of precursor supply; and the integration of monoterpene and higher terpenoid metabolism.

  18. Current progress of targetron technology: development, improvement and application in metabolic engineering.

    PubMed

    Liu, Ya-Jun; Zhang, Jie; Cui, Gu-Zhen; Cui, Qiu

    2015-06-01

    Targetrons are mobile group II introns that can recognize their DNA target sites by base-pairing RNA-DNA interactions with the aid of site-specific binding reverse transcriptases. Targetron technology stands out from recently developed gene targeting methods because of the flexibility, feasibility, and efficiency, and is particularly suitable for the genetic engineering of difficult microorganisms, including cellulolytic bacteria that are considered promising candidates for biomass conversion via consolidated bioprocessing. Along with the development of the thermotargetron method for thermophiles, targetron technology becomes increasingly important for the metabolic engineering of industrial microorganisms aiming at biofuel/chemical production. To summarize the current progress of targetron technology and provide new insights on the use of the technology, this paper reviews the retrohoming mechanisms of both mesophilic and thermophilic targetron methods based on various group II introns, investigates the improvement of targetron tools for high target efficiency and specificity, and discusses the current applications in the metabolic engineering for bacterial producers. Although there are still intellectual property and technical restrictions in targetron applications, we propose that targetron technology will contribute to both biochemistry research and the metabolic engineering for industrial productions. Copyright © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  19. Recent progress in development of synthetic biology platforms and metabolic engineering of Corynebacterium glutamicum.

    PubMed

    Woo, Han Min; Park, Jin-Byung

    2014-06-20

    The paradigm of synthetic biology has been evolving, along with relevant engineering, to achieve designed bio-systems. Synthetic biology has reached the point where it is possible to develop microbial strains to produce desired chemicals. Recent advances in this field have promoted metabolic engineering of Corynebacterium glutamicum as an amino-acid producer for use in intelligent microbial-cell factories. Here, we review recent advances that address C. glutamicum as a potential model organism for synthetic biology, and evaluate their industrial applications. Finally, we highlight the perspective of developing C. glutamicum as a step toward advanced microbial-cell factories that could produce valuable chemicals from renewable resources.

  20. Obesity dependent metabolic signatures associated with nonalcoholic fatty liver disease progression

    PubMed Central

    Barr, J.; Caballería, J.; Martínez-Arranz, I.; Domínguez-Díez, A.; Alonso, C.; Muntané, J.; Pérez-Cormenzana, M.; García-Monzón, C.; Mayo, R.; Martín-Duce, A.; Romero-Gómez, M.; Iacono, O. Lo; Tordjman, J.; Andrade, R.J.; Pérez-Carreras, M.; Le Marchand-Brustel, Y.; Tran, A.; Fernández-Escalante, C.; Arévalo, E.; García–Unzueta, M.; Clement, K.; Crespo, J.; Gual, P.; Gómez-Fleitas, M.; Martínez-Chantar, M.L.; Castro, A.; Lu, S.C.; Vázquez-Chantada, M.; Mato, J.M.

    2012-01-01

    Our understanding of the mechanisms by which nonalcoholic fatty liver disease (NAFLD) progresses from simple steatosis to steatohepatitis (NASH) is still very limited. Despite the growing number of studies linking the disease with altered serum metabolite levels, an obstacle to the development of metabolome-based NAFLD predictors has been the lack of large cohort data from biopsy-proven patients matched for key metabolic features such as obesity. We studied 467 biopsied individuals with normal liver histology (n=90) or diagnosed with NAFLD (steatosis, n=246; NASH, n=131), randomly divided into estimation (80% of all patients) and validation (20% of all patients) groups. Qualitative determinations of 540 serum metabolite variables were performed using ultra-performance liquid chromatography coupled to mass spectrometry (UPLC-MS). The metabolic profile was dependent on patient body-mass index (BMI), suggesting that the NAFLD pathogenesis mechanism may be quite different depending on an individual’s level of obesity. A BMI-stratified multivariate model based on the NAFLD serum metabolic profile was used to separate patients with and without NASH. The area under the receiver operating characteristic curve was 0.87 in the estimation and 0.85 in the validation group. The cutoff (0.54) corresponding to maximum average diagnostic accuracy (0.82) predicted NASH with a sensitivity of 0.71 and a specificity of 0.92 (negative/positive predictive values = 0.82/0.84). The present data, indicating that a BMI-dependent serum metabolic profile may be able to reliably distinguish NASH from steatosis patients, have significant implications for the development of NASH biomarkers and potential novel targets for therapeutic intervention. PMID:22364559

  1. Environmentally conscious manufacturing & technology access project: Final technical progress report, April 1, 1994--September 30, 1996

    SciTech Connect

    1997-05-01

    This final report is being submitted in fulfillment of the management obligations associated with the TRP/DOE grant which funded the Environmentally Conscious Manufacturing & Technology Access (ECM) Project. A {open_quotes}Federal Assistance Project Status Report{close_quotes} is also being submitted with this form. This report will elaborate on the successful completion of this project in achieving and in most cases exceeding its programmatic goals and fulfilling it statutory financial match obligation. A review of the Year 1 {open_quotes}Technical Progress Report{close_quotes} and the Quarterly Reports filed during the project period, clearly portray that, in all substantive areas, the Environmentally Conscious Manufacturing & Technology Access Project (ECM Project) achieved or exceeded its goals. The success of the Project is largely due to the tremendous support provided by the Center for Technology Transfer (CTT) and the Maine Metal Products Association (MMPA). Both organizations provided extensive administrative and financial support and were instrumental in promoting the work of the project within the metals industry. The programmatic oversight provided by the industry Steering Committee and the broad partnership represented on the Board of Advisors were invaluable in developing, promoting and implementing the work of the ECM Project.

  2. Rawlins UCG Demonstration Project. Final technical progress report, January 1, 1987--February 9, 1988

    SciTech Connect

    Not Available

    1988-08-03

    Department of Energy Participation in the Rawlins UCG Demonstration Project began officially on November 9, 1987. Even though their financial participation began at this time, they will receive technical information from the start of the project which was on January 1, 1987. The Rawlins UCG Demonstration Project is progressing in Phase I with the majority of the emphasis on facility design, site characterization and the environmental work. The site characterization field work is estimated to be completed by the end of February with the final report completion towards the end of Phase I. The facility design effort is close to the 40% level. It is anticipated that all permits will be applied for in Phase I and most of them will be granted by the end of Phase I. The obtaining of the private financing continues to be a major activity in the project. All of the financing must be in place before the continuation for DOE funding to Phase II will be applied for.

  3. Aβ AMYLOID & GLUCOSE METABOLISM IN THREE VARIANTS OF PRIMARY PROGRESSIVE APHASIA

    PubMed Central

    Rabinovici, G.D.; Jagust, W.J.; Furst, A.J.; Ogar, J.M.; Racine, C.A.; Mormino, E.C.; O’Neil, J.P.; Lal, R.A.; Dronkers, N.F.; Miller, B.L.; Gorno-Tempini, M.L.

    2009-01-01

    OBJECTIVE Alzheimer’s disease (AD) is found at autopsy in up to one-third of patients with primary progressive aphasia (PPA), but clinical features that predict AD pathology in PPA are not well defined. We studied the relationships between language presentation, Aβ amyloidosis and glucose metabolism in three variants of PPA using [11C]PIB and [18F]FDG-PET. METHODS Patients meeting PPA criteria (N=15) were classified as logopenic aphasia (LPA), progressive non-fluent aphasia (PNFA) or semantic dementia (SD) based on language testing. [11C]PIB distribution volume ratios were calculated using Logan graphical analysis (cerebellar reference). [18F]FDG images were normalized to pons. Partial volume correction was applied. RESULTS Elevated cortical PIB (by visual inspection) was more common in LPA (4/4 patients) than in PNFA (1/6) and SD (1/5) (p<0.02). In all PIB-positive cases, PIB uptake was diffuse and indistinguishable from the pattern in matched AD patients (N=10). FDG patterns were focal and varied by PPA subtype, with left temporoparietal hypometabolism in LPA, left frontal hypometabolism in PNFA, and left anterior temporal hypometabolism in SD. FDG patterns in PIB-positive PNFA and SD were similar to PIB-negative cases. Language regions showed asymmetric left hypometabolism in PPA (p<0.005) but not in AD. INTERPRETATION LPA is associated with Aβ amyloidosis, suggesting that sub-classification of PPA based on language features can help predict the likelihood of underlying AD pathology. Language phenotype in PPA is closely related to metabolic changes that are focal and anatomically distinct between subtypes, but not to amyloid deposition patterns that are diffuse and similar to AD. PMID:18991338

  4. [Physiology and genetics of metabolic flux control in Zymomonas mobilis]. Progress report

    SciTech Connect

    Conway, T.

    1992-07-01

    The funded research deals with the physiology and genetics of glycolytic flux control in Zymomonas mobilis. Two fundamental biological questions are begin addressed: First, how do the enzymes of glycolytic pathways act in concert to regulate metabolic flux? Second, what is the role of gene expression in regulating high level synthesis of the glycolytic enzymes in a balance that allows proper glycolytic flux control? The specific objectives of the grant are as follows: 1. To clone the structural and regulatory regions of the Z. mobilis genes encoding glucose-6-phosphate dehydrogenase, phosphoglucose isomerase, enolase, 6-phosphogluconate dehydratase, 2- keto-3-deoxy- 6-phosphogluconate aldolase, glucokinase and fructokinase. 2. To characterize the structure of these genes with respect to nucleotide sequence, transcriptional initiation sites promoter location, evolutionary relatedness to similar genes from other organisms, and organization of these genes on the genome. 3. To investigate the effects of genetically engineered alterations in the levels of the cloned enzymes on metabolic flux and cell growth. 4. To study transcriptional and post-transcriptional regulation of the genes encoding the enzymes of the Entner-Doudoroff pathway. The first two specific objectives have now been fully completed. Significant progress has been made on the fourth objective and work on the third objective is well underway.

  5. Global reprogramming of transcription and metabolism in Medicago truncatula during progressive drought and after rewatering

    PubMed Central

    Zhang, Ji-Yi; Cruz de Carvalho, Maria H; Torres-Jerez, Ivone; Kang, Yun; Allen, Stacy N; Huhman, David V; Tang, Yuhong; Murray, Jeremy; Sumner, Lloyd W; Udvardi, Michael K

    2014-01-01

    Medicago truncatula is a model legume forage crop native to the arid and semi-arid environments of the Mediterranean. Given its drought-adapted nature, it is an ideal candidate to study the molecular and biochemical mechanisms conferring drought resistance in plants. Medicago plants were subjected to a progressive drought stress over 14 d of water withholding followed by rewatering under controlled environmental conditions. Based on physiological measurements of plant water status and changes in morphology, plants experienced mild, moderate and severe water stress before rehydration. Transcriptome analysis of roots and shoots from control, mildly, moderately and severely stressed, and rewatered plants, identified many thousands of genes that were altered in expression in response to drought. Many genes with expression tightly coupled to the plant water potential (i.e. drought intensity) were identified suggesting an involvement in Medicago drought adaptation responses. Metabolite profiling of drought-stressed plants revealed the presence of 135 polar and 165 non-polar compounds in roots and shoots. Combining Medicago metabolomic data with transcriptomic data yielded insight into the regulation of metabolic pathways operating under drought stress. Among the metabolites detected in drought-stressed Medicago plants, myo-inositol and proline had striking regulatory profiles indicating involvement in Medicago drought tolerance. Global transcriptional and metabolic responses to drought and rewatering were investigated in Medicago truncatula, a naturally drought-adapted model legume species. Integration of metabolomic and transcriptomic data yielded insights into the regulation of metabolic pathways underlying drought-stress adaptation. Many genes and metabolites with expression tightly coupled to drought intensity were identified, suggesting active involvement in Medicago drought resistance. These could prove useful targets for future translational approaches to improve

  6. Final Technical Progress Report: Development of Low-Cost Suspension Heliostat; December 7, 2011 - December 6, 2012

    SciTech Connect

    Bender, W.

    2013-01-01

    Final technical progress report of SunShot Incubator Solaflect Energy. The project succeeded in demonstrating that the Solaflect Suspension Heliostat design is viable for large-scale CSP installations. Canting accuracy is acceptable and is continually improving as Solaflect improves its understanding of this design. Cost reduction initiatives were successful, and there are still many opportunities for further development and further cost reduction.

  7. Schaumburg Early Education Center (SEEC): Sixth Progress Performance Report 1978-1979. Final Report (Outreach) 1976-1979.

    ERIC Educational Resources Information Center

    Community Consolidated School District 54, Schaumburg, IL.

    The document presents the sixth progress performance report for 1978-1979 and a final outreach report (focusing on demonstration activities) for 1976-1979 for the Schaumburg (Illinois) Early Education Center (SEEC), a Piaget based early education program for 3 to 5 year olds with developmental delays in the following areas: language,…

  8. Dissolved organic matter and lake metabolism. Technical progress report, 1 July 1979-30 June 1980

    SciTech Connect

    Wetzel, R.G.

    1980-01-01

    Progress in research to evaluate the impact of utilization of fossil fuels on surface water is reported. Analyses of regulatory mechanisms of growth and rates of carbon cycling center on evaluation of quantitative control interactions among the microflora of the pelagial zones of several lakes of progressively greater eutrophy, littoral photosynthetic producer-decomposer complex, and allochthonous inorganic-organic influxes and their biotic processing. The underlying thesis is that quantification of the dynamic carbon fluxes among these components and their rate control mechanisms by physical and chemical factors are fundamental to elucidation of the rate functions of lake eutrophication. A major portion of the research has been directed towards the fate and nutrient mechanisms regulating qualitative and quantitative utilization and losses of organic carbon synthesized within lakes and their drainage basins. It has become increasingly apparent that the wetland and littoral flora, and attendant epiphytic and benthic microflora, have major regulatory controls on biogeochemical cycling of whole lake systems. A major effort on factors regulating the metabolism of littoral macrophytes and attached algae has been coupled to integrated studies on their decomposition and the fate of detrital dissolved and particulate organic matter. These organic products are being coupled to influences on enzymatic activity and inorganic nutrient cycling.

  9. microRNA-17 family promotes polycystic kidney disease progression through modulation of mitochondrial metabolism

    PubMed Central

    Hajarnis, Sachin; Lakhia, Ronak; Yheskel, Matanel; Williams, Darren; Sorourian, Mehran; Liu, Xueqing; Aboudehen, Karam; Zhang, Shanrong; Kersjes, Kara; Galasso, Ryan; Li, Jian; Kaimal, Vivek; Lockton, Steven; Davis, Scott; Flaten, Andrea; Johnson, Joshua A.; Holland, William L.; Kusminski, Christine M.; Scherer, Philipp E.; Harris, Peter C.; Trudel, Marie; Wallace, Darren P.; Igarashi, Peter; Lee, Edmund C.; Androsavich, John R.; Patel, Vishal

    2017-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent genetic cause of renal failure. Here we identify miR-17 as a target for the treatment of ADPKD. We report that miR-17 is induced in kidney cysts of mouse and human ADPKD. Genetic deletion of the miR-17∼92 cluster inhibits cyst proliferation and PKD progression in four orthologous, including two long-lived, mouse models of ADPKD. Anti-miR-17 treatment attenuates cyst growth in short-term and long-term PKD mouse models. miR-17 inhibition also suppresses proliferation and cyst growth of primary ADPKD cysts cultures derived from multiple human donors. Mechanistically, c-Myc upregulates miR-17∼92 in cystic kidneys, which in turn aggravates cyst growth by inhibiting oxidative phosphorylation and stimulating proliferation through direct repression of Pparα. Thus, miR-17 family is a promising drug target for ADPKD, and miR-17-mediated inhibition of mitochondrial metabolism represents a potential new mechanism for ADPKD progression. PMID:28205547

  10. microRNA-17 family promotes polycystic kidney disease progression through modulation of mitochondrial metabolism.

    PubMed

    Hajarnis, Sachin; Lakhia, Ronak; Yheskel, Matanel; Williams, Darren; Sorourian, Mehran; Liu, Xueqing; Aboudehen, Karam; Zhang, Shanrong; Kersjes, Kara; Galasso, Ryan; Li, Jian; Kaimal, Vivek; Lockton, Steven; Davis, Scott; Flaten, Andrea; Johnson, Joshua A; Holland, William L; Kusminski, Christine M; Scherer, Philipp E; Harris, Peter C; Trudel, Marie; Wallace, Darren P; Igarashi, Peter; Lee, Edmund C; Androsavich, John R; Patel, Vishal

    2017-02-16

    Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent genetic cause of renal failure. Here we identify miR-17 as a target for the treatment of ADPKD. We report that miR-17 is induced in kidney cysts of mouse and human ADPKD. Genetic deletion of the miR-17∼92 cluster inhibits cyst proliferation and PKD progression in four orthologous, including two long-lived, mouse models of ADPKD. Anti-miR-17 treatment attenuates cyst growth in short-term and long-term PKD mouse models. miR-17 inhibition also suppresses proliferation and cyst growth of primary ADPKD cysts cultures derived from multiple human donors. Mechanistically, c-Myc upregulates miR-17∼92 in cystic kidneys, which in turn aggravates cyst growth by inhibiting oxidative phosphorylation and stimulating proliferation through direct repression of Pparα. Thus, miR-17 family is a promising drug target for ADPKD, and miR-17-mediated inhibition of mitochondrial metabolism represents a potential new mechanism for ADPKD progression.

  11. LKB1 Inhibits HPV-Associated Cancer Progression by Targeting Cellular Metabolism

    PubMed Central

    Zeng, Qinghua; Chen, Jianfeng; Li, Yining; Werle, Kaitlin D.; Zhao, Rui-Xun; Quan, Cheng-Shi; Wang, Yi-Shu; Zhai, Ying-Xian; Wang, Jian-Wei; Youssef, Mariam; Cui, Rutao; Liang, Jiyong; Genovese, Nicholas; Chow, Louise T.; Li, Yu-Lin; Xu, Zhi-Xiang

    2016-01-01

    Liver kinase B1 (LKB1) is mutationally inactivated in Peutz-Jeghers syndrome and in a variety of cancers including human papillomavirus (HPV)-caused cervical cancer. However, the significance of LKB1 mutations in cervical cancer initiation and progress has not been examined. Herein, we demonstrated that, in mouse embryonic fibroblasts, loss of LKB1 and transduction of HPV16 E6/E7 had an additive effect on constraining cell senescence while promoting cell proliferation and increasing glucose consumption, lactate production, and ATP generation. Knock-down of LKB1 increased and ectopic expression of LKB1 decreased glycolysis, anchorage-independent cell growth, and cell migration and invasion in HPV transformed cells. In the tumorigenesis and lung metastasis model in syngeneic mice, depletion of LKB1 markedly increased tumor metastatic colonies in lungs without affecting subcutaneous tumor growth. We showed that HPV16 E6/E7 enhanced the expression of hexokinase-ll (HK-II) in the glycolytic pathway through elevated c-MYC. Ectopic LKB1 reduced HK-II along with glycolysis. The inverse relationship between HK-II and LKB1 was also observed in normal and HPV-associated cervical lesions. We propose that LKB1 acts as a safeguard against HPV-stimulated aerobic glycolysis and tumor progression. These findings may eventually aid in the development of therapeutic strategy for HPV-associated malignancies by targeting cell metabolism. PMID:27546620

  12. The role of proteomics in progressing insights into plant secondary metabolism

    PubMed Central

    Martínez-Esteso, María J.; Martínez-Márquez, Ascensión; Sellés-Marchart, Susana; Morante-Carriel, Jaime A.; Bru-Martínez, Roque

    2015-01-01

    The development of omics has enabled the genome-wide exploration of all kinds of biological processes at the molecular level. Almost every field of plant biology has been analyzed at the genomic, transcriptomic and proteomic level. Here we focus on the particular contribution that proteomic technologies have made in progressing knowledge and characterising plant secondary metabolism (SM) pathways since early expectations were created 15 years ago. We analyzed how three major issues in the proteomic analysis of plant SM have been implemented in various research studies. These issues are: (i) the selection of a suitable plant material rich in secondary metabolites of interest, such as specialized tissues and organs, and in vitro cell cultures; (ii) the proteomic strategy to access target proteins, either a comprehensive or a differential analysis; (iii) the proteomic approach, represented by the hypothesis-free discovery proteomics and the hypothesis-driven targeted proteomics. We also examine to what extent the most-advanced technologies have been incorporated into proteomic research in plant SM and highlight some cutting edge techniques that would strongly benefit the progress made in this field. PMID:26217358

  13. Improved methods for water shutoff. Final technical progress report, October 1, 1997--September 30, 1998

    SciTech Connect

    Seright, R.S.; Liang, J.T.; Schrader, R.; Hagstrom, J. II; Liu, J.; Wavrik, K.

    1998-10-01

    In the United States, more than 20 billion barrels of salt water are produced each year during oilfield operations. A tremendous economic incentive exists to reduce water production if that can be accomplished without significantly sacrificing hydrocarbon production. This three-year research project had three objectives. The first objective was to identify chemical blocking agents that will (a) during placement, flow readily through fractures without penetrating significantly into porous rock and with screening out or developing excessive pressure gradients and (b) at a predictable and controllable time, become immobile and resistant breakdown upon exposure to moderate to high pressure gradients. The second objective was to identify schemes that optimize placement of the above blocking agents. The third objective was to explain why gels and other chemical blocking agents reduce permeability to one phase (e.g., water) more than that to another phase (e.g., oil or gas). The authors also wanted to identify conditions that maximize this phenomenon. This project consisted of three tasks, each of which addressed one of the above objectives. This report describes work performed during the third and final period of the project. During this three-year project, they: (1) Developed a procedure and software for sizing gelant treatments in hydraulically fractured production wells; (2) Developed a method (based on interwell tracer results) to determine the potential for applying gel treatments in naturally fractured reservoirs; (3) Characterized gel properties during extrusion through fractures; (4) Developed a method to predict gel placement in naturally fractured reservoirs; (5) Made progress in elucidating the mechanism for why some gels can reduce permeability to water more than that to oil; (6) Demonstrated the limitations of using water/oil ratio diagnostic plots to distinguish between channeling and coning; and (7) Proposed a philosophy for diagnosing and attacking water

  14. Identifying Voxels at Risk for Progression in Glioblastoma Based on Dosimetry, Physiologic and Metabolic MRI.

    PubMed

    Anwar, Mekhail; Molinaro, Annette M; Morin, Olivier; Chang, Susan M; Haas-Kogan, Daphne A; Nelson, Sarah J; Lupo, Janine M

    2017-09-01

    Despite the longstanding role of radiation in cancer treatment and the presence of advanced, high-resolution imaging techniques, delineation of voxels at-risk for progression remains purely a geometric expansion of anatomic images, missing subclinical disease at risk for recurrence while treating potentially uninvolved tissue and increasing toxicity. This remains despite the modern ability to precisely shape radiation fields. A striking example of this is the treatment of glioblastoma, a highly infiltrative tumor that may benefit from accurate identification of subclinical disease. In this study, we hypothesize that parameters from physiologic and metabolic magnetic resonance imaging (MRI) at diagnosis could predict the likelihood of voxel progression at radiographic recurrence in glioblastoma by identifying voxel characteristics that indicate subclinical disease. Integrating dosimetry can reveal its effect on voxel outcome, enabling risk-adapted voxel dosing. As a system example, 24 patients with glioblastoma treated with radiotherapy, temozolomide and an anti-angiogenic agent were analyzed. Pretreatment median apparent diffusion coefficient (ADC), fractional anisotropy (FA), relative cerebral blood volume (rCBV), vessel leakage (percentage recovery), choline-to-NAA index (CNI) and dose of voxels in the T2 nonenhancing lesion (NEL), T1 post-contrast enhancing lesion (CEL) or normal-appearing volume (NAV) of brain, were calculated for voxels that progressed [NAV→NEL, CEL (N = 8,765)] and compared against those that remained stable [NAV→NAV (N = 98,665)]. Voxels that progressed (NAV→NEL) had significantly different (P < 0.01) ADC (860), FA (0.36) and CNI (0.67) versus stable voxels (804, 0.43 and 0.05, respectively), indicating increased cell turnover, edema and decreased directionality, consistent with subclinical disease. NAV→CEL voxels were more abnormal (1,014, 0.28, 2.67, respectively) and leakier (percentage recovery = 70). A predictive model

  15. Correlating Structure and Function of Drug-Metabolizing Enzymes: Progress and Ongoing Challenges

    PubMed Central

    Johnson, Eric F.; Connick, J. Patrick; Reed, James R.; Backes, Wayne L.; Desai, Manoj C.; Xu, Lianhong; Estrada, D. Fernando; Laurence, Jennifer S.

    2014-01-01

    This report summarizes a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics at Experimental Biology held April 20-24 in Boston, MA. Presentations discussed the status of cytochrome P450 (P450) knowledge, emphasizing advances and challenges in relating structure with function and in applying this information to drug design. First, at least one structure of most major human drug-metabolizing P450 enzymes is known. However, the flexibility of these active sites can limit the predictive value of one structure for other ligands. A second limitation is our coarse-grain understanding of P450 interactions with membranes, other P450 enzymes, NADPH–cytochrome P450 reductase, and cytochrome b5. Recent work has examined differential P450 interactions with reductase in mixed P450 systems and P450:P450 complexes in reconstituted systems and cells, suggesting another level of functional control. In addition, protein nuclear magnetic resonance is a new approach to probe these protein/protein interactions, identifying interacting b5 and P450 surfaces, showing that b5 and reductase binding are mutually exclusive, and demonstrating ligand modulation of CYP17A1/b5 interactions. One desired outcome is the application of such information to control drug metabolism and/or design selective P450 inhibitors. A final presentation highlighted development of a CYP3A4 inhibitor that slows clearance of human immunodeficiency virus drugs otherwise rapidly metabolized by CYP3A4. Although understanding P450 structure/function relationships is an ongoing challenge, translational advances will benefit from continued integration of existing and new biophysical approaches. PMID:24130370

  16. Correlating structure and function of drug-metabolizing enzymes: progress and ongoing challenges.

    PubMed

    Johnson, Eric F; Connick, J Patrick; Reed, James R; Backes, Wayne L; Desai, Manoj C; Xu, Lianhong; Estrada, D Fernando; Laurence, Jennifer S; Scott, Emily E

    2014-01-01

    This report summarizes a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics at Experimental Biology held April 20-24 in Boston, MA. Presentations discussed the status of cytochrome P450 (P450) knowledge, emphasizing advances and challenges in relating structure with function and in applying this information to drug design. First, at least one structure of most major human drug-metabolizing P450 enzymes is known. However, the flexibility of these active sites can limit the predictive value of one structure for other ligands. A second limitation is our coarse-grain understanding of P450 interactions with membranes, other P450 enzymes, NADPH-cytochrome P450 reductase, and cytochrome b5. Recent work has examined differential P450 interactions with reductase in mixed P450 systems and P450:P450 complexes in reconstituted systems and cells, suggesting another level of functional control. In addition, protein nuclear magnetic resonance is a new approach to probe these protein/protein interactions, identifying interacting b5 and P450 surfaces, showing that b5 and reductase binding are mutually exclusive, and demonstrating ligand modulation of CYP17A1/b5 interactions. One desired outcome is the application of such information to control drug metabolism and/or design selective P450 inhibitors. A final presentation highlighted development of a CYP3A4 inhibitor that slows clearance of human immunodeficiency virus drugs otherwise rapidly metabolized by CYP3A4. Although understanding P450 structure/function relationships is an ongoing challenge, translational advances will benefit from continued integration of existing and new biophysical approaches.

  17. Testosterone deficiency induced by progressive stages of diabetes mellitus impairs glucose metabolism and favors glycogenesis in mature rat Sertoli cells.

    PubMed

    Rato, Luís; Alves, Marco G; Duarte, Ana I; Santos, Maria S; Moreira, Paula I; Cavaco, José E; Oliveira, Pedro F

    2015-09-01

    The incidence of type 2 diabetes mellitus and its prodromal stage, pre-diabetes, is rapidly increasing among young men, leading to disturbances in testosterone synthesis. However, the impact of testosterone deficiency induced by these progressive stages of diabetes on the metabolic behavior of Sertoli cells remains unknown. We evaluated the effects of testosterone deficiency associated with pre-diabetes and type 2 diabetes on Sertoli cells metabolism, by measuring (1) the expression and/or activities of glycolysis and glycogen metabolism-related proteins and (2) the metabolite secretion/consumption in Sertoli cells obtained from rat models of different development stages of the disease, to unveil the mechanisms by which testosterone deregulation may affect spermatogenesis. Glucose and pyruvate uptake were decreased in cells exposed to the testosterone concentration found in pre-diabetic rats (600nM), whereas the decreased testosterone concentrations found in type 2 diabetic rats (7nM) reversed this profile. Lactate production was not altered, although the expression and/or activity of lactate dehydrogenase and monocarboxylate transporter 4 were affected by progressive testosterone-deficiency. Sertoli cells exposed to type 2 diabetic conditions exhibited intracellular glycogen accumulation. These results illustrate that gradually reduced levels of testosterone, induced by progressive stages of diabetes mellitus, favor a metabolic reprogramming toward glycogen synthesis. Our data highlights a pivotal role for testosterone in the regulation of spermatogenesis metabolic support by Sertoli cells, particularly in individuals suffering from metabolic diseases. Such alterations may be in the basis of male subfertility/infertility associated with the progression of diabetes mellitus.

  18. Global reprogramming of transcription and metabolism in Medicago truncatula during progressive drought and after rewatering.

    PubMed

    Zhang, Ji-Yi; Cruz DE Carvalho, Maria H; Torres-Jerez, Ivone; Kang, Yun; Allen, Stacy N; Huhman, David V; Tang, Yuhong; Murray, Jeremy; Sumner, Lloyd W; Udvardi, Michael K

    2014-11-01

    Medicago truncatula is a model legume forage crop native to the arid and semi-arid environments of the Mediterranean. Given its drought-adapted nature, it is an ideal candidate to study the molecular and biochemical mechanisms conferring drought resistance in plants. Medicago plants were subjected to a progressive drought stress over 14 d of water withholding followed by rewatering under controlled environmental conditions. Based on physiological measurements of plant water status and changes in morphology, plants experienced mild, moderate and severe water stress before rehydration. Transcriptome analysis of roots and shoots from control, mildly, moderately and severely stressed, and rewatered plants, identified many thousands of genes that were altered in expression in response to drought. Many genes with expression tightly coupled to the plant water potential (i.e. drought intensity) were identified suggesting an involvement in Medicago drought adaptation responses. Metabolite profiling of drought-stressed plants revealed the presence of 135 polar and 165 non-polar compounds in roots and shoots. Combining Medicago metabolomic data with transcriptomic data yielded insight into the regulation of metabolic pathways operating under drought stress. Among the metabolites detected in drought-stressed Medicago plants, myo-inositol and proline had striking regulatory profiles indicating involvement in Medicago drought tolerance. © 2014 The Authors. Plant, Cell & Environment published by John Wiley & Sons Ltd.

  19. Metabolic Profiling of IDH Mutation and Malignant Progression in Infiltrating Glioma

    PubMed Central

    Jalbert, Llewellyn E.; Elkhaled, Adam; Phillips, Joanna J.; Neill, Evan; Williams, Aurelia; Crane, Jason C.; Olson, Marram P.; Molinaro, Annette M.; Berger, Mitchel S.; Kurhanewicz, John; Ronen, Sabrina M.; Chang, Susan M.; Nelson, Sarah J.

    2017-01-01

    Infiltrating low grade gliomas (LGGs) are heterogeneous in their behavior and the strategies used for clinical management are highly variable. A key factor in clinical decision-making is that patients with mutations in the isocitrate dehydrogenase 1 and 2 (IDH1/2) oncogenes are more likely to have a favorable outcome and be sensitive to treatment. Because of their relatively long overall median survival, more aggressive treatments are typically reserved for patients that have undergone malignant progression (MP) to an anaplastic glioma or secondary glioblastoma (GBM). In the current study, ex vivo metabolic profiles of image-guided tissue samples obtained from patients with newly diagnosed and recurrent LGG were investigated using proton high-resolution magic angle spinning spectroscopy (1H HR-MAS). Distinct spectral profiles were observed for lesions with IDH-mutated genotypes, between astrocytoma and oligodendroglioma histologies, as well as for tumors that had undergone MP. Levels of 2-hydroxyglutarate (2HG) were correlated with increased mitotic activity, axonal disruption, vascular neoplasia, and with several brain metabolites including the choline species, glutamate, glutathione, and GABA. The information obtained in this study may be used to develop strategies for in vivo characterization of infiltrative glioma, in order to improve disease stratification and to assist in monitoring response to therapy. PMID:28327577

  20. Nuclear Reprogramming: Kinetics of Cell Cycle and Metabolic Progression as Determinants of Success

    PubMed Central

    Balbach, Sebastian Thomas; Esteves, Telma Cristina; Houghton, Franchesca Dawn; Siatkowski, Marcin; Pfeiffer, Martin Johannes; Tsurumi, Chizuko; Kanzler, Benoit; Fuellen, Georg; Boiani, Michele

    2012-01-01

    Establishment of totipotency after somatic cell nuclear transfer (NT) requires not only reprogramming of gene expression, but also conversion of the cell cycle from quiescence to the precisely timed sequence of embryonic cleavage. Inadequate adaptation of the somatic nucleus to the embryonic cell cycle regime may lay the foundation for NT embryo failure and their reported lower cell counts. We combined bright field and fluorescence imaging of histone H2b-GFP expressing mouse embryos, to record cell divisions up to the blastocyst stage. This allowed us to quantitatively analyze cleavage kinetics of cloned embryos and revealed an extended and inconstant duration of the second and third cell cycles compared to fertilized controls generated by intracytoplasmic sperm injection (ICSI). Compared to fertilized embryos, slow and fast cleaving NT embryos presented similar rates of errors in M phase, but were considerably less tolerant to mitotic errors and underwent cleavage arrest. Although NT embryos vary substantially in their speed of cell cycle progression, transcriptome analysis did not detect systematic differences between fast and slow NT embryos. Profiling of amino acid turnover during pre-implantation development revealed that NT embryos consume lower amounts of amino acids, in particular arginine, than fertilized embryos until morula stage. An increased arginine supplementation enhanced development to blastocyst and increased embryo cell numbers. We conclude that a cell cycle delay, which is independent of pluripotency marker reactivation, and metabolic restraints reduce cell counts of NT embryos and impede their development. PMID:22530006

  1. Metabolic Profiling of IDH Mutation and Malignant Progression in Infiltrating Glioma

    NASA Astrophysics Data System (ADS)

    Jalbert, Llewellyn E.; Elkhaled, Adam; Phillips, Joanna J.; Neill, Evan; Williams, Aurelia; Crane, Jason C.; Olson, Marram P.; Molinaro, Annette M.; Berger, Mitchel S.; Kurhanewicz, John; Ronen, Sabrina M.; Chang, Susan M.; Nelson, Sarah J.

    2017-03-01

    Infiltrating low grade gliomas (LGGs) are heterogeneous in their behavior and the strategies used for clinical management are highly variable. A key factor in clinical decision-making is that patients with mutations in the isocitrate dehydrogenase 1 and 2 (IDH1/2) oncogenes are more likely to have a favorable outcome and be sensitive to treatment. Because of their relatively long overall median survival, more aggressive treatments are typically reserved for patients that have undergone malignant progression (MP) to an anaplastic glioma or secondary glioblastoma (GBM). In the current study, ex vivo metabolic profiles of image-guided tissue samples obtained from patients with newly diagnosed and recurrent LGG were investigated using proton high-resolution magic angle spinning spectroscopy (1H HR-MAS). Distinct spectral profiles were observed for lesions with IDH-mutated genotypes, between astrocytoma and oligodendroglioma histologies, as well as for tumors that had undergone MP. Levels of 2-hydroxyglutarate (2HG) were correlated with increased mitotic activity, axonal disruption, vascular neoplasia, and with several brain metabolites including the choline species, glutamate, glutathione, and GABA. The information obtained in this study may be used to develop strategies for in vivo characterization of infiltrative glioma, in order to improve disease stratification and to assist in monitoring response to therapy.

  2. Quantitative Tools for Dissection of Hydrogen-Producing Metabolic Networks-Final Report

    SciTech Connect

    Rabinowitz, Joshua D.; Dismukes, G.Charles.; Rabitz, Herschel A.; Amador-Noguez, Daniel

    2012-10-19

    During this project we have pioneered the development of integrated experimental-computational technologies for the quantitative dissection of metabolism in hydrogen and biofuel producing microorganisms (i.e. C. acetobutylicum and various cyanobacteria species). The application of these new methodologies resulted in many significant advances in the understanding of the metabolic networks and metabolism of these organisms, and has provided new strategies to enhance their hydrogen or biofuel producing capabilities. As an example, using mass spectrometry, isotope tracers, and quantitative flux-modeling we mapped the metabolic network structure in C. acetobutylicum. This resulted in a comprehensive and quantitative understanding of central carbon metabolism that could not have been obtained using genomic data alone. We discovered that biofuel production in this bacterium, which only occurs during stationary phase, requires a global remodeling of central metabolism (involving large changes in metabolite concentrations and fluxes) that has the effect of redirecting resources (carbon and reducing power) from biomass production into solvent production. This new holistic, quantitative understanding of metabolism is now being used as the basis for metabolic engineering strategies to improve solvent production in this bacterium. In another example, making use of newly developed technologies for monitoring hydrogen and NAD(P)H levels in vivo, we dissected the metabolic pathways for photobiological hydrogen production by cyanobacteria Cyanothece sp. This investigation led to the identification of multiple targets for improving hydrogen production. Importantly, the quantitative tools and approaches that we have developed are broadly applicable and we are now using them to investigate other important biofuel producers, such as cellulolytic bacteria.

  3. Genetic alterations in fatty acid transport and metabolism genes are associated with metastatic progression and poor prognosis of human cancers.

    PubMed

    Nath, Aritro; Chan, Christina

    2016-01-04

    Reprogramming of cellular metabolism is a hallmark feature of cancer cells. While a distinct set of processes drive metastasis when compared to tumorigenesis, it is yet unclear if genetic alterations in metabolic pathways are associated with metastatic progression of human cancers. Here, we analyzed the mutation, copy number variation and gene expression patterns of a literature-derived model of metabolic genes associated with glycolysis (Warburg effect), fatty acid metabolism (lipogenesis, oxidation, lipolysis, esterification) and fatty acid uptake in >9000 primary or metastatic tumor samples from the multi-cancer TCGA datasets. Our association analysis revealed a uniform pattern of Warburg effect mutations influencing prognosis across all tumor types, while copy number alterations in the electron transport chain gene SCO2, fatty acid uptake (CAV1, CD36) and lipogenesis (PPARA, PPARD, MLXIPL) genes were enriched in metastatic tumors. Using gene expression profiles, we established a gene-signature (CAV1, CD36, MLXIPL, CPT1C, CYP2E1) that strongly associated with epithelial-mesenchymal program across multiple cancers. Moreover, stratification of samples based on the copy number or expression profiles of the genes identified in our analysis revealed a significant effect on patient survival rates, thus confirming prominent roles of fatty acid uptake and metabolism in metastatic progression and poor prognosis of human cancers.

  4. Genetic alterations in fatty acid transport and metabolism genes are associated with metastatic progression and poor prognosis of human cancers

    PubMed Central

    Nath, Aritro; Chan, Christina

    2016-01-01

    Reprogramming of cellular metabolism is a hallmark feature of cancer cells. While a distinct set of processes drive metastasis when compared to tumorigenesis, it is yet unclear if genetic alterations in metabolic pathways are associated with metastatic progression of human cancers. Here, we analyzed the mutation, copy number variation and gene expression patterns of a literature-derived model of metabolic genes associated with glycolysis (Warburg effect), fatty acid metabolism (lipogenesis, oxidation, lipolysis, esterification) and fatty acid uptake in >9000 primary or metastatic tumor samples from the multi-cancer TCGA datasets. Our association analysis revealed a uniform pattern of Warburg effect mutations influencing prognosis across all tumor types, while copy number alterations in the electron transport chain gene SCO2, fatty acid uptake (CAV1, CD36) and lipogenesis (PPARA, PPARD, MLXIPL) genes were enriched in metastatic tumors. Using gene expression profiles, we established a gene-signature (CAV1, CD36, MLXIPL, CPT1C, CYP2E1) that strongly associated with epithelial-mesenchymal program across multiple cancers. Moreover, stratification of samples based on the copy number or expression profiles of the genes identified in our analysis revealed a significant effect on patient survival rates, thus confirming prominent roles of fatty acid uptake and metabolism in metastatic progression and poor prognosis of human cancers. PMID:26725848

  5. FINAL Progress Report DOE Grant DE-FG02-04ER15587

    SciTech Connect

    Mullins, Charles Buddie

    2016-11-03

    Catalysis Program - Viviane Schwartz Program Manager This Final Report discusses several archival journal articles that have been published that present and discuss the results that were discovered through this DOE grant.

  6. Mineral metabolism factors predict accelerated progression of common carotid intima-media thickness in chronic kidney disease: the NEFRONA study.

    PubMed

    Abajo, Maria; Betriu, Àngels; Arroyo, David; Gracia, Marta; Del Pino, M Dolores; Martínez, Isabel; Valdivielso, Jose M; Fernández, Elvira

    2016-08-27

    The leading cause of premature death in chronic kidney disease (CKD) is cardiovascular disease (CVD), but risk assessment in renal patients is challenging. The aim of the study was to analyse the factors that predict accelerated progression of common carotid intima-media thickness (CCIMT) in a CKD cohort after 2 years of follow-up (2010-12). The study included 1152 patients from the NEFRONA cohort with CKD stages 3-5D and without a clinical history of CVD. CCIMT was measured at the far wall on both common carotids. CCIMT progression was defined as the change between CCIMT at baseline and at 24 months for each side, averaged and normalized as change per year. Accelerated progressors were defined as those with a CCIMT change ≥75th percentile. The median CCIMT progression rate was 0.0125 mm/year, without significant differences between CKD stages. The cut-off value for defining accelerated progression was 0.0425 mm/year. After adjustment, age was a common factor among all CKD stages. Traditional cardiovascular risk factors, such as diabetes and systolic blood pressure, were predictors of progression in CKD stages 4-5, whereas high-density lipoprotein and low-density lipoprotein cholesterol predicted progression in women in stage 3. Mineral metabolism factors predicting accelerated progression were serum phosphorus in stages 3 and 5D; low 25-hydroxyvitamin D and parathyroid hormone levels >110 pg/mL in stages 4-5 and intact parathyroid hormone levels out of the recommended range in stage 5D. Mineral metabolism parameters might predict accelerated CCIMT progression from early CKD stages. © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

  7. Printing and Scoring Activities, Final Report, Year 11, National Assessment of Educational Progress.

    ERIC Educational Resources Information Center

    Education Commission of the States, Denver, CO. National Assessment of Educational Progress.

    This report summarizes all Year 11 National Assessment of Educational Progress activities performed under Westinghouse DataScore Systems contracts. The general time frame for DataScore's contract activities runs from March 1979 through October 1980 (with the exception of the Year 10 Art Scoring activities which were projected for February 1981…

  8. Perspectives on Progress: The School-to-Work National Customer Dialogues. Final Report.

    ERIC Educational Resources Information Center

    Public Forum Inst., Washington, DC.

    "Perspectives on Progress: The School-to-Work (STW) National Customer Dialogues" was a series of six regional and two national discussions that were held between December 1999 and July 2000 to gather the views of more than 700 employers, educators, labor union representatives, students, parents, community-based organizations, and state…

  9. Seminar on Foci for Progress in Scientific Publications: A Summary and Final Report.

    ERIC Educational Resources Information Center

    Battelle Memorial Inst., Columbus, OH.

    A one-day seminar was convened on November 4, 1969, to consider problems involved in communicating scientific information and the progress that has been made in improving the scientific publication mechanism. Thirty participants representing different types of information producers, users, and organizations contributed to the seminar discussion.…

  10. National Assessment of Educational Progress Grade 12 Preparedness Research College Course Content Analysis Study: Final Report

    ERIC Educational Resources Information Center

    Educational Policy Improvement Center, 2014

    2014-01-01

    The National Assessment Governing Board is an independent, bipartisan organization that sets policy for the National Assessment of Educational Progress (NAEP). The Governing Board established the NAEP Program of 12th Grade Preparedness Research to assess what NAEP can report on the academic preparedness of 12th grade students entering college and…

  11. Regulation of alcohol fermentation in Escherichia coli: (Final) progress report, July 1985--June 1988

    SciTech Connect

    Clark, D.P.

    1988-01-01

    This report describes progress in research on the biochemical degradation of alcohols by genetically modified bacteria. Topics include the genetics of the adh system, the characterization of the ADH/ACDH protein, the regulation of the adh gene, the isolation of two lactate dehydrogenase mutants, mutations that affect anaerobic growth, and regulation of the anaerobic gene fusions. (TEM)

  12. Development of Career Progression Systems for Employees in the Foodservice Industry. Final Report.

    ERIC Educational Resources Information Center

    National Restaurant Association, Chicago, IL.

    Firms representing four segments of the foodservice industry (institutional foodservice (9 jobs), commercial restaurants (19 jobs), hotel foodservice (100 jobs), and airline foodservice (10 jobs), participated in a career and training study to test the feasibility of designing and implementing career progression (c.p.) systems within these…

  13. Integration of Carbon, Nitrogen, and Oxygen Metabolism in Escherichia coli--Final Report

    SciTech Connect

    Rabinowitz, Joshua D; Wingreen, Ned s; Rabitz, Herschel A; Xu, Yifan

    2012-10-22

    A key challenge for living systems is balancing utilization of multiple elemental nutrients, such as carbon, nitrogen, and oxygen, whose availability is subject to environmental fluctuations. As growth can be limited by the scarcity of any one nutrient, the rate at which each nutrient is assimilated must be sensitive not only to its own availability, but also to that of other nutrients. Remarkably, across diverse nutrient conditions, E. coli grows nearly optimally, balancing effectively the conversion of carbon into energy versus biomass. To investigate the link between the metabolism of different nutrients, we quantified metabolic responses to nutrient perturbations using LC-MS based metabolomics and built differential equation models that bridge multiple nutrient systems. We discovered that the carbonaceous substrate of nitrogen assimilation, -ketoglutarate, directly inhibits glucose uptake and that the upstream glycolytic metabolite, fructose-1,6-bisphosphate, ultrasensitively regulates anaplerosis to allow rapid adaptation to changing carbon availability. We also showed that NADH controls the metabolic response to changing oxygen levels. Our findings support a general mechanism for nutrient integration: limitation for a nutrient other than carbon leads to build-up of the most closely related product of carbon metabolism, which in turn feedback inhibits further carbon uptake.

  14. Metabolism of proposed nerve agent pretreatment, pyridostigmine bromide. Final report, December 1995-December 1996

    SciTech Connect

    Leo, K.U.

    1996-12-01

    A reverse phase High Pressure Liquid Chromatography (HPLC) method was developed to separate pyridostigmine bromide from four potential metabolites. Using male and female microsomes from both rat and human, our data suggest that pyridostigmine bromide is not metabolized by the human live microsomes or DNA expressed human CYP-450s via direct observation of no metabolites being formed for incubations up to 90 minutes. Indirect evidence that pyridostigmine metabolism is not via the major human hepatic CYP-450s involved in drug metabolism, 1A2, 2C9, 2E1, 2D6, and 3A4, was observed by failure to inhibit these isozymes while co-incubated with substrates specific for those isozymes at concentrations of 2-3 times Km. The following CYP-450 substrates were co-incubated with pyridostigmine: phenacetin, tolbutamide, chlorzoxazone, bufuralol, and testosterone. Using unlabelled and 14C-pyridostigmine, metabolite formation was not observed in both male and female rat and human subcellular fractions, specifically cytosol and S9, or under conditions favoring human FMO activity (pH 8.3). These findings indicate the metabolism of pyridostigmine bromide is unlikely to be under any component of sexual dimorphism.

  15. D-erythroascorbic acid: Its preparations, chemistry, and metabolism (fungi and plants). Final report

    SciTech Connect

    Loewus, F.A.; Seib, P.A.

    1991-12-31

    The origin of oxalate in plants has received considerable attention and glycolate metabolism has been generally regarded as a prime precursor candidate although studies on the metabolism of L-ascorbic acid single out that plant constituent as well. Experiments with oxalate-accumulating plants that contain little or no tartaric acid revealed the presence of a comparable L-ascorbic acid metabolism with the exception that the cleavage products were oxalic acid and L-threonic acid or products of L-threonic acid metabolism. A reasonable mechanism for cleavage of L-ascorbic acid at the endiolic bond is found in studies on the photooxygenation of L-ascorbic acid. Presumably, analogs of L-ascorbic acid that differ only in the substituent at C4 also form a hydroperoxide in the presence of alkaline hydrogen peroxide and subsequently yield oxalic acid and the corresponding aldonic acid or its lactone. We became interested in such a possibility when we discovered that L-ascorbic acid was rare or absent in certain yeasts and fungi whereas a L-ascorbic acid analog, D-glycero-pent-2-enono- 1,4-lactone (D-erythroascorbic acid), was present. It has long been known that oxalate occurs in yeasts and fungi and its production plays a role in plant pathogenesis. As to the biosynthetic origin of fungal oxalic acid there is little information although it is generally assumed that oxaloacetate or possibly, glycolate, might be that precursor.

  16. Combining Targeted Metabolomic Data with a Model of Glucose Metabolism: Toward Progress in Chondrocyte Mechanotransduction

    PubMed Central

    Salinas, Daniel; Carlson, Ross P.; McCutchen, Carley N.

    2017-01-01

    Osteoarthritis is a debilitating disease likely involving altered metabolism of the chondrocytes in articular cartilage. Chondrocytes can respond metabolically to mechanical loads via cellular mechanotransduction, and metabolic changes are significant because they produce the precursors to the tissue matrix necessary for cartilage health. However, a comprehensive understanding of how energy metabolism changes with loading remains elusive. To improve our understanding of chondrocyte mechanotransduction, we developed a computational model to calculate the rate of reactions (i.e. flux) across multiple components of central energy metabolism based on experimental data. We calculated average reaction flux profiles of central metabolism for SW1353 human chondrocytes subjected to dynamic compression for 30 minutes. The profiles were obtained solving a bounded variable linear least squares problem, representing the stoichiometry of human central energy metabolism. Compression synchronized chondrocyte energy metabolism. These data are consistent with dynamic compression inducing early time changes in central energy metabolism geared towards more active protein synthesis. Furthermore, this analysis demonstrates the utility of combining targeted metabolomic data with a computational model to enable rapid analysis of cellular energy utilization. PMID:28056047

  17. Metabolism

    MedlinePlus

    Metabolism refers to all the physical and chemical processes in the body that convert or use energy, ... Tortora GJ, Derrickson BH. Metabolism. In: Tortora GJ, Derrickson ... Physiology . 14th ed. Hoboken, NJ: John Wiley & Sons; 2014:chap ...

  18. Metabolism

    MedlinePlus

    ... El metabolismo Metabolism Basics Our bodies get the energy they need from food through metabolism, the chemical ... that convert the fuel from food into the energy needed to do everything from moving to thinking ...

  19. [Experimental and theoretical plasma physics program]. [Final progress report, 1982--1983

    SciTech Connect

    Griem, H.

    1983-12-31

    In recent years, members of the Maryland Theory Group have made significant contributions to the national fusion theory programs, and, in many cases, these theoretical developments helped to interpret experimental results and to design new experimental programs. In the following, the authors summarize the technical progress in five major areas: (1) RF interaction with plasmas including wave propagation and RF heating, (2) spheromak formation, equilibrium, and stability; (3) stability of nonaxisymmetric systems (EBT, mirrors, etc.); (4) stability theory of toroidal plasmas (tokamak, RFP, etc); and (5) nonlinear theory.

  20. Experimental Program Final Technical Progress Report: 15 February 2007 to 30 September 2012

    SciTech Connect

    Kinney, Edward R.

    2014-09-12

    This is the final technical report of the grant DE-FG02-04ER41301 to the University of Colorado at Boulder entitled "Intermediate Energy Nuclear Physics" and describes the results of our funded activities during the period 15 February 2007 to 30 September 2012. These activities were primarily carried out at Fermilab, RHIC, and the German lab DESY. Significant advances in these experiments were carried out by members of the Colorado group and are described in detail.

  1. 2001 Gordon Research Conference on Applied and Environmental Microbiology. Final progress report [agenda and attendee list

    SciTech Connect

    Drake, Harold

    2001-07-26

    The Gordon Research Conference on Applied and Environmental Microbiology was held at Connecticut College, New London, Connecticut, July 22-27, 2001. The conference was attended by 121 participants. The attendees represented the spectrum of endeavor in this field, coming from academia, industry, and government laboratories, and included US and foreign scientists, senior researchers, young investigators, and students. Emphasis was placed on current unpublished research and discussion of the future target areas in this field. There was a conscious effort to stimulate discussion about the key issues in the field today. Session topics included the following: Environmental and applied genomics, Cell-to-cell signaling and multicellular behavior, Emerging technologies and methods, Novel metabolisms and ecosystems, Directed evolution of enzymes and pathways, Symbiotic and trophic relationships, Synthesis and application of novel biopolymers, and Microbes at the oxic-anoxic interface. There was also a special lecture titled ''Under the umbrella of the big tree: microbial biology into the 21st century.''

  2. 2012 Gordon Research Conference on Cellular and Molecular Fungal Biology, Final Progress Report

    SciTech Connect

    Berman, Judith

    2012-06-22

    The Gordon Research Conference on Cellular and Molecular Fungal Biology was held at Holderness School, Holderness New Hampshire, June 17 - 22, 2012. The 2012 Gordon Conference on Cellular and Molecular Fungal Biology (CMFB) will present the latest, cutting-edge research on the exciting and growing field of molecular and cellular aspects of fungal biology. Topics will range from yeast to filamentous fungi, from model systems to economically important organisms, and from saprophytes and commensals to pathogens of plants and animals. The CMFB conference will feature a wide range of topics including systems biology, cell biology and morphogenesis, organismal interactions, genome organisation and regulation, pathogenesis, energy metabolism, biomass production and population genomics. The Conference was well-attended with 136 participants. Gordon Research Conferences does not permit publication of meeting proceedings.

  3. Genetics of thermophilic bacteria. Final progress report, May 1, 1984--April 30, 1991

    SciTech Connect

    Welker, N.E.

    1991-12-31

    Organisms adapted to high temperature have evolved a variety of unique solutions to the biochemical problems imposed by this environment. Adaptation is commonly used to describe the biochemical properties of organisms which have become adapted to their environment (genetic adaptation). It can also mean the direct response-at the cellular level-of an organism to changes in temperature (physiological adaptation). Thermophilic bacilli (strains of Bacillus stearothermophilus) can exhibit a variety of biochemical adaptations in response to changes in temperature. These include changes in the composition and stability of the membrane, metabolic potential, the transport of amino acids, regulatory mechanisms, ribose methylation of tRNA, protein thermostability, and nutritional requirements. The objectives of the research were to develop efficient and reliable genetic systems to analyze and manipulate B. Stearothermophilus, and to use these systems initiate a biochemical, molecular, and genetic investigations of genes that are required for growth at high temperature.

  4. The association between metabolic syndrome and prostate cancer: Effect on its aggressiveness and progression.

    PubMed

    Sanchís-Bonet, A; Ortiz-Vico, F; Morales-Palacios, N; Sánchez-Chapado, M

    2015-04-01

    To evaluate the impact of metabolic syndrome and its individual components on prostate biopsy findings, the radical prostatectomy specimen and on biochemical recurrence. An observational study was conducted of 1319 men who underwent prostate biopsy between January 2007 and December 2011. The impact on the biopsy findings, the radical prostatectomy specimen and biochemical recurrence was evaluated using logistic regression and Cox regression. Of the 1319 patients, 275 (21%) had metabolic syndrome, and 517 prostate cancers were diagnosed. A greater percentage of metabolic syndrome was found among patients with prostate cancer than among patients without prostate cancer (25% vs. 18%; P=.002). Poorer results were found in the radical prostatectomy specimens (Gleason score ≥ 7, P<.001; stage ≥ T2c, P<.001; positive surgical margins, P<.001), and there was a greater percentage of biochemical recurrence in patients with metabolic syndrome than in those without metabolic syndrome (24% vs. 13%; P=.003). Metabolic syndrome behaved as an independent predictive factor of finding a Gleason score ≥ 7 for the specimen, as well as for finding a specimen stage ≥ T2c. Metabolic syndrome was also able to independently predict a greater rate of biochemical recurrence (OR: 3.6, P<.001; OR: 3.2, P=.03; HR: 1.7; respectively). Metabolic syndrome is associated with poorer findings in the radical prostatectomy specimens and is an independent prognostic factor of biochemical recurrence. Copyright © 2014 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.

  5. Research progress on prevention and treatment of glucolipid metabolic disease with integrated traditional Chinese and Western medicine.

    PubMed

    Guo, Jiao

    2017-06-01

    Hyperlipidemia, type 2 diabetes mellitus, nonalcoholic fatty liver and many other metabolic disorder are frequently co-existing in patients. In addition, these diseases are closely related in pathophysiological settings. However, increasing of the disease incidence, lacking of comprehensive prevention and control measurements against the key pathology point concomitant occurrence with the pattern of the single disease, single target therapy, that is leading therapeutic strategy for these metabolic disorders in the setting of Western medicine (WM). On the basis of the combination of the advantages of integrated Chinese medicine (CM) and WM, with unified understanding of such diseases, the new concept of glucolipid metabolic disease (GLMD) is introduced. In this new concept, disorders in glucose and lipid metabolism are recognized as the key trigger and major driving force for the progress of GLMD. The key points of pathology included dysfunction of neuronal-endocrine-immune system, insulin resistance, oxidative stress, inflammation and intestinal flora imbalance. In the core pathogenic perspective of CM, it can be explained as "Gan (Liver) Shi Shu Xie" (dysfunction of Gan in metabolism and emotion regulation) that will lead to the occurence/production of endogenous dampness and phlegm, blood stasis and turbid. This leads to the new concept of "Liver-based regulatory system for metabolic homeostasis" to be introduced further. The comprehensive prevention and control strategy "Tiao Gan Qi Shu Hua Zhuo" (modulating Gan, trigging key metabolic system to resolve pathogenic factors such as phlegm retention and dampness). Its representative formula Fufang Zhenzhu Tiaozhi Capsule () is innovated under such rationales. Comment for some commonly-used CM GLMD therapeutic drugs was presented. High-level evidence-based and epidemiological and mechanism studies should be carried out to further interpret and explain of the scientific connotation of GLMD.

  6. Medium-energy nuclear physics research. Final technical progress report, May 1, 1971-November 30, 1981

    SciTech Connect

    Willard, H.B.

    1981-11-30

    Final results are summarized for this program with the primary emphasis on measurement of ten independent parameters for proton-proton elastic scattering at 800 MeV and four independent such parameters at 650 MeV. Inelastic proton-proton reactions have also been measured at 800 MeV. Proton-deuteron elastic scattering cross sections and polarization analyzing powers have been obtained at 800 MeV. Proton-nucleus total and total reaction cross sections were measured at 700 MeV for a number of nuclei. Major instrumentation was designed and constructed to carry out this program.

  7. [Tampa Electric Company IGCC project]. Final public design report; Technical progress report

    SciTech Connect

    1996-07-01

    This final Public Design Report (PDR) provides completed design information about Tampa Electric Company`s Polk Power Station Unit No. 1, which will demonstrate in a commercial 250 MW unit the operating parameters and benefits of the integration of oxygen-blown, entrained-flow coal gasification with advanced combined cycle technology. Pending development of technically and commercially viable sorbent for the Hot Gas Cleanup System, the HGCU also is demonstrated. The report is organized under the following sections: design basis description; plant descriptions; plant systems; project costs and schedule; heat and material balances; general arrangement drawings; equipment list; and miscellaneous drawings.

  8. Implications of quantum metabolism and natural selection for the origin of cancer cells and tumor progression.

    PubMed

    Davies, Paul; Demetrius, Lloyd A; Tuszynski, Jack A

    2012-03-01

    Empirical studies give increased support for the hypothesis that the sporadic form of cancer is an age-related metabolic disease characterized by: (a) metabolic dysregulation with random abnormalities in mitochondrial DNA, and (b) metabolic alteration - the compensatory upregulation of glycolysis to offset mitochondrial impairments. This paper appeals to the theory of Quantum Metabolism and the principles of natural selection to formulate a conceptual framework for a quantitative analysis of the origin and proliferation of the disease. Quantum Metabolism, an analytical theory of energy transduction in cells inspired by the methodology of the quantum theory of solids, elucidates the molecular basis for differences in metabolic rate between normal cells, utilizing predominantly oxidative phosphorylation, and cancer cells utilizing predominantly glycolysis. The principles of natural selection account for the outcome of competition between the two classes of cells. Quantum Metabolism and the principles of natural selection give an ontogenic and evolutionary rationale for cancer proliferation and furnish a framework for effective therapeutic strategies to impede the spread of the disease.

  9. Implications of quantum metabolism and natural selection for the origin of cancer cells and tumor progression

    NASA Astrophysics Data System (ADS)

    Davies, Paul; Demetrius, Lloyd A.; Tuszynski, Jack A.

    2012-03-01

    Empirical studies give increased support for the hypothesis that the sporadic form of cancer is an age-related metabolic disease characterized by: (a) metabolic dysregulation with random abnormalities in mitochondrial DNA, and (b) metabolic alteration - the compensatory upregulation of glycolysis to offset mitochondrial impairments. This paper appeals to the theory of Quantum Metabolism and the principles of natural selection to formulate a conceptual framework for a quantitative analysis of the origin and proliferation of the disease. Quantum Metabolism, an analytical theory of energy transduction in cells inspired by the methodology of the quantum theory of solids, elucidates the molecular basis for differences in metabolic rate between normal cells, utilizing predominantly oxidative phosphorylation, and cancer cells utilizing predominantly glycolysis. The principles of natural selection account for the outcome of competition between the two classes of cells. Quantum Metabolism and the principles of natural selection give an ontogenic and evolutionary rationale for cancer proliferation and furnish a framework for effective therapeutic strategies to impede the spread of the disease.

  10. Carbon metabolism in legume nodules. Progress report, July 1982-July 1983

    SciTech Connect

    LaRue, T.A.

    1983-01-01

    The goal is to understand how the legume nodule metabolizes carbohydrate to provide energy and reductant for symbiotic fixation. The working hypothesis has been that the plant cytosol is microacrobic and that some carbon metabolism may be via anaerobic pathways similar to those in roots of flood tolerant plants. A method of analyzing redox changes in intact mitochondria, bacteroids or bacteria was adapted; a method of manipulating nitrogenase activity by oxygen inhibition was developed; the production of alcohol by soybean nodules was studied; and enzymes metabolizing alcohol/aldehyde were found in other nitrogen fixing systems. (ACR)

  11. Energy efficient louver and blind. Final technical progress report, third quarter 1996

    SciTech Connect

    Khajavi, S.

    1996-10-14

    In the month of July, we completed the energy testing at Lawrence Berkeley Labs. The final testing was done with blinds in 15 degree position. This is a comfortable blind angle that allows for view of the outside while allowing for natural light to enter the room. It was found that the energy savings are much higher at this angle. At zero degree blind angle the savings were 150W/sq. meter, in the 15 degree the heat gain is cut by 225W/sq. meter. During the same period the heat gain in control chamber was 500W. (See graph plotting {open_quotes}Sample Heat Flows{close_quotes} From July 21 to 29 on next 3 pages). The heat gain reduction achieved in tests if used in commercial blinds, would result in an energy pay back period or one year and nine months.

  12. E-ELT M4 adaptive unit final design and construction: a progress report

    NASA Astrophysics Data System (ADS)

    Biasi, Roberto; Manetti, Mauro; Andrighettoni, Mario; Angerer, Gerald; Pescoller, Dietrich; Patauner, Christian; Gallieni, Daniele; Tintori, Matteo; Mantegazza, Marco; Fumi, Pierluigi; Lazzarini, Paolo; Briguglio, Runa; Xompero, Marco; Pariani, Giorgio; Riccardi, Armando; Vernet, Elise; Pettazzi, Lorenzo; Lilley, Paul; Cayrel, Marc

    2016-07-01

    The E-ELT M4 adaptive unit is a fundamental part of the E-ELT: it provides the facility level adaptive optics correction that compensates the wavefront distortion induced by atmospheric turbulence and partially corrects the structural deformations caused by wind. The unit is based on the contactless, voice-coil technology already successfully deployed on several large adaptive mirrors, like the LBT, Magellan and VLT adaptive secondary mirrors. It features a 2.4m diameter flat mirror, controlled by 5316 actuators and divided in six segments. The reference structure is monolithic and the cophasing between the segments is guaranteed by the contactless embedded metrology. The mirror correction commands are usually transferred as modal amplitudes, that are checked by the M4 controller through a smart real-time algorithm that is capable to handle saturation effects. A large hexapod provides the fine positioning of the unit, while a rotational mechanism allows switching between the two Nasmyth foci. The unit has entered the final design and construction phase in July 2015, after an advanced preliminary design. The final design review is planned for fall 2017; thereafter, the unit will enter the construction and test phase. Acceptance in Europe after full optical calibration is planned for 2022, while the delivery to Cerro Armazones will occur in 2023. Even if the fundamental concept has remained unchanged with respect to the other contactless large deformable mirrors, the specific requirements of the E-ELT unit posed new design challenges that required very peculiar solutions. Therefore, a significant part of the design phase has been focused on the validation of the new aspects, based on analysis, numerical simulations and experimental tests. Several experimental tests have been executed on the Demonstration Prototype, which is the 222 actuators prototype developed in the frame of the advanced preliminary design. We present the main project phases, the current design

  13. Comprehensive Plasma Metabolomic Analyses of Atherosclerotic Progression Reveal Alterations in Glycerophospholipid and Sphingolipid Metabolism in Apolipoprotein E-deficient Mice

    PubMed Central

    Dang, Vi T.; Huang, Aric; Zhong, Lexy H.; Shi, Yuanyuan; Werstuck, Geoff H.

    2016-01-01

    Atherosclerosis is the major underlying cause of most cardiovascular diseases. Despite recent advances, the molecular mechanisms underlying the pathophysiology of atherogenesis are not clear. In this study, comprehensive plasma metabolomics were used to investigate early-stage atherosclerotic development and progression in chow-fed apolipoprotein E-deficient mice at 5, 10 and 15 weeks of age. Comprehensive plasma metabolomic profiles, based on 4365 detected metabolite features, differentiate atherosclerosis-prone from atherosclerosis-resistant models. Metabolites in the sphingomyelin pathway were significantly altered prior to detectable lesion formation and at all subsequent time-points. The cytidine diphosphate-diacylglycerol pathway was up-regulated during stage I of atherosclerosis, while metabolites in the phosphatidylethanolamine and glycosphingolipid pathways were augmented in mice with stage II lesions. These pathways, involving glycerophospholipid and sphingolipid metabolism, were also significantly affected during the course of atherosclerotic progression. Our findings suggest that distinct plasma metabolomic profiles can differentiate the different stages of atherosclerotic progression. This study reveals that alteration of specific, previously unreported pathways of glycerophospholipid and sphingolipid metabolism are associated with atherosclerosis. The clear difference in the level of several metabolites supports the use of plasma lipid profiling as a diagnostic tool of atherogenesis. PMID:27721472

  14. Final Progress Report: Coupled Biogeochemical Process Evaluation for Conceptualizing Trichloroethylene Cometabolism

    SciTech Connect

    Crawford, Ronald L; Paszczynski, Andrzej J

    2010-02-19

    Our goal within the overall project is to demonstrate the presence and abundance of methane monooxygenases (MMOs) enzymes and their genes within the microbial community of the Idaho National Laboratory (INL) Test Area North (TAN) site. MMOs are thought to be the primary catalysts of natural attenuation of trichloroethylene (TCE) in contaminated groundwater at this location. The actual presence of the proteins making up MMO complexes would provide direct evidence for its participation in TCE degradation. The quantitative estimation of MMO genes and their translation products (sMMO and pMMO proteins) and the knowledge about kinetics and substrate specificity of MMOs will be used to develop mathematical models of the natural attenuation process in the TAN aquifer. The model will be particularly useful in prediction of TCE degradation rate in TAN and possibly in the other DOE sites. Bacteria known as methanotrophs produce a set of proteins that assemble to form methane monooxygenase complexes (MMOs), enzymes that oxidize methane as their natural substrate, thereby providing a carbon and energy source for the organisms. MMOs are also capable of co-metabolically transforming chlorinated solvents like TCE into nontoxic end products such as carbon dioxide and chloride. There are two known forms of methane monooxygenase, a membrane-bound particulate form (pMMO) and a cytoplasmic soluble form (sMMO). pMMO consists of two components, pMMOH (a hydroxylase comprised of 47-, 27-, and 24-kDa subunits) and pMMOR (a reductase comprised of 63 and 8-kDa subunits). sMMO consists of three components: a hydroxylase (protein A-250 kDa), a dimer of three subunits (α2β2γ2), a regulatory protein (protein B-15.8 kDa), and a reductase (protein C-38.6 kDa). All methanotrophs will produce a methanol dehydrogenase to channel the product of methane oxidation (methanol) into the central metabolite formaldehyde. University of Idaho (UI) efforts focused on proteomic analyses using mass

  15. FY08 LDRD Final Report Probabilistic Inference of Metabolic Pathways from Metagenomic Sequence Data

    SciTech Connect

    D'haeseleer, P

    2009-03-01

    Metagenomic 'shotgun' sequencing of environmental microbial communities has the potential to revolutionize microbial ecology, allowing a cultivation-independent, yet sequence-based analysis of the metabolic capabilities and functions present in an environmental sample. Although its intensive sequencing requirements are a good match for the continuously increasing bandwidth at sequencing centers, the complexity, seemingly inexhaustible novelty, and 'scrambled' nature of metagenomic data is also proving a tremendous challenge for analysis. In fact, many metagenomics projects do not go much further than providing a list of novel gene variants and over- or under-represented functional gene categories. In this project, we proposed to develop a set of novel metagenomic sequence analysis tools, including a binning method to group sequences by species, inference of phenotypes and metabolic pathways from these reconstructed species, and extraction of coarse-grained flux models. We proposed to closely collaborate with the DOE Joint Genome Institute to align these tools with their metagenomics analysis needs and the developing IMG/M metagenomics pipeline. Results would be cross-validated with simulated metagenomic data using a testing platform developed at the JGI.

  16. Advanced Coal Conversion Process Demonstration Project. Final technical progress report, January 1, 1995--December 31, 1995

    SciTech Connect

    1997-05-01

    This report describes the technical progress made on the Advanced Coal Conversion Process (ACCP) Demonstration Project from January 1, 1995 through December 31, 1995. This project demonstrates an advanced, thermal, coal upgrading process, coupled with physical cleaning techniques, that is designed to upgrade high-moisture, low-rank coals to a high-quality, low-sulfur fuel, registered as the SynCoal Process. The coal is processed through three stages (two heating stages followed by an inert cooling stage) of vibrating fluidized bed reactors that remove chemically bound water, carboxyl groups, and volatile sulfur compounds. After thermal upgrading, the coal is put through a deep-bed stratifier cleaning process to separate the pyrite-rich ash from the coal. The SynCoal Process enhances low-rank, western coals, usually with a moisture content of 25 to 55 percent, sulfur content of 0.5 to 1.5 percent, and heating value of 5,5000 to 9,000 British thermal units per pound (Btu/lb), by producing a stable, upgraded, coal product with a moisture content as low as 1 percent, sulfur content as low as 0.3 percent, and heating value up to 12,000 Btu/lb. During this reporting period, the primary focus for the ACCP Demonstration Project team was to expand SynCoal market awareness and acceptability for both the products and the technology. The ACCP Project team continued to focus on improving the operation, developing commercial markets, and improving the SynCoal products as well as the product`s acceptance.

  17. Final Progress Report for Award DE-FG07-05ID14637.pdf

    SciTech Connect

    Cathy Dixon

    2012-03-09

    2004-2011 Final Report for AFCI University Fellowship Program. The goal of this effort was to be supportive of university students and university programs - particularly those students and programs that will help to strengthen the development of nuclear-related fields. The program also supported the stability of the nuclear infrastructure and developed research partnerships that are helping to enlarge the national nuclear science technology base. In this fellowship program, the U.S. Department of Energy sought master's degree students in nuclear, mechanical, or chemical engineering, engineering/applied physics, physics, chemistry, radiochemistry, or fields of science and engineering applicable to the AFCI/Gen IV/GNEP missions in order to meet future U.S. nuclear program needs. The fellowship program identified candidates and selected full time students of high-caliber who were taking nuclear courses as part of their degree programs. The DOE Academic Program Managers encouraged fellows to pursue summer internships at national laboratories and supported the students with appropriate information so that both the fellows and the nation's nuclear energy objectives were successful.

  18. Final Progress Report: Isotope Identification Algorithm for Rapid and Accurate Determination of Radioisotopes Feasibility Study

    SciTech Connect

    Rawool-Sullivan, Mohini; Bounds, John Alan; Brumby, Steven P.; Prasad, Lakshman; Sullivan, John P.

    2012-04-30

    This is the final report of the project titled, 'Isotope Identification Algorithm for Rapid and Accurate Determination of Radioisotopes,' PMIS project number LA10-HUMANID-PD03. The goal of the work was to demonstrate principles of emulating a human analysis approach towards the data collected using radiation isotope identification devices (RIIDs). It summarizes work performed over the FY10 time period. The goal of the work was to demonstrate principles of emulating a human analysis approach towards the data collected using radiation isotope identification devices (RIIDs). Human analysts begin analyzing a spectrum based on features in the spectrum - lines and shapes that are present in a given spectrum. The proposed work was to carry out a feasibility study that will pick out all gamma ray peaks and other features such as Compton edges, bremsstrahlung, presence/absence of shielding and presence of neutrons and escape peaks. Ultimately success of this feasibility study will allow us to collectively explain identified features and form a realistic scenario that produced a given spectrum in the future. We wanted to develop and demonstrate machine learning algorithms that will qualitatively enhance the automated identification capabilities of portable radiological sensors that are currently being used in the field.

  19. Theoretical studies in nuclear structure. Final progress report, June 1, 1991--July 31, 1996

    SciTech Connect

    Marshalek, E.R.

    1997-06-01

    The general purview of the project is the theory of collective motion in atomic nuclei. The chief aim is to elucidate the phenomena of (1) anharmonic multiphonon excitations, and (2) collective tilted rotation, both of which are topics of considerable current interest. In the primary stage of an investigation it is often necessary to develop appropriate mathematical tools, as was the case here. In the next stage, the formalism must be tested on simple soluble models. The work described here is mainly concerned with these two stages. The final stage of realistic applications will require more time, manpower and, of course, the necessary funding. Some planning for this last stage has been carried out and anticipated problems axe briefly discussed. As it turns out, both of the above topics can be approached within the unified framework of a theorem that I developed, called the Cranking Bifurcation Theorem (CBT) to be described below. The CBT can be regarded as an outgrowth of the boson expansion method, which provides a general, and, in principal, exact formalism for treating collective excitations. We begin with a brief discussion of the CBT and then continue on to the applications.

  20. Coal plasticity at high heating rates and temperatures. Final technical progress report

    SciTech Connect

    Gerjarusak, S.; Peters, W.A.; Howard, J.B.

    1995-05-01

    Plastic coals are important feedstocks in coke manufacture, coal liquefaction, gasification, and combustion. During these processes, the thermoplastic behavior of these coals is also important since it may contribute to desirable or undesirable characteristics. For example, during liquefaction, the plastic behavior is desired since it leads to liquid-liquid reactions which are faster than solid-liquid reactions. During gasification, the elastic behavior is undesired since it leads to caking and agglomeration of coal particles which result in bed bogging in fixed or fluidized bed gasifiers. The plastic behavior of different coals was studied using a fast-response plastometer. A modified plastometer was used to measure the torque required to turn at constant angular speed a cone-shaped disk embedded in a thin layer of coal. The coal particles were packed between two metal plates which are heated electrically. Heating rates, final temperatures, pressures, and durations of experiment ranged from 200--800 K/s, 700--1300 K, vacuum-50 atm helium, and 0--40 s, respectively. The apparent viscosity of the molten coal was calculated from the measured torque using the governing equation of the cone-and-plate viscometer. Using a concentrated suspension model, the molten coal`s apparent viscosity was related to the quantity of the liquid metaplast present during pyrolysis. Seven coals from Argonne National Laboratory Premium Coal Sample Bank were studied. Five bituminous coals, from high-volatile to low-volatile bituminous, were found to have very good plastic behavior. Coal type strongly affects the magnitude and duration of plasticity. Hvb coals were most plastic. Mvb and lvb coals, though the maximum plasticity and plastic period were less. Low rank coals such as subbituminous and lignite did not exhibit any plasticity in the present studies. Coal plasticity is moderately well correlated with simple indices of coal type such as the elemental C,O, and H contents.

  1. Carbon monoxide metabolism by the photosynthetic bacterium Rhodospirillum rubrum. Progress report, November 15, 1990--November 15, 1991

    SciTech Connect

    Ludden, P.W.; Roberts, G.P.

    1991-12-31

    Research continued on carbon monoxide metabolism by Rhodospirillum rubrum. In the past year, progress was made in: (1) the identification and isolation of the physiological electron carrier from monoxide dehydrogenase (CODH) to hydrogenase in R. rubrum; (2) the isolation, sequencing and mutagenesis of the genes encoding the components of the CO oxidation system in R. rubrum, (3) the purification and characterization of the CO-induced hydrogenase activity of R. rubrum; (4) the spectroscopic investigation of the cobalt-substituted form of the enzyme.

  2. The Cryogenic AntiCoincidence detector for ATHENA: the progress towards the final pixel design

    NASA Astrophysics Data System (ADS)

    Macculi, Claudio; Piro, Luigi; Cea, Donatella; Colasanti, Luca; Lotti, Simone; Natalucci, Lorenzo; Gatti, Flavio; Bagliani, Daniela; Biasotti, Michele; Corsini, Dario; Pizzigoni, Giulio; Torrioli, Guido; Barbera, Marco; Mineo, Teresa; Perinati, Emanuele

    2014-07-01

    related to one of the last sample produced (namely AC-S5), and steps to reach the final detector design will be discussed.

  3. Final Progress Report for the NASA Inductrack Model Rocket Launcher at the Lawrence Livermore National Laboratory

    SciTech Connect

    Tung, L S; Post, R F; Martinez-Frias, J

    2001-06-27

    The Inductrack magnetic levitation system, developed at the Lawrence Livermore National Laboratory, was studied for its possible use for launching rockets. Under NASA sponsorship, a small model system was constructed at the Laboratory to pursue key technical aspects of this proposed application. The Inductrack is a passive magnetic levitation system employing special arrays of high-field permanent magnets (Halbach arrays) on the levitating cradle, moving above a ''track'' consisting of a close-packed array of shorted coils with which are interleaved with special drive coils. Halbach arrays produce a strong spatially periodic magnetic field on the front surface of the arrays, while canceling the field on their back surface. Relative motion between the Halbach arrays and the track coils induces currents in those coils. These currents levitate the cradle by interacting with the horizontal component of the magnetic field. Pulsed currents in the drive coils, synchronized with the motion of the carrier, interact with the vertical component of the magnetic field to provide acceleration forces. Motional stability, including resistance to both vertical and lateral aerodynamic forces, is provided by having Halbach arrays that interact with both the upper and the lower sides of the track coils. At present, a 7.8 meter track composed of drive and levitation coils has been built and the electronic drive circuitry performs as designed. A 9 kg cradle that carries the Halbach array of permanent magnets has been built. A mechanical launcher is nearly complete which will provide an initial cradle velocity of 9 m/s into the electronic drive section. We have found that the drag forces from the levitation coils were higher than in our original design. However, measurements of drag force at velocities less than 1 m/s are exactly as predicted by theory. Provided here are recommended design changes to improve the track's performance so that a final velocity of 40 m/s can be achieved with

  4. Progress of succinic acid production from renewable resources: Metabolic and fermentative strategies.

    PubMed

    Jiang, Min; Ma, Jiangfeng; Wu, Mingke; Liu, Rongming; Liang, Liya; Xin, Fengxue; Zhang, Wenming; Jia, Honghua; Dong, Weiliang

    2017-06-03

    Succinic acid is a four-carbon dicarboxylic acid, which has attracted much interest due to its abroad usage as a precursor of many industrially important chemicals in the food, chemicals, and pharmaceutical industries. Facing the shortage of crude oil supply and demand of sustainable development, biological production of succinic acid from renewable resources has become a topic of worldwide interest. In recent decades, robust producing strain selection, metabolic engineering of model strains, and process optimization for succinic acid production have been developed. This review provides an overview of succinic acid producers and cultivation technology, highlight some of the successful metabolic engineering approaches. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Final Technical Progress Report Long term risk from actinides in the environment: Modes of mobility

    SciTech Connect

    Thomas B. Kirchner

    2002-03-22

    in diameter and approximately 22 cm long. A thin ''marker layer'' of white soil was added to the top of each column followed by a thin layer of soil that had been spiked with 137Cs, cerium and lanthanum was applied to the surface. Approximately 900 cm of water (the equivalent of about 30 years of rainfall) was then applied at a rate of 3.2 L d-1. All of the activity contained in the soil core appeared to be in the top few mm of soil, i.e. there was virtually no movement of the 134Cs labeled particles. Finally, a library of object-oriented model components was created using Visual Basic to support the construction of contaminant transport models. These components greatly simplify the task of building 1- to 3- dimensional simulation models for risk assessment. The model components created under this funding were subsequently applied to help answer questions regarding risks from irrigation associated with potential releases from the Yucca Mountain waste repository.

  6. Time and Circumstances: Cancer Cell Metabolism at Various Stages of Disease Progression.

    PubMed

    Weber, Georg F

    2016-01-01

    Over the past decade, research into the unique ways, in which cancer cells skew their metabolism, has had a renaissance-for the repeated time over more than 80 years since the discovery of an inherent preference for glycolysis. Importantly, the Warburg effect that arises in primary neoplasms is not the sole prominent metabolic phenomenon. Once the transformed cells are shed from their initial growth and begin the process of metastasis, their energy requirements change and they adapt to the increased demand for adenosine triphosphate, which if not satisfied would lead to anoikis. At that stage, oxidoreductases and the respiratory chain are activated. Furthermore, the intrinsic metabolic characteristics of tumor cells may be influenced by extrinsic factors, comprising metabolite secretions from stromal cells or acidification and nutrient deprivation in the late-stage hypoxic environment. While there is metabolic adjustment in cancer cells throughout the disease history, its phenotypic manifestation changes at various times. This stage selectivity has implications for pharmacotherapy ambitions.

  7. Time and Circumstances: Cancer Cell Metabolism at Various Stages of Disease Progression

    PubMed Central

    Weber, Georg F.

    2016-01-01

    Over the past decade, research into the unique ways, in which cancer cells skew their metabolism, has had a renaissance—for the repeated time over more than 80 years since the discovery of an inherent preference for glycolysis. Importantly, the Warburg effect that arises in primary neoplasms is not the sole prominent metabolic phenomenon. Once the transformed cells are shed from their initial growth and begin the process of metastasis, their energy requirements change and they adapt to the increased demand for adenosine triphosphate, which if not satisfied would lead to anoikis. At that stage, oxidoreductases and the respiratory chain are activated. Furthermore, the intrinsic metabolic characteristics of tumor cells may be influenced by extrinsic factors, comprising metabolite secretions from stromal cells or acidification and nutrient deprivation in the late-stage hypoxic environment. While there is metabolic adjustment in cancer cells throughout the disease history, its phenotypic manifestation changes at various times. This stage selectivity has implications for pharmacotherapy ambitions. PMID:28018856

  8. Newborn Screening for Genetic-Metabolic Diseases: Progress, Principles and Recommendations.

    ERIC Educational Resources Information Center

    Holtzman, Neil A.

    This monograph, designed for persons involved in the organization and regulation of screening of newborns infants for Phenylketonuria (PKU) and other genetic-metabolic diseases reviews new developments in the field, makes recommendations, and provides information about specific conditions other than PKU that are detectable by screening. Discussed…

  9. Microarray analysis of differentially expressed genes regulating lipid metabolism during melanoma progression.

    PubMed

    Sumantran, Venil N; Mishra, Pratik; Sudhakar, N

    2015-04-01

    A new hallmark of cancer involves acquisition of a lipogenic phenotype which promotes tumorigenesis. Little is known about lipid metabolism in melanomas. Therefore, we used BRB (Biometrics Research Branch) class comparison tool with multivariate analysis to identify differentially expressed genes in human cutaneous melanomas, compared with benign nevi and normal skin derived from the microarray dataset (GDS1375). The methods were validated by identifying known melanoma biomarkers (CITED1, FGFR2, PTPRF, LICAM, SPP1 and PHACTR1) in our results. Eighteen genes regulating metabolism of fatty acids, lipid second messengers and gangliosides were 2-9 fold upregulated in melanomas of GDS-1375. Out of the 18 genes, 13 were confirmed by KEGG pathway analysis and 10 were also significantly upregulated in human melanoma cell lines of NCI-60 Cell Miner database. Results showed that melanomas upregulated PPARGC1A transcription factor and its target genes regulating synthesis of fatty acids (SCD) and complex lipids (FABP3 and ACSL3). Melanoma also upregulated genes which prevented lipotoxicity (CPT2 and ACOT7) and regulated lipid second messengers, such as phosphatidic acid (AGPAT-4, PLD3) and inositol triphosphate (ITPKB, ITPR3). Genes for synthesis of pro-tumorigenic GM3 and GD3 gangliosides (UGCG, HEXA, ST3GAL5 and ST8SIA1) were also upregulated in melanoma. Overall, the microarray analysis of GDS-1375 dataset indicated that melanomas can become lipogenic by upregulating genes, leading to increase in fatty acid metabolism, metabolism of specific lipid second messengers, and ganglioside synthesis.

  10. Physiology and genetics of metabolic flux control in Zymomonas mobilis. Progress report

    SciTech Connect

    Conway, T.

    1992-08-01

    This work seeks to understand the role of gene expression in regulating glycolytic enzyme synthesis in a balance that allows proper glycoltic flux control. The seven genes targeted for study in this laboratory have been cloned and sequenced, and molecular details of regulation have been investigated. Clear that glycolytic enzyme synthesis is coordinated to prevent the build up of toxic metabolic intermediates. The genetic mechanisms responsible for regulating balanced expression of the EntnerDoudoroff and glycolytic genes in Z. mobilis are beginning to be understood. Several layers of genetic control, perhaps in a hierarchal arrangement act in concert to determine the relative abundance of the glycolytic enzymes. These genetic controls involve differential translational efficiency, highly conserved promoter sequences, transcription factors, differential mRNA stabilities, and nucleolytic mRNA processing. The serendipitous cloning of the glucose facilitator, glf, as a result of linkage to several other genes of interest will have a significant impact on the study of Z. mobilis metabolism. The glucose facilitator is being characterized in a genetically reconstituted system in E. coli. Molecular genetic studies indicate that the ratio of glf expression to that of glk, zmf, and edd is carefully regulated, and suggests a critical role in metabolic control. Regulation of glycolytic gene expression is now sufficiently well understood to allow use of the glycolytic genes as tools to manipulate specified enzyme levels for the purpose of analyzing metabolic flux control. The critical genes have been subcloned for stable expression in Z. mobilis and placed under control of a regulated promoter system involving the tac promoter, the lacI repressor, and gene induction in by IPTG. HPLC methods have been developed that allow quantitation of virtually all of the metabolic intermediates in the cell pool.

  11. Metabolism

    MedlinePlus

    ... symptoms. Metabolic diseases and conditions include: Hyperthyroidism (pronounced: hi-per-THIGH-roy-dih-zum). Hyperthyroidism is caused ... or through surgery or radiation treatments. Hypothyroidism (pronounced: hi-po-THIGH-roy-dih-zum). Hypothyroidism is caused ...

  12. Effects of Moderate and Subsequent Progressive Weight Loss on Metabolic Function and Adipose Tissue Biology in Humans with Obesity.

    PubMed

    Magkos, Faidon; Fraterrigo, Gemma; Yoshino, Jun; Luecking, Courtney; Kirbach, Kyleigh; Kelly, Shannon C; de Las Fuentes, Lisa; He, Songbing; Okunade, Adewole L; Patterson, Bruce W; Klein, Samuel

    2016-04-12

    Although 5%-10% weight loss is routinely recommended for people with obesity, the precise effects of 5% and further weight loss on metabolic health are unclear. We conducted a randomized controlled trial that evaluated the effects of 5.1% ± 0.9% (n = 19), 10.8% ± 1.3% (n = 9), and 16.4% ± 2.1% (n = 9) weight loss and weight maintenance (n = 14) on metabolic outcomes. 5% weight loss improved adipose tissue, liver and muscle insulin sensitivity, and β cell function, without a concomitant change in systemic or subcutaneous adipose tissue markers of inflammation. Additional weight loss further improved β cell function and insulin sensitivity in muscle and caused stepwise changes in adipose tissue mass, intrahepatic triglyceride content, and adipose tissue expression of genes involved in cholesterol flux, lipid synthesis, extracellular matrix remodeling, and oxidative stress. These results demonstrate that moderate 5% weight loss improves metabolic function in multiple organs simultaneously, and progressive weight loss causes dose-dependent alterations in key adipose tissue biological pathways. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Apple Peel Supplemented Diet Reduces Parameters of Metabolic Syndrome and Atherogenic Progression in ApoE-/- Mice.

    PubMed

    Gonzalez, Jaime; Donoso, Wendy; Sandoval, Nathalie; Reyes, María; Gonzalez, Priscila; Gajardo, Monica; Morales, Erik; Neira, Amalia; Razmilic, Iván; Yuri, José A; Moore-Carrasco, Rodrigo

    2015-01-01

    Cardiovascular Diseases (CVD) represent about 30% of all causes of death worldwide. The development of CVD is related in many cases with the previous existence of metabolic syndrome (MS). It is known that apple consumption has a cardiovascular protecting effect, containing phenolic compounds with antioxidant effect, which are concentrated in the fruit peel. The objective of this study was to test the effect of apple peel consumption in a murine model of MS and apoE-/- mice. Apple supplemented diets reduced the biochemical parameters (glycaemia, total cholesterol, HDL-cholesterol, LDL-cholesterol, ureic nitrogen, triglycerides, insulin, and asymmetric dimethylarginine (ADMA)) of MS model in CF1 mice significantly. The model apoE-/- mouse was used to evaluate the capacity of the apple peel to revert the progression of the atherogenesis. FD with HAP reverts cholesterol significantly and slows down the progression of the plate diminishing the cholesterol accumulation area. With these results, it can be concluded that the consumption of apple peel reduces several MS parameters and the atherogenic progression in mice.

  14. Apple Peel Supplemented Diet Reduces Parameters of Metabolic Syndrome and Atherogenic Progression in ApoE−/− Mice

    PubMed Central

    Gonzalez, Jaime; Donoso, Wendy; Sandoval, Nathalie; Reyes, María; Gonzalez, Priscila; Gajardo, Monica; Morales, Erik; Neira, Amalia; Razmilic, Iván; Yuri, José A.

    2015-01-01

    Cardiovascular Diseases (CVD) represent about 30% of all causes of death worldwide. The development of CVD is related in many cases with the previous existence of metabolic syndrome (MS). It is known that apple consumption has a cardiovascular protecting effect, containing phenolic compounds with antioxidant effect, which are concentrated in the fruit peel. The objective of this study was to test the effect of apple peel consumption in a murine model of MS and apoE−/− mice. Apple supplemented diets reduced the biochemical parameters (glycaemia, total cholesterol, HDL-cholesterol, LDL-cholesterol, ureic nitrogen, triglycerides, insulin, and asymmetric dimethylarginine (ADMA)) of MS model in CF1 mice significantly. The model apoE−/− mouse was used to evaluate the capacity of the apple peel to revert the progression of the atherogenesis. FD with HAP reverts cholesterol significantly and slows down the progression of the plate diminishing the cholesterol accumulation area. With these results, it can be concluded that the consumption of apple peel reduces several MS parameters and the atherogenic progression in mice. PMID:26075004

  15. Final Technical Progress Report

    SciTech Connect

    J.Y. Hwang; R.C. Greenlund

    2002-12-31

    Michigan Technological University has demonstrated major inroads in establishing the viability of utilizing aluminum smelting by-product waste materials in lightweight concrete product applications. The research identified key elements of producing various forms of lightweight concrete products through utilizing various procedures and mixture components with the by-product materials. A process was developed through pilot plant testing that results in additional aluminum recovery at finer sizes, a clean returnable salt product through spray drying technology, and a low-salt-content oxide product with enough aluminum metal content that it can be used to form lightweight cementitious mixtures. Having three distinct products aids in generating favorable process economics. Revenue projections from aluminum recovery and salt recovery are enough to cover processing costs and create a cost-free oxide product to market for lightweight concrete applications. This supply side commercialization strategy offers aluminum by-product recyclers a potentially no cost product, which has been demonstrated through this project to create desirable and marketable lightweight concrete products of various forms. Environmental benefits to the public are tremendous. At best, all dross and salt cake materials have the potential to be completely recycled and utilized. At worst, disposal sites would see a reduced amount of material: a post processed oxide product with little salt and no hydrogen sulfide or ammonia gas generating capability, which, if isolated from high alkali conditions, would pose no reactivity concerns. The US aluminum industry has historically, along with the steel industry, been a leader in recycling metal. The findings from this project, increased metal recovery, improved salt recycling, and demonstrated end uses for oxide residues, will go a long way in helping the aluminum industry obtain 100% material utilization and zero discharge.

  16. Final Progress Report

    SciTech Connect

    Bernstein, Herbert J

    2012-02-06

    The BIOMOL grant was for 'Local System Support for PDB Biological Unit Search and Display' to augment Rasmol's [Bernstein 2000] [Sayle, Milner-White 1995] existing macromolecular display functions with new capabilities by taking advantage of recent increases in local computing power in order to move functionality that is now scattered among various local and remote systems into one local package. Work included new algorithms for molecular surface display, an extended format for Protein Data Bank Entries, work on issues relating to the integration of multiple diffraction images formats.

  17. Final Progress Report

    SciTech Connect

    Kotov, Valeri

    2016-05-29

    The research in this program involves theoretical investigations of electronic, optical and mechanical properties of graphene and its derivatives, such as bi-layer graphene, graphene-based van der Waals heterostructures, strained graphene, as well as graphene on various surfaces. One line of research has been development of theoretical models that support graphene’s large array of possible technological applications. For example one of our goals has been the understanding of surface plasmons and spin relaxation mechanisms in graphene, related to novel optoelectronics and spintronics applications. Our current research focus is on understanding the role of correlations in graphene under mechanical deformations, such as strain. The main goal is to describe the mutual interplay between strain and electron-electron interactions which could lead to the formation of novel elec- tronic phases with strongly modified electronic, magnetic and optical properties. This direction of research contributes to deeper understanding of interactions in graphene and related atomically-thin materials - a subject at the forefront of research on graphene and its derivatives.

  18. Limited brain metabolism changes differentiate between the progression and clearance of rabies virus.

    PubMed

    Schutsky, Keith; Portocarrero, Carla; Hooper, D Craig; Dietzschold, Bernhard; Faber, Milosz

    2014-01-01

    Central nervous system (CNS) metabolic profiles were examined from rabies virus (RABV)-infected mice that were either mock-treated or received post-exposure treatment (PET) with a single dose of the live recombinant RABV vaccine TriGAS. CNS tissue harvested from mock-treated mice at middle and late stage infection revealed numerous changes in energy metabolites, neurotransmitters and stress hormones that correlated with replication levels of viral RNA. Although the large majority of these metabolic changes were completely absent in the brains of TriGAS-treated mice most likely due to the strong reduction in virus spread, TriGAS treatment resulted in the up-regulation of the expression of carnitine and several acylcarnitines, suggesting that these compounds are neuroprotective. The most striking change seen in mock-treated RABV-infected mice was a dramatic increase in brain and serum corticosterone levels, with the later becoming elevated before clinical signs or loss of body weight occurred. We speculate that the rise in corticosterone is part of a strategy of RABV to block the induction of immune responses that would otherwise interfere with its spread. In support of this concept, we show that pharmacological intervention to inhibit corticosterone biosynthesis, in the absence of vaccine treatment, significantly reduces the pathogenicity of RABV. Our results suggest that widespread metabolic changes, including hypothalamic-pituitary-adrenal axis activation, contribute to the pathogenesis of RABV and that preventing these alterations early in infection with PET or pharmacological blockade helps protect brain homeostasis, thereby reducing disease mortality.

  19. Monitoring genetic and metabolic potential for in situ bioremediation: Mass spectrometry. 1997 annual progress report

    SciTech Connect

    Buchanan, M.V.; Hurst, G.B.; Britt, P.F.; McLuckey, S.A.; Doktycz, M.J.

    1997-09-01

    'A number of US Department of Energy (DOE) sites are contaminated with mixtures of dense non-aqueous phase liquids (DNAPLs) such as carbon tetrachloride, chloroform,. perchloroethylene, and trichloroethylene. At many of these sites, in situ microbial bioremediation is an attractive strategy for cleanup because it has the potential to degrade DNAPLs in situ without producing toxic byproducts. A rapid screening method to determine the broad range metabolic and genetic potential for contaminant degradation would greatly reduce the cost and time involved in assessment for in situ bioremediation as well as for monitoring ongoing bioremediation treatment. In this project, the ORNL Organic Mass Spectrometry (OMS) group is developing mass-spectrometry-based methods to screen for the genetic and metabolic potential for assessment and monitoring of in situ bioremediation of DNAPLs. In close collaboration, Professor Mary Lidstrom''s group at the University of Washington is identifying short DNA sequences related to microbial processes involved in the biodegradation of pollutants. This work will lay the foundation for development of a field-portable mass-spectrometry-based technique for rapid assessment and monitoring of bioremediation processes on site.'

  20. 2-Deoxy-D-glucose reduces epilepsy progression by NRSF-CtBP-dependent metabolic regulation of chromatin structure.

    PubMed

    Garriga-Canut, Mireia; Schoenike, Barry; Qazi, Romena; Bergendahl, Karen; Daley, Timothy J; Pfender, Rebecca M; Morrison, John F; Ockuly, Jeffrey; Stafstrom, Carl; Sutula, Thomas; Roopra, Avtar

    2006-11-01

    Temporal lobe epilepsy is a common form of drug-resistant epilepsy that sometimes responds to dietary manipulation such as the 'ketogenic diet'. Here we have investigated the effects of the glycolytic inhibitor 2-deoxy-D-glucose (2DG) in the rat kindling model of temporal lobe epilepsy. We show that 2DG potently reduces the progression of kindling and blocks seizure-induced increases in the expression of brain-derived neurotrophic factor and its receptor, TrkB. This reduced expression is mediated by the transcription factor NRSF, which recruits the NADH-binding co-repressor CtBP to generate a repressive chromatin environment around the BDNF promoter. Our results show that 2DG has anticonvulsant and antiepileptic properties, suggesting that anti-glycolytic compounds may represent a new class of drugs for treating epilepsy. The metabolic regulation of neuronal genes by CtBP will open avenues of therapy for neurological disorders and cancer.

  1. The impact of RNA binding motif protein 4-regulated splicing cascade on the progression and metabolism of colorectal cancer cells.

    PubMed

    Liang, Yu-Chih; Lin, Wei-Cheng; Lin, Ying-Ju; Lin, Jung-Chun

    2015-11-10

    Dysregulated splicing of pre-messenger (m)RNA is considered a molecular occasion of carcinogenesis. However, the underlying mechanism is complex and remains to be investigated. Herein, we report that the upregulated miR-92a reduced the RNA-binding motif 4 (RBM4) protein expression, leading to the imbalanced expression of the neuronal polypyrimidine tract-binding (nPTB) protein through alternative splicing-coupled nonsense mediated decay (NMD) mechanism. Increase in nPTB protein enhances the relative level of fibroblast growth factor receptor 2 IIIc (FGFR2) and pyruvate kinase M2 (PKM2) transcripts which contribute to the progression and metabolic signature of CRC cells. Expression profiles of RBM4 and downstream alternative splicing events are consistently observed in cancerous tissues compared to adjacent normal tissues. These results constitute a mechanistic understanding of RBM4 on repressing the carcinogenesis of colorectal cells.

  2. Metabolic therapy with Deanna Protocol supplementation delays disease progression and extends survival in amyotrophic lateral sclerosis (ALS) mouse model.

    PubMed

    Ari, Csilla; Poff, Angela M; Held, Heather E; Landon, Carol S; Goldhagen, Craig R; Mavromates, Nicholas; D'Agostino, Dominic P

    2014-01-01

    Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig's disease, is a neurodegenerative disorder of motor neurons causing progressive muscle weakness, paralysis, and eventual death from respiratory failure. There is currently no cure or effective treatment for ALS. Besides motor neuron degeneration, ALS is associated with impaired energy metabolism, which is pathophysiologically linked to mitochondrial dysfunction and glutamate excitotoxicity. The Deanna Protocol (DP) is a metabolic therapy that has been reported to alleviate symptoms in patients with ALS. In this study we hypothesized that alternative fuels in the form of TCA cycle intermediates, specifically arginine-alpha-ketoglutarate (AAKG), the main ingredient of the DP, and the ketogenic diet (KD), would increase motor function and survival in a mouse model of ALS (SOD1-G93A). ALS mice were fed standard rodent diet (SD), KD, or either diets containing a metabolic therapy of the primary ingredients of the DP consisting of AAKG, gamma-aminobutyric acid, Coenzyme Q10, and medium chain triglyceride high in caprylic triglyceride. Assessment of ALS-like pathology was performed using a pre-defined criteria for neurological score, accelerated rotarod test, paw grip endurance test, and grip strength test. Blood glucose, blood beta-hydroxybutyrate, and body weight were also monitored. SD+DP-fed mice exhibited improved neurological score from age 116 to 136 days compared to control mice. KD-fed mice exhibited better motor performance on all motor function tests at 15 and 16 weeks of age compared to controls. SD+DP and KD+DP therapies significantly extended survival time of SOD1-G93A mice by 7.5% (p = 0.001) and 4.2% (p = 0.006), respectively. Sixty-three percent of mice in the KD+DP and 72.7% of the SD+DP group lived past 125 days, while only 9% of the control animals survived past that point. Targeting energy metabolism with metabolic therapy produces a therapeutic effect in ALS mice which may prolong

  3. Metabolic Therapy with Deanna Protocol Supplementation Delays Disease Progression and Extends Survival in Amyotrophic Lateral Sclerosis (ALS) Mouse Model

    PubMed Central

    Ari, Csilla; Poff, Angela M.; Held, Heather E.; Landon, Carol S.; Goldhagen, Craig R.; Mavromates, Nicholas; D’Agostino, Dominic P.

    2014-01-01

    Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, is a neurodegenerative disorder of motor neurons causing progressive muscle weakness, paralysis, and eventual death from respiratory failure. There is currently no cure or effective treatment for ALS. Besides motor neuron degeneration, ALS is associated with impaired energy metabolism, which is pathophysiologically linked to mitochondrial dysfunction and glutamate excitotoxicity. The Deanna Protocol (DP) is a metabolic therapy that has been reported to alleviate symptoms in patients with ALS. In this study we hypothesized that alternative fuels in the form of TCA cycle intermediates, specifically arginine-alpha-ketoglutarate (AAKG), the main ingredient of the DP, and the ketogenic diet (KD), would increase motor function and survival in a mouse model of ALS (SOD1-G93A). ALS mice were fed standard rodent diet (SD), KD, or either diets containing a metabolic therapy of the primary ingredients of the DP consisting of AAKG, gamma-aminobutyric acid, Coenzyme Q10, and medium chain triglyceride high in caprylic triglyceride. Assessment of ALS-like pathology was performed using a pre-defined criteria for neurological score, accelerated rotarod test, paw grip endurance test, and grip strength test. Blood glucose, blood beta-hydroxybutyrate, and body weight were also monitored. SD+DP-fed mice exhibited improved neurological score from age 116 to 136 days compared to control mice. KD-fed mice exhibited better motor performance on all motor function tests at 15 and 16 weeks of age compared to controls. SD+DP and KD+DP therapies significantly extended survival time of SOD1-G93A mice by 7.5% (p = 0.001) and 4.2% (p = 0.006), respectively. Sixty-three percent of mice in the KD+DP and 72.7% of the SD+DP group lived past 125 days, while only 9% of the control animals survived past that point. Targeting energy metabolism with metabolic therapy produces a therapeutic effect in ALS mice which may

  4. The Role of DNA Methylation in the Metabolic Memory Phenomenon Associated With the Continued Progression of Diabetic Retinopathy

    PubMed Central

    Mishra, Manish; Kowluru, Renu A.

    2016-01-01

    Purpose Clinical and experimental studies have shown that diabetic retinopathy progression does not halt after termination of hyperglycemia, suggesting a “metabolic memory” phenomenon. DNA is highly dynamic, and cytosine methylation changes can last for several years. In diabetes, DNA methylation regulates expression of many genes associated with retinal mitochondrial homeostasis. Our aim was to investigate the role of DNA methylation in the metabolic memory. Methods Reversal of 4 days of 20 mM glucose by 4 to 8 days of 5 mM glucose, in the presence/absence of Dnmt inhibitor (5-aza-2′-deoxycytidine), was investigated on DNA methylation and its machinery in human retinal endothelial cells. The key parameters were confirmed in the retina from diabetic rats maintained in good glycemic control (glycated hemoglobin ∼6%) for 3 months after 3 months of poor control (glycated hemoglobin >10%). Results DNA methyltransferase 1 (Dnmt 1) remained active after 4 days of normal glucose that followed 4 days of high glucose, and mtDNA stayed hypermethylated with impaired transcription. Hydroxymethylating enzyme Tet2, and matrix metalloproteinase-9 (regulated by hydroxymethylation) also remained upregulated. But, 8 days of normal glucose after 4 days of high glucose ameliorated mtDNA methylation and MMP-9 hydroxymethylation. Direct Dnmt targeting by Aza during the reversal period benefited methylation status of mtDNA and MMP-9 DNA. Similarly, reinstitution of good control after 3 months of poor control in rats did not reverse diabetes-induced increase in retinal Dnmt1 and Tet2, and alter the methylation status of mtDNA and MMP-9. Conclusions Retinal DNA methylation-hydroxymethylation machinery does not benefit immediately from reversal of hyperglycemia. Maintenance of good glycemic control for longer duration, and/or direct targeting DNA methylation ameliorates continuous mitochondrial damage, and could retard/halt diabetic retinopathy progression. PMID:27787562

  5. Metabolic tumor volume predicts disease progression and survival in patients with squamous cell carcinoma of the anal canal.

    PubMed

    Bazan, Jose G; Koong, Albert C; Kapp, Daniel S; Quon, Andrew; Graves, Edward E; Loo, Billy W; Chang, Daniel T

    2013-01-01

    PET imaging has become a useful diagnostic tool in patients with anal cancer. We evaluated the prognostic value of metabolic tumor volume (MTV) in patients with anal cancer treated with definitive chemoradiotherapy. Patients with anal cancer who underwent PET imaging for pretreatment staging or radiation therapy planning from 2003 to 2011 were included. PET parameters included MTV and maximum standardized uptake value (SUVmax). Total MTV (MTV-T) was defined as the sum of the volumes above a standardized uptake value 50% of the SUVmax within the primary tumor and involved nodes. Kaplan-Meier and Cox regression models were used to test for associations between metabolic or clinical endpoints and overall survival (OS), progression-free survival (PFS), and event-free survival (EFS). Thirty-nine patients were included. Median follow-up for the cohort was 22 mo. Overall, 6 patients died and 9 patients had disease progression. The 2-y OS, PFS, and EFS for the entire cohort were 88%, 74%, and 69%, respectively. Higher MTV-T was associated with worse OS (P = 0.04), PFS (P = 0.004), and EFS (P = 0.002) on univariate analysis. Patients with an MTV greater than 26 cm(3) had worse PFS than did those with an MTV of 26 cm(3) or less (33% vs. 82%, P = 0.003). SUVmax was not prognostic for any outcome. Higher T classification (T3/T4 vs. T1/T2) was associated with worse PFS and EFS. When adjusting for T classification, MTV-T remained a significant predictor for PFS (P = 0.01) and EFS (P = 0.02). MTV-T yields prognostic information on PFS and EFS beyond that of established prognostic factors in patients with anal cancer.

  6. Response to diet-induced obesity produces time-dependent induction and progression of metabolic osteoarthritis in rat knees.

    PubMed

    Collins, Kelsey H; Hart, David A; Reimer, Raylene A; Seerattan, Ruth A; Herzog, Walter

    2016-06-01

    Obesity, and corresponding chronic-low grade inflammation, is associated with the onset and progression of knee OA. The origin of this inflammation is poorly understood. Here, the effect of high fat, high sucrose (HFS) diet induced obesity (DIO) on local (synovial fluid), and systemic (serum) inflammation is evaluated after a 12-week obesity induction and a further 16-week adaptation period. For 12-weeks of obesity induction, n = 40 DIO male Sprague-Dawley rats consumed a HFS diet while the control group (n = 14) remained on chow. DIO rats were allocated to prone (DIO-P, top 33% based on weight change) or resistant (DIO-R, bottom 33%) groups at 12-weeks. Animals were euthanized at 12- and after an additional 16-weeks on diet (28-weeks). At sacrifice, body composition and knee joints were collected and assessed. Synovial fluid and sera were profiled using cytokine array analysis. At 12-weeks, DIO-P animals demonstrated increased Modified Mankin scores compared to DIO-R and chow (p = 0.026), and DIO-R had higher Mankin scores compared to chow (p = 0.049). While numerous systemic and limited synovial fluid inflammatory markers were increased at 12-weeks in DIO animals compared to chow, by 28-weeks there were limited systemic differences but marked increases in local synovial fluid inflammatory marker concentrations. Metabolic OA may manifest from an initial systemic inflammatory disturbance. Twelve weeks of obesity induction leads to a unique inflammatory profile and induction of metabolic OA which is altered after a further 16-weeks of obesity and HFS diet intake, suggesting that obesity is a dynamic, progressive process. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1010-1018, 2016. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

  7. Cytochrome P450-mediated metabolic engineering: current progress and future challenges.

    PubMed

    Renault, Hugues; Bassard, Jean-Etienne; Hamberger, Björn; Werck-Reichhart, Danièle

    2014-06-01

    Cytochromes P450 catalyze a broad range of regiospecific, stereospecific and irreversible steps in the biosynthetic routes of plant natural metabolites with important applications in pharmaceutical, cosmetic, fragrance and flavour, or polymer industries. They are consequently essential drivers for the engineered bioproduction of such compounds. Two ground-breaking developments of commercial products driven by the engineering of P450s are the antimalarial drug precursor artemisinic acid and blue roses or carnations. Tedious optimizations were required to generate marketable products. Hurdles encountered in P450 engineering and their potential solutions are summarized here. Together with recent technical developments and novel approaches to metabolic engineering, the lessons from this pioneering work should considerably boost exploitation of the amazing P450 toolkit emerging from accelerated sequencing of plant genomes. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

  8. Metabolism of fatty acids by Syntrophomonas wolfei. Progress report, March 15, 1983-December 15, 1984

    SciTech Connect

    McInerney, M.J.

    1984-01-01

    The main objective in this research is to obtain basic information on the metabolism and physiology of the H/sub 2/-producing acetogenic bacteria. Syntrophomonas wolfei degrades butyrate, caproate and caprylate to acetate and H/sub 2/, valerate and heptanoate to acetate, propionate and H/sub 2/, and isoheptanoate to acetate, isovalerate and H/sub 2/. Since the degradation of these compounds with H/sub 2/ production is energetically favorable only when the partial pressure of H/sub 2/ is maintained at a very low level, S. wolfei can only be grown in coculture with H/sub 2/-using bacteria. The first objectives of this research were to determine if S. wolfei could be grown alone if the partial pressure of H/sub 2/ was maintained at a low level by sparging the culture with anaerobic gas.

  9. [Regulation of terpene metabolism]. Annual progress report, March 15, 1989--March 14, 1990

    SciTech Connect

    Croteau, R.

    1989-11-09

    Terpenoid oils, resins, and waxes from plants are important renewable resources. The objective of this project is to understand the regulation of terpenoid metabolism using the monoterpenes (C{sub 10}) as a model. The pathways of monoterpene biosynthesis and catabolism have been established, and the relevant enzymes characterized. Developmental studies relating enzyme levels to terpene accumulation within the oil gland sites of synthesis, and work with bioregulators, indicate that monoterpene production is controlled by terpene cyclases, the enzymes catalyzing the first step of the monoterpene pathway. As the leaf oil glands mature, cyclase levels decline and monoterpene biosynthesis ceases. Yield then decreases as the monoterpenes undergo catabolism by a process involving conversion to a glycoside and transport from the leaf glands to the root. At this site, the terpenoid is oxidatively degraded to acetate that is recycled into other lipid metabolites. During the transition from terpene biosynthesis to catabolism, the oil glands undergo dramatic ultrastructural modification. Degradation of the producing cells results in mixing of previously compartmentized monoterpenes with the catabolic enzymes, ultimately leading to yield decline. This regulatory model is being applied to the formation of other terpenoid classes (C{sub 15} C{sub 20}, C{sub 30}, C{sub 40}) within the oil glands. Preliminary investigations on the formation of sesquiterpenes (C{sub 15}) suggest that the corresponding cyclases may play a lesser role in determining yield of these products, but that compartmentation effects are important. From these studies, a comprehensive scheme for the regulation of terpene metabolism is being constructed. Results from this project wail have important consequences for the yield and composition of terpenoid natural products that can be made available for industrial exploitation.

  10. Progressive hyperpigmentation in a Taiwanese child due to an inborn error of vitamin B12 metabolism (cblJ).

    PubMed

    Takeichi, T; Hsu, C-K; Yang, H-S; Chen, H-Y; Wong, T-W; Tsai, W-L; Chao, S-C; Lee, J Y-Y; Akiyama, M; Simpson, M A; McGrath, J A

    2015-04-01

    The physiology of human skin pigmentation is varied and complex, with an extensive melanogenic paracrine network involving mesenchymal and epithelial cells, contributing to the regulation of melanocyte survival and proliferation and melanogenesis. Mutations in several genes, involving predominantly the KIT ligand/c-Kit and Ras/mitogen-activated protein kinase signalling pathways, have been implicated in a spectrum of diseases in which there is hyperpigmentation, hypopigmentation or both. Here, we report on a 12-year-old girl from Taiwan with a 6-year history of diffuse progressive skin hyperpigmentation resulting from a different aetiology: an inborn metabolic disorder of vitamin B12 (cobalamin), designated cblJ. Using whole-exome sequencing we identified a homozygous mutation in ABCD4 (c.423C>G; p.Asn141Lys), which encodes an ATP-binding cassette transporter with a role in the intracellular processing of cobalamin. The patient had biochemical and haematological evidence of cobalamin deficiency but no other clinical abnormalities apart from a slight lightening of her previously black hair. Of note, she had no neurological symptoms or signs. Treatment with oral cobalamin (3 mg daily) led to metabolic correction and some reduction in the skin hyperpigmentation at the 3-month follow-up. This case demonstrates that defects or deficiencies of cobalamin should be remembered in the differential diagnosis of diffuse hyperpigmentary skin disorders. © 2014 British Association of Dermatologists.

  11. Role of Mitochondrial Metabolism in the Control of Early Lineage Progression and Aging Phenotypes in Adult Hippocampal Neurogenesis.

    PubMed

    Beckervordersandforth, Ruth; Ebert, Birgit; Schäffner, Iris; Moss, Jonathan; Fiebig, Christian; Shin, Jaehoon; Moore, Darcie L; Ghosh, Laboni; Trinchero, Mariela F; Stockburger, Carola; Friedland, Kristina; Steib, Kathrin; von Wittgenstein, Julia; Keiner, Silke; Redecker, Christoph; Hölter, Sabine M; Xiang, Wei; Wurst, Wolfgang; Jagasia, Ravi; Schinder, Alejandro F; Ming, Guo-Li; Toni, Nicolas; Jessberger, Sebastian; Song, Hongjun; Lie, D Chichung

    2017-02-08

    Precise regulation of cellular metabolism is hypothesized to constitute a vital component of the developmental sequence underlying the life-long generation of hippocampal neurons from quiescent neural stem cells (NSCs). The identity of stage-specific metabolic programs and their impact on adult neurogenesis are largely unknown. We show that the adult hippocampal neurogenic lineage is critically dependent on the mitochondrial electron transport chain and oxidative phosphorylation machinery at the stage of the fast proliferating intermediate progenitor cell. Perturbation of mitochondrial complex function by ablation of the mitochondrial transcription factor A (Tfam) reproduces multiple hallmarks of aging in hippocampal neurogenesis, whereas pharmacological enhancement of mitochondrial function ameliorates age-associated neurogenesis defects. Together with the finding of age-associated alterations in mitochondrial function and morphology in NSCs, these data link mitochondrial complex function to efficient lineage progression of adult NSCs and identify mitochondrial function as a potential target to ameliorate neurogenesis-defects in the aging hippocampus. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Chronic signaling via the metabolic checkpoint kinase mTORC1 induces macrophage granuloma formation and marks sarcoidosis progression.

    PubMed

    Linke, Monika; Pham, Ha Thi Thanh; Katholnig, Karl; Schnöller, Thomas; Miller, Anne; Demel, Florian; Schütz, Birgit; Rosner, Margit; Kovacic, Boris; Sukhbaatar, Nyamdelger; Niederreiter, Birgit; Blüml, Stephan; Kuess, Peter; Sexl, Veronika; Müller, Mathias; Mikula, Mario; Weckwerth, Wolfram; Haschemi, Arvand; Susani, Martin; Hengstschläger, Markus; Gambello, Michael J; Weichhart, Thomas

    2017-03-01

    The aggregation of hypertrophic macrophages constitutes the basis of all granulomatous diseases, such as tuberculosis or sarcoidosis, and is decisive for disease pathogenesis. However, macrophage-intrinsic pathways driving granuloma initiation and maintenance remain elusive. We found that activation of the metabolic checkpoint kinase mTORC1 in macrophages by deletion of the gene encoding tuberous sclerosis 2 (Tsc2) was sufficient to induce hypertrophy and proliferation, resulting in excessive granuloma formation in vivo. TSC2-deficient macrophages formed mTORC1-dependent granulomatous structures in vitro and showed constitutive proliferation that was mediated by the neo-expression of cyclin-dependent kinase 4 (CDK4). Moreover, mTORC1 promoted metabolic reprogramming via CDK4 toward increased glycolysis while simultaneously inhibiting NF-κB signaling and apoptosis. Inhibition of mTORC1 induced apoptosis and completely resolved granulomas in myeloid TSC2-deficient mice. In human sarcoidosis patients, mTORC1 activation, macrophage proliferation and glycolysis were identified as hallmarks that correlated with clinical disease progression. Collectively, TSC2 maintains macrophage quiescence and prevents mTORC1-dependent granulomatous disease with clinical implications for sarcoidosis.

  13. The increased level of COX-dependent arachidonic acid metabolism in blood platelets from secondary progressive multiple sclerosis patients.

    PubMed

    Morel, Agnieszka; Miller, Elzbieta; Bijak, Michal; Saluk, Joanna

    2016-09-01

    Platelet activation is increasingly postulated as a possible component of the pathogenesis of multiple sclerosis (MS), especially due to the increased risk of cardiovascular events in MS. Arachidonic acid cascade metabolized by cyclooxygenase (COX) is a key pathway of platelet activation. The aim of our study was to investigate the COX-dependent arachidonic acid metabolic pathway in blood platelets from secondary progressive multiple sclerosis (SP MS) patients. The blood samples were obtained from 50 patients (man n = 22; female n = 28), suffering from SP MS, diagnosed according to the revised McDonald criteria. Platelet aggregation was measured in platelet-rich plasma after arachidonic acid stimulation. The level of COX activity and thromboxane B2 concentration were determined by ELISA method. Lipid peroxidation was assessed by measuring the level of malondialdehyde. The results were compared with a control group of healthy volunteers. We found that blood platelets obtained from SP MS patients were more sensitive to arachidonic acid and their response measured as platelet aggregation was stronger (about 14 %) relative to control. We also observed a significantly increased activity of COX (about 40 %) and synthesis of thromboxane B2 (about 113 %). The generation of malondialdehyde as a marker of lipid peroxidation was about 10 % higher in SP MS than in control. Cyclooxygenase-dependent arachidonic acid metabolism is significantly increased in blood platelets of patients with SP MS. Future clinical studies are required to recommend the use of low-dose aspirin, and possibly other COX inhibitors in the prevention of cardiovascular risk in MS.

  14. Relationship of Insulin Resistance to Prevalence and Progression of Coronary Artery Calcification Beyond Metabolic Syndrome Components: Shiga Epidemiological Study of Subclinical Atherosclerosis.

    PubMed

    Yamazoe, Masahiro; Hisamatsu, Takashi; Miura, Katsuyuki; Kadowaki, Sayaka; Zaid, Maryam; Kadota, Aya; Torii, Sayuki; Miyazawa, Itsuko; Fujiyoshi, Akira; Arima, Hisatomi; Sekikawa, Akira; Maegawa, Hiroshi; Horie, Minoru; Ueshima, Hirotsugu

    2016-08-01

    The association between insulin resistance (IR) and coronary artery calcification (CAC) has been uncertain after adjustment for metabolic syndrome components. We aimed to evaluate whether IR is associated with CAC prevalence or progression independently of metabolic syndrome components. We conducted a population-based study in a random sample of Japanese men aged 40 to 79 years and determined IR using the homeostasis model assessment of insulin resistance (HOMA-IR). The associations of HOMA-IR and other diabetic parameters per 1-SD increase with CAC prevalence and progression were evaluated using multivariable logistic regression. Of 1006 total participants at baseline (mean age, 64±10 years), CAC prevalence was observed in 646 (64.2%), and of 789 participants at follow-up (mean duration, 4.9±1.3 years), CAC progression was observed in 365 (46.3%). After adjustment for covariates including metabolic syndrome components, higher HOMA-IR was independently associated with CAC prevalence (adjusted odds ratio 1.34, 95% confidence interval 1.10-1.63; P=0.003) and progression (odds ratio 1.32, 95% confidence interval 1.09-1.60; P=0.004). In participants without diabetes mellitus, positive associations were similarly observed (prevalence: odds ratio 1.29, 95% confidence interval 1.04-1.60; P=0.022; and progression: odds ratio 1.25, 95% confidence interval 1.01-1.55; P=0.042), whereas glucose and hemoglobin A1c were not associated with CAC prevalence and progression. Higher IR was associated with CAC prevalence and progression independently of metabolic syndrome components in Japanese men and also in those without diabetes mellitus. Among diabetic measures, IR and fasting insulin, but not glucose and hemoglobin A1c, predicted CAC progression in men without diabetes mellitus. © 2016 American Heart Association, Inc.

  15. Altered Intramuscular Lipid Metabolism Relates to Diminished Insulin Action in Men, but Not Women, in Progression to Diabetes

    PubMed Central

    Perreault, Leigh; Bergman, Bryan C.; Hunerdosse, Devon M.; Eckel, Robert H.

    2011-01-01

    Whether sex differences in intramuscular triglyceride (IMTG) metabolism underlie sex differences in the progression to diabetes are unknown. Therefore, the current study examined IMTG concentration and fractional synthesis rate (FSR) in obese men and women with normal glucose tolerance (NGT) vs. those with prediabetes (PD). PD (n = 13 men and 7 women) and NGT (n = 7 men and 12 women) groups were matched for age and anthropometry. Insulin action was quantified using a hyperinsulinemic–euglycemic clamp with infusion of [6,6-2H2]-glucose. IMTG concentration was measured by gas chromatography/mass spectrometry (GC/MS) and FSR by GC/combustion isotope ratio MS (C-IRMS), from muscle biopsies taken after infusion of [U-13C]palmitate during 4 h of rest. In PD men, the metabolic clearance rate (MCR) of glucose was lower during the clamp (4.71 ± 0.77 vs. 8.62 ± 1.26 ml/kg fat-free mass (FFM)/min, P = 0.04; with a trend for lower glucose rate of disappearance (Rd), P = 0.07), in addition to higher IMTG concentration (41.2 ± 5.0 vs. 21.2 ± 3.4 μg/mg dry weight, P ≤ 0.01), lower FSR (0.21 ± 0.03 vs. 0.42 ± 0.06 %/h, P ≤ 0.01), and lower oxidative capacity (P = 0.03) compared to NGT men. In contrast, no difference in Rd, IMTG concentration, or FSR was seen in PD vs. NGT women. Surprisingly, glucose Rd during the clamp was not different between NGT men and women (P = 0.25) despite IMTG concentration being higher (42.6 ± 6.1 vs. 21.2 ± 3.4 μg/mg dry weight, P = 0.03) and FSR being lower (0.23 ± 0.04 vs. 0.42 ± 0.06 %/h, P = 0.02) in women. Alterations in IMTG metabolism relate to diminished insulin action in men, but not women, in the progression toward diabetes. PMID:20379150

  16. 18F-FDG PET/CT in solitary plasmacytoma: metabolic behavior and progression to multiple myeloma.

    PubMed

    Albano, Domenico; Bosio, Giovanni; Treglia, Giorgio; Giubbini, Raffaele; Bertagna, Francesco

    2017-08-19

    Solitary plasmacytoma (SP) is a rare plasma-cell neoplasm, which can develop both in skeletal and/or soft tissue and frequently progresses to multiple myeloma (MM). Our aim was to study the metabolic behavior of SP and the role of 18F-FDG-PET/CT in predicting progression to MM. Sixty-two patients with SP who underwent 18F-FDG-PET/CT before any treatment were included. PET images were qualitatively and semiquantitatively analyzed by measuring the maximum standardized uptake value body weight (SUVbw), lean body mass (SUVlbm), body surface area (SUVbsa), metabolic tumor volume (MTV), total lesion glycolysis (TLG) and compared with age, sex, site of primary disease, and tumor size. Fifty-one patients had positive 18F-FDG-PET/CT (average SUVbw was 8.3 ± 4.7; SUVlbm 5.8 ± 2.6; SUVbsa 2 ± 1; MTV 45.4 ± 37; TLG 227 ± 114); the remaining 11 were not 18F-FDG-avid. Tumor size was significantly higher in patients avid lesions compared to FDG not avid; no other features are associated with FDG-avidity. Progression to MM occurred in 29 patients with an average of 18.3 months; MM was more likely to develop in patients with bone plasmacytoma and in patients with 18F-FDG avid lesion. Time to transformation in MM (TTMM) was significantly shorter in patients with osseous SP, in 18F-FDG avid lesion, for SUVlbm > 5.2 and SUVbsa > 1.7. 18F-FDG pathological uptake in SP occurred in most cases, being independently associated with tumor size. PET/CT seemed to be correlated to a higher risk of transformation in MM, in particular for 18F-FDG avid plasmacytoma and SBP. Among semiquantitative features, SUVlbm > 5.2 and SUVbsa > 1.7 were significantly correlated with TTMM.

  17. [Regulation of terpene metabolism]. Annual progress report, March 15, 1990--March 14, 1991

    SciTech Connect

    Croteau, R.

    1991-12-31

    During the last grant period, we have completed studies on the key pathways of monoterpene biosynthesis and catabolism in sage and peppermint, and have, by several lines of evidence, deciphered the rate-limiting step of each pathway. We have at least partially purified and characterized the relevant enzymes of each pathway. We have made a strong case, based on analytical, in vivo, and in vitro studies, that terpene accumulation depends upon the balance between biosynthesis and catabolism, and provided supporting evidence that these processes are developmentally-regulated and very closely associated with senescence of the oil glands. Oil gland ontogeny has been characterized at the ultrastructural level. We have exploited foliar-applied bioregulators to delay gland senescence, and have developed tissue explant and cell culture systems to study several elusive aspects of catabolism. We have isolated pure gland cell clusters and localized monoterpene biosynthesis and catabolism within these structures, and have used these preparations as starting materials for the purification to homogeneity of target ``regulatory`` enzymes. We have thus developed the necessary background knowledge, based on a firm understanding of enzymology, as well as the necessary experimental tools for studying the regulation of monoterpene metabolism at the molecular level. Furthermore, we are now in a position to extend our systematic approach to other terpenoid classes (C{sub 15}-C{sub 30}) produced by oil glands.

  18. A Network-Based Approach to Visualize Prevalence and Progression of Metabolic Syndrome Components

    PubMed Central

    Völker, Uwe; Völzke, Henry; Kroemer, Heyo; Nauck, Matthias; Wallaschofski, Henri

    2012-01-01

    Background The additional clinical value of clustering cardiovascular risk factors to define the metabolic syndrome (MetS) is still under debate. However, it is unclear which cardiovascular risk factors tend to cluster predominately and how individual risk factor states change over time. Methods & Results We used data from 3,187 individuals aged 20–79 years from the population-based Study of Health in Pomerania for a network-based approach to visualize clustered MetS risk factor states and their change over a five-year follow-up period. MetS was defined by harmonized Adult Treatment Panel III criteria, and each individual's risk factor burden was classified according to the five MetS components at baseline and follow-up. We used the map generator to depict 32 (25) different states and highlight the most important transitions between the 1,024 (322) possible states in the weighted directed network. At baseline, we found the largest fraction (19.3%) of all individuals free of any MetS risk factors and identified hypertension (15.4%) and central obesity (6.3%), as well as their combination (19.0%), as the most common MetS risk factors. Analyzing risk factor flow over the five-year follow-up, we found that most individuals remained in their risk factor state and that low high-density lipoprotein cholesterol (HDL) (6.3%) was the most prominent additional risk factor beyond hypertension and central obesity. Also among individuals without any MetS risk factor at baseline, low HDL (3.5%), hypertension (2.1%), and central obesity (1.6%) were the first risk factors to manifest during follow-up. Conclusions We identified hypertension and central obesity as the predominant MetS risk factor cluster and low HDL concentrations as the most prominent new onset risk factor. PMID:22724019

  19. [THE FACTORS OF THE PROGRESSION OF METABOLIC DISORDERS IN THE PANCREAS IN PATIENTS WITH ASSOCIATED CLINICAL VARIANTS OF THE CHRONIC PANCREATITIS AND TYPE 2 DIABETES MELLITUS].

    PubMed

    Zhuravlyova, L V; Shekhovtsova, Y O

    2015-01-01

    The purpose of the present study was to determine the causal factors of the progression of metabolic disorders in pancreatic tissue and their relationships in patients with assotiated clinical variants of chronic pancreatitis (CP) and type 2 diabetes mellitus (T2DM). The study involved of 76 patients with CP and T2DM. The causes of progression of metabolic disorders in the pancreas in patients with associated clinical variants of CP and T2DM has been analyzed. The most significant of them were insulin resistance and abdominal obesity, which promotes early formation of the metabolic syndrome and the activation of fibrogenesis and steatosis in the pancreas and is caused by dyslipidemia, impaired glucose metabolism and the development of systemic inflammation and imbalance of adipocytokines. The relationships between adipocytokines, body weight and individual components of the metabolic syndrome in patients with CP and T2DM suggests the involvement of these hormones of adipose tissue in the formation of the metabolic syndrome and its components.

  20. The progression from a lower to a higher invasive stage of bladder cancer is associated with severe alterations in glucose and pyruvate metabolism

    SciTech Connect

    Conde, Vanessa R.; Oliveira, Pedro F.; Ramalhosa, Elsa; Pereira, José A.; Alves, Marco G.; Silva, Branca M.

    2015-07-01

    Cancer cells present a particular metabolic behavior. We hypothesized that the progression of bladder cancer could be accompanied by changes in cells glycolytic profile. We studied two human bladder cancer cells, RT4 and TCCSUP, in which the latter represents a more invasive stage. The levels of glucose, pyruvate, alanine and lactate in the extracellular media were measured by Proton Nuclear Magnetic Resonance. The protein expression levels of glucose transporters 1 (GLUT1) and 3 (GLUT3), monocarboxylate transporter 4 (MCT4), phosphofructokinase-1 (PFK1), glutamic-pyruvate transaminase (GPT) and lactate dehydrogenase (LDH) were determined. Our data showed that glucose consumption and GLUT3 levels were similar in both cell lines, but TCCSUP cells displayed lower levels of GLUT1 and PFK expression. An increase in pyruvate consumption, concordant with the higher levels of lactate and alanine production, was also detected in TCCSUP cells. Moreover, TCCSUP cells presented lower protein expression levels of GPT and LDH. These results illustrate that bladder cancer progression is associated with alterations in cells glycolytic profile, namely the switch from glucose to pyruvate consumption in the more aggressive stage. This may be useful to develop new therapies and to identify biomarkers for cancer progression. - Highlights: • Metabolic phenotype of less and high invasive bladder cancer cells was studied. • Bladder cancer progression involves alterations in cells glycolytic profile. • More invasive bladder cancer cells switch from glucose to pyruvate consumption. • Our results may help to identify metabolic biomarkers of bladder cancer progression.

  1. Circulating ribonucleic acids and metabolic stress parameters may reflect progression of autoimmune or inflammatory conditions in juvenile type 1 diabetes.

    PubMed

    Kocic, Gordana; Pavlovic, Radmila; Najman, Stevo; Nikolic, Goran; Sokolovic, Dusan; Jevtovic-Stoimenov, Tatjana; Musovic, Dijana; Veljkovic, Andrej; Kocic, Radivoj; Djindjic, Natasa

    2011-07-28

    The sensing of ribonucleic acids (RNAs) by the monocyte/macrophage system occurs through the TLR7/8 Toll-like receptor family, the retinoic acid-inducible protein I (RIG-I), and the melanoma differentiation-associated protein-5 (MDA-5). The aim of the present study was to evaluate the effect of circulating RNAs, isolated from juvenile type 1 diabetic patients and healthy control children, on the inflammatory, apoptotic, and antiviral response in human peripheral blood mononuclear cells (PBMCs) isolated from a healthy donor. Obtained effects were compared to the effects of metabolic stress parameters (hyperglycemia, oxidative and nitrosative stress). Forty-eight patients with juvenile type 1 diabetes and control children were included in the study. By performing the chromatographic analysis of circulating RNAs, the peak at the retention time 0.645 min for diabetic and control RNA samples was identified. To determine whether circulating RNAs have an agonistic or antagonistic effect on the signaling pathways involved in inflammatory, apoptotic, and antiviral cascade, their effect on TLR8, RIG-I, MDA-5, MyD88, NF-KB, IRF-3, phosphoIRF-3, IRF-7, RIP, and p38 was evaluated. A significantly lower level was achieved by cultivating PBMCs with circulating RNAs isolated from type 1 diabetic children, compared to the intact PBMCs, in relation to TLR-8, MDA-5, NF-KB, phospho IRF-3, and RIP, while it was higher for Bax. All the metabolic stress conditions up-regulated NF-KB, Bcl-2, and Bax. The NF-êB determination seems to be the most sensitive parameter that may reflect disease processes associated with the progression of autoimmune or inflammatory conditions, while the IRF3/phosphoIRF3 ratio may suggest an insufficient antiviral response.

  2. Effect on SO/sub 2/ light modulation of plant metabolism. Final progress report, June 1, 1983-May 31, 1985

    SciTech Connect

    Anderson, L.E.

    1985-01-01

    The effect of sulfite and arsenite on light activation in two pisum cultivars was examined. The experiments indicate that the difference in sensitivity to SO/sub 2/ is directly reflected in sensitivity of a thylakoid bound factor to SO/sub 2/. 2 figs. (DT)

  3. Mapping methyl jasmonate-mediated transcriptional reprogramming of metabolism and cell cycle progression in cultured Arabidopsis cells

    PubMed Central

    Pauwels, Laurens; Morreel, Kris; De Witte, Emilie; Lammertyn, Freya; Van Montagu, Marc; Boerjan, Wout; Inzé, Dirk; Goossens, Alain

    2008-01-01

    Jasmonates (JAs) are plant-specific signaling molecules that steer a diverse set of physiological and developmental processes. Pathogen attack and wounding inflicted by herbivores induce the biosynthesis of these hormones, triggering defense responses both locally and systemically. We report on alterations in the transcriptome of a fast-dividing cell culture of the model plant Arabidopsis thaliana after exogenous application of methyl JA (MeJA). Early MeJA response genes encoded the JA biosynthesis pathway proteins and key regulators of MeJA responses, including most JA ZIM domain proteins and MYC2, together with transcriptional regulators with potential, but yet unknown, functions in MeJA signaling. In a second transcriptional wave, MeJA reprogrammed cellular metabolism and cell cycle progression. Up-regulation of the monolignol biosynthesis gene set resulted in an increased production of monolignols and oligolignols, the building blocks of lignin. Simultaneously, MeJA repressed activation of M-phase genes, arresting the cell cycle in G2. MeJA-responsive transcription factors were screened for their involvement in early signaling events, in particular the regulation of JA biosynthesis. Parallel screens based on yeast one-hybrid and transient transactivation assays identified both positive (MYC2 and the AP2/ERF factor ORA47) and negative (the C2H2 Zn finger proteins STZ/ZAT10 and AZF2) regulators, revealing a complex control of the JA autoregulatory loop and possibly other MeJA-mediated downstream processes. PMID:18216250

  4. Metabolic Syndrome and Prostate Cancer: a Review of Complex Interplay Amongst Various Endocrine Factors in the Pathophysiology and Progression of Prostate Cancer.

    PubMed

    Rhee, Handoo; Vela, Ian; Chung, Eric

    2016-04-01

    The human prostate gland is an endocrine organ where dysregulation of various hormonal factors may play a pivotal role in the pathogenesis of prostate cancer. There is emerging epidemiological data to support the role of components of metabolic syndrome, namely, obesity, hypercholesterolaemia, diabetes and hyperinsulinaemia on the development and/or the progression of prostate cancer. Although the exact mechanisms behind the relationship between metabolic syndrome and prostate cancer remain largely unknown, various in vitro and animal experiments of metabolic syndrome models have been shown to promote survival, mitogenesis, metastasis and treatment resistance pathways, through various adaptive responses such as intracellular steroidogenesis and lipogenesis. Also, in a large proportion of men with metabolic syndrome, alteration in levels of hormones such as testosterone, leptin and adiponectin has been shown to contribute towards the aggression of prostate cancer. Whilst the exact bio-pathophysiological mechanisms between metabolic syndrome and prostate cancer are yet to be fully elucidated, medications that target specific components of metabolic syndrome have further provided evidence for the inter-relationship between metabolic syndrome, its components and prostate cancer. Emerging in vitro and molecular data is likely to bring us closer to utilizing this knowledge to target particular cancer survival pathways and improving outcomes for men with prostate cancer.

  5. Final Technical Progress Report; Closeout Certifications; CSSV Newsletter Volume I; CSSV Newsletter Volume II; CSSV Activity Journal; CSSV Final Financial Report

    SciTech Connect

    Houston, Johnny L; Geter, Kerry

    2013-08-23

    This Project?s third year of implementation in 2007-2008, the final year, as designated by Elizabeth City State University (ECSU), in cooperation with the National Association of Mathematicians (NAM) Inc., in an effort to promote research and research training programs in computational science ? scientific visualization (CSSV). A major goal of the Project was to attract the energetic and productive faculty, graduate and upper division undergraduate students of diverse ethnicities to a program that investigates science and computational science issues of long-term interest to the Department of Energy (DoE) and the nation. The breadth and depth of computational science?scientific visualization and the magnitude of resources available are enormous for permitting a variety of research activities. ECSU?s Computational Science-Science Visualization Center will serve as a conduit for directing users to these enormous resources.

  6. Dietary polyphenols against metabolic disorders: How far have we progressed in the understanding of the molecular mechanisms of action of these compounds?

    PubMed

    García-Conesa, María-Teresa

    2017-06-13

    The aim of this review was to critically assess the evidence supporting the metabolic and anti-inflammatory effects attributed to polyphenols and the potential mechanisms of action underlying these effects. The metabolic and anti-inflammatory properties of polyphenols and polyphenol-rich products have been shown mostly in rodents. These compounds appear to share multiple mechanisms of action at different body sites (gastrointestinal tract, microbiota, host organs) and the responsible molecules may be the original plant compounds, the microbial metabolites and (or) the host derived conjugates. Polyphenols may modify digestion and absorption of nutrients, microbiota composition and metabolism, and host tissue metabolic pathways but none of these mechanisms have been fully demonstrated in vivo and thus, more and better designed studies are needed. Furthermore, human clinical trials show inconsistent evidence of the metabolic and inflammation regulatory properties of polyphenols. Some of the principal limitations of these studies as well as recommendations to further progress in the understanding of the metabolic effects and mechanisms of action of polyphenols are discussed.

  7. Mitophagy or how to control the Jekyll and Hyde embedded in mitochondrial metabolism: implications for melanoma progression and drug resistance.

    PubMed

    Soengas, María S

    2012-11-01

    Proteins and pathways that control cell fate are placed under intense scrutiny. The same tight regulation applies to essential organelles that can both sustain cell survival or promote self-degradation programs. Mitochondria are perhaps the prime example of cellular machineries with split functions (personalities). As a main source of ATP, mitochondria represent the main powerhouse of eukaryotic cells. However, mitochondrial respiration has the hidden complication of the production of potentially harmful reactive oxygen species (ROS). Moreover, mitochondria holds an armamentarium of stress-response factors, which depending on the context, may lead to pro-inflammatory signals, and to various forms of cell death, ranging from apoptosis to necrosis. A main clearance mechanism to eliminate superfluous, damaged or hyperactive mitochondria is selective mitophagy. Mitophagy, in fact, is emerging as a key quality-control mechanism in cancer cells. Specifically, malignant transformation has been found to induce marked changes in mitochondrial dynamics and structure. Moreover, a key hallmark of tumor progression is metabolic reprogramming, which further deregulates ROS content and renders cells more susceptible to mitochondrial perturbations. Despite its increasing relevance in cancer biology, the field of mitophagy remains virtually unexplored in melanoma. However, given unique antioxidant mechanisms in melanocytic cells (e.g., linked to melanin) and the idiosyncratic interplay between ROS and hypoxia (both mitophagy inducers) in melanoma, this tumor type represents an ideal scenario for physiological studies of mitochondrial turnover. This perspective summarizes proof of concept for in-depth basic and translational studies of mitophagy in melanoma. Particular emphasis is dedicated to new opportunities for gene discovery and drug design in this still aggressive disease. © 2012 John Wiley & Sons A/S.

  8. Procedures for Handling Retaliation Complaints Under Section 31307 of the Moving Ahead for Progress in the 21st Century Act (MAP-21). Final rule.

    PubMed

    2016-12-14

    On March 16, 2016, the Occupational Safety and Health Administration (OSHA) of the U.S. Department of Labor (Department) issued an interim final rule (IFR) that provided procedures for the Department's processing of complaints under the employee protection (retaliation or whistleblower) provisions of Section 31307 of the Moving Ahead for Progress in the 21st Century Act (MAP-21). The IFR established procedures and time frames for the handling of retaliation complaints under MAP-21, including procedures and time frames for employee complaints to OSHA, investigations by OSHA, appeals of OSHA determinations to an administrative law judge (ALJ) for a hearing de novo, hearings by ALJs, review of ALJ decisions by the Administrative Review Board (ARB) (acting on behalf of the Secretary of Labor) and judicial review of the Secretary's final decision. It also set forth the Department's interpretations of the MAP-21 whistleblower provisions on certain matters. This final rule adopts, without change, the IFR.

  9. Comparison of Performance and Career Progression of High School Graduates and Non-Graduates in the Air Force. Final Report.

    ERIC Educational Resources Information Center

    Kantor, Jeffrey E.; Guinn, Nancy

    The performance and career progression of a sample of 20,705 airmen were monitored throughout their initial tour of service. For comparative purposes, this sample was divided into high school graduate and nongraduate groups and further subdivided by Armed Forces Qualification Test (AFOT) mental categories. Points of comparison included:…

  10. Gamma scattering in condensed matter with high intensity Moessbauer radiation. Final technical progress report, January 16, 1993--January 15, 1996

    SciTech Connect

    1997-06-01

    Progress is reported on work with high intensity radiation. Moessbauer radioisotopes of exceptional high intensity have been the source of photons for most experiments. Topics include lattice dynamics, studies of glass forming liquids, and line-shape and it`s role in finding materials and nuclear parameters.

  11. Main research accomplishments since the grant was last reviewed competitively. [Final technical progress report, November 1, 1992--July 31, 1993

    SciTech Connect

    Prakash, L.

    1993-11-01

    This project deals with the characterization of DNA repair genes and their encoded proteins involved in the incision step of excision repair and in postreplication repair and mutagenesis following exposure to UV light in eukaryotes: the yeast Saccharomyces cerevisiae and humans. Summarized in this report is progress in achieving the goals of this project.

  12. Piloting the Oregon A.I.M. Project: Measuring Progress for Program Evaluation and Accountability. Final Report, 1997-98.

    ERIC Educational Resources Information Center

    Greater Pittsburgh Literacy Council, PA.

    A pilot project was conducted to implement the Oregon A.I.M. (Assessment, Instruction, Mastery), a tutor program accountability system developed in Oregon, in 15 volunteer-based programs in Pennsylvania and to make recommendations on the usefulness of this system as a means of collecting and aggregating data on student progress for these and…

  13. Myocardial oxidative stress, osteogenic phenotype, and energy metabolism are differentially involved in the initiation and early progression of δ-sarcoglycan-null cardiomyopathy

    PubMed Central

    Missihoun, Comlan; Zisa, David; Shabbir, Arsalan; Lin, Huey

    2009-01-01

    Dilated cardiomyopathy (DCM) is a common cause of heart failure, and identification of early pathogenic events occurring prior to the onset of cardiac dysfunction is of mechanistic, diagnostic, and therapeutic importance. The work characterized early biochemical pathogenesis in TO2 strain hamsters lacking δ-sarcoglycan. Although the TO2 hamster heart exhibits normal function at 1 month of age (presymptomatic stage), elevated levels of myeloperoxidase, monocyte chemotactic protein-1, malondialdehyde, osteopontin, and alkaline phosphatase were evident, indicating the presence of inflammation, oxidative stress, and osteogenic phenotype. These changes were localized primarily to the myocardium. Derangement in energy metabolism was identified at the symptomatic stage (4 month), and is marked by attenuated activity and expression of pyruvate dehydrogenase E1 subunit, which catalyzes the rate-limiting step in aerobic glucose metabolism. Thus, this study illustrates differential involvement of oxidative stress, osteogenic phenotype, and glucose metabolism in the initiation and early progression of δ-sarcoglycan-null DCM. PMID:18726675

  14. Metabolic products, mass spectral analyses, and synthesis of toxic trichothecenes. Final report, 15 April 1982-14 July 1985

    SciTech Connect

    Mirocha, C.J.

    1985-07-31

    A mass spectral library of the trichothecenes was developed and delivered to USAMRIID. The structure of Fusarochromanone (causes bone deformation) was elucidated and the biological activity of this metabolite was determined. Metabolic studies of T-2 toxin were determined in chickens and the metabolites were identified. Similarly, a kinetic study of T-2 metabolism was done using a cow as the subject. De-epoxy-diacetoxyscirpenol was found in a Fusarium culture for the first time and de-epoxy-T2 tetraol was found in cow urine for the first time. Morphologic lesions of T-2 toxin in the cat were described.

  15. 40 CFR 62.14565 - How do I comply with the increment of progress for achieving final compliance?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... DESIGNATED FACILITIES AND POLLUTANTS Federal Plan Requirements for Commercial and Industrial Solid Waste Incineration Units That Commenced Construction On or Before November 30, 1999 Compliance Schedule and... complete retrofit construction of control devices, as specified in the final control plan, so that,...

  16. Effect of petroleum-related pollutants on Aurelia growth and development. Final progress report, September 12, 1977-August 31, 1982

    SciTech Connect

    Spangenberg, D.B.

    1982-01-01

    Petroleum-related hydrocarbons were tested using the Aurelia Metamorphosis Test System. In addition, extensive studies were made of the effects of Alaskan crude petroleum oil, cadmium, and sodium azide on Aurelia metamorphosis. The Aurelia Budding Test System was applied to phenol, aniline, and naphthalene and the Aurelia Genetic Modification Test System was developed to determine whether chemically-treated organisms had genetic damage which could be revealed in progeny over a long period of time. The Aurelia Genetic Modification Test System was applied to aniline, phenol, Alaskan crude petroleum oil, and sodium azide-treated organisms. It is concluded that the Aurelia can be used effectively to ferret out subtle effects of marine pollutants as well as far-reaching effects passed on through progeny over a long period of time. Pollutant effects are most rapidly revealed, however, in organisms undergoing metamorphosis especially with regard to effects related to iodine metabolism, calcium metabolism, and behavioral and morphological teratology. The premise is that specific effects of environmental pollutants must be known in order that these effects may be neutralized or prevented. Through an understanding of mechanisms of action of various pollutant components in simple indicator organisms such as Aurelia, it may ultimately be possible to maintain high standards of energy production and to have a safe and productive marine environment at the same time.

  17. Final Progress Report for Collaborative Research: Aging of Black Carbon during Atmospheric Transport: Understanding Results from the DOE’s 2010 CARES and 2012 ClearfLo Campaigns

    SciTech Connect

    Mazzoleni, Claudio; Subramanian, R.

    2016-08-31

    Over the course of this project, we have analyzed data and samples from the Carbonaceous Aerosol and Radiative Effects Study (CARES) and the Clear air for London (ClearfLo) campaign, as well as conducted or participated in laboratory experiments designed to better understand black carbon mixing state and climate-relevant properties. The laboratory campaigns took place at the Pacific Northwest National Laboratory and Carnegie Mellon University to study various climate-relevant aerosol properties of different sources of soot mixing with secondary organic aerosol precursors. Results from some of these activities were summarized in the previous progress report. This final report presents the manuscripts that have been published (many in the period since the last progress report), lists presentations at different conferences based on grant-related activities, and presents some results that are likely to be submitted for publication in the near future.

  18. Abiraterone acetate for patients with metastatic castration-resistant prostate cancer progressing after chemotherapy: final analysis of a multicentre, open-label, early-access protocol trial.

    PubMed

    Sternberg, Cora N; Castellano, Daniel; Daugaard, Gedske; Géczi, Lajos; Hotte, Sebastien J; Mainwaring, Paul N; Saad, Fred; Souza, Ciro; Tay, Miah H; Garrido, José M Tello; Galli, Luca; Londhe, Anil; De Porre, Peter; Goon, Betty; Lee, Emma; McGowan, Tracy; Naini, Vahid; Todd, Mary B; Molina, Arturo; George, Daniel J

    2014-10-01

    In the final analysis of the phase 3 COU-AA-301 study, abiraterone acetate plus prednisone significantly prolonged overall survival compared with prednisone alone in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy. Here, we present the final analysis of an early-access protocol trial that was initiated after completion of COU-AA-301 to enable worldwide preapproval access to abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy. We did a multicentre, open-label, early-access protocol trial in 23 countries. We enrolled patients who had metastatic castration-resistant prostate cancer progressing after taxane chemotherapy. Participants received oral doses of abiraterone acetate (1000 mg daily) and prednisone (5 mg twice a day) in 28-day cycles until disease progression, development of sustained side-effects, or abiraterone acetate becoming available in the respective country. The primary outcome was the number of adverse events arising during study treatment and within 30 days of discontinuation. Efficacy measures (time to prostate-specific antigen [PSA] progression and time to clinical progression) were gathered to guide treatment decisions. We included in our analysis all patients who received at least one dose of abiraterone acetate. This study is registered with ClinicalTrials.gov, number NCT01217697. Between Nov 17, 2010, and Sept 30, 2013, 2314 patients were enrolled into the early-access protocol trial. Median follow-up was 5·7 months (IQR 3·5-10·6). 952 (41%) patients had a grade 3 or 4 treatment-related adverse event, and grade 3 or 4 serious adverse events were recorded in 585 (25%) people. The most common grade 3 and 4 adverse events were hepatotoxicity (188 [8%]), hypertension (99 [4%]), cardiac disorders (52 [2%]), osteoporosis (31 [1%]), hypokalaemia (28 [1%]), and fluid retention or oedema (23 [1%]). 172 (7%) patients discontinued the study

  19. Toms Creek Integrated Gasification Combined Cycle Demonstration Project. Final quarterly technical progress report for the period ending March 31, 1993

    SciTech Connect

    Feher, G.

    1993-05-24

    This Quarterly Technical Progress Report for the period ending March 31, 1993 summarizes the work done to data by Tampella Power Corporation and Enviropower, Inc. on the integrated combined-cycle power plant project. Efforts were concentrated on the Toms Creek PDS (Preliminary Design and Studies). Tampella Power Corporation`s efforts were concentrated on the Toms Creek Preliminary Process Flow Diagram (PFD) and Piping and Instrument Diagrams (P&IDs). Tampella Power Corporation also prepared Heat and Material Balances (H&MBs) for different site-specific cases.

  20. Fusion reactor systems studies. Progress report for the period November 1, 1996--October 31, 1997, and final report

    SciTech Connect

    El-Guebaly, L.A.; Blanchard, J.P.; Kulcinski, G.L.

    1997-08-01

    During FY97, the University of Wisconsin Fusion Technology Institute personnel have participated in the ARIES-RS and the ARIES-ST projects. The main areas of effort are: (1) neutronics analysis; (2) shielding of components and personnel; (3) neutron wall loading distribution; (4) radiation damage to in-vessel components; (5) components lifetimes; (6) embrittled materials designs issues; (7) stress and structural analysis; (8) activation, LOCA, and safety analysis; (9) support and fabrication of components; (10) vacuum system; and (11) maintenance. Progress made in these areas are summarized.

  1. Development of a Coal Quality Expert. Final technical progress report No. 12, [January 1--March 31, 1993

    SciTech Connect

    Not Available

    1993-08-12

    During the past quarter, Tasks 3, 4, 5, and 6 were active. Task 3 Pilot Scale Combustion Testing activity included data analysis of pilot- and bench-scale combustion samples in support of the development of CQE slogging and fouling models. Under Task 4, field testing at the fifth host utility site -- New England Power Service Company`s Brayton Point Unit 3 -- was completed in March with the testing of the alternate coal. Test plans were finalized for the sixth and final field test to be performed at Brayton Point Unit 2 in April 1993. Tasks 5 and 6 activities were directed at design and development of CQE base classes and objects, continued formulation and integration of CQE algorithms and submodels, development of the user interface prototype, and preparation of the Fireside Advisor.

  2. Primate polonium metabolic models and their use in estimation of systemic radiation doses from bioassay data. Final report

    SciTech Connect

    Cohen, N.

    1989-03-15

    A Polonium metabolic model was derived and incorporated into a Fortran algorithm which estimates the systemic radiation dose from {sup 210}Po when applied to occupational urine bioassay data. The significance of the doses estimated are examined by defining the degree of uncertainty attached to them through comprehensive statistical testing procedures. Many parameters necessary for dosimetry calculations (such as organ partition coefficients and excretion fractions), were evaluated from metabolic studies of {sup 210}Po in non-human primates. Two tamarins and six baboons were injected intravenously with {sup 210}Po citrate. Excreta and blood samples were collected. Five of the baboons were sacrificed at times ranging from 1 day to 3 months post exposure. Complete necropsies were performed and all excreta and the majority of all skeletal and tissue samples were analyzed radiochemically for their {sup 210}Po content. The {sup 210}Po excretion rate in the baboon was more rapid than in the tamarin. The biological half-time of {sup 210}Po excretion in the baboon was approximately 15 days while in the tamarin, the {sup 210}Po excretion rate was in close agreement with the 50 day biological half-time predicted by ICRP 30. Excretion fractions of {sup 210}Po in the non-human primates were found to be markedly different from data reported elsewhere in other species, including man. A thorough review of the Po urinalysis procedure showed that significant recovery losses resulted when metabolized {sup 210}Po was deposited out of raw urine. Polonium-210 was found throughout the soft tissues of the baboon but not with the partition coefficients for liver, kidneys, and spleen that are predicted by the ICRP 30 metabolic model. A fractional distribution of 0.29 for liver, 0.07 for kidneys, and 0.006 for spleen was determined. Retention times for {sup 210}Po in tissues are described by single exponential functions with biological half-times ranging from 15 to 50 days.

  3. Final Technical Progress Report: High-Efficiency Low-Cost Thin-Film GaAs Photovoltaic Module Development Program; July 14, 2010 - January 13, 2012

    SciTech Connect

    Mattos, L.

    2012-03-01

    This is the final technical progress report of the High-Efficiency Low-Cost Thin-Film GaAs Photovoltaic Module Development Program. Alta Devices has successfully completed all milestones and deliverables established as part of the NREL PV incubator program. During the 18 months of this program, Alta has proven all key processes required to commercialize its solar module product. The incubator focus was on back end process steps directed at conversion of Alta's high quality solar film into high efficiency 1-sun PV modules. This report describes all program deliverables and the work behind each accomplishment.

  4. Metabolic effects of microwave radiation and convection heating on human mononuclear leukocytes. Final report, January 1985-May 1986

    SciTech Connect

    Kiel, J.L.; Wong, L.S.; Erwin, D.N.

    1986-01-01

    Investigated here were the effects of microwave (MW) radiation (2450-MHz, continuous-wave, mean specific absorption rate of 103.5 + or - 4.2 W/kg) and convention heating on the nonphosphorylating oxidative metabolism of human peripheral mononuclear leukocytes (96% lymphocytes, 4% monocytes) at 37 C. Metabolic activity, determined by chemiluminescence (CL) of cells challenged with luminol (5-aminO-2, 3-dihydro-1, 4-phthalazinedione) linked to bovine serum albumin, was detected with a brightness photomer. A significant stimulation after after MW exposure (p < 0.005) over total CL of matched 37 C-incubator controls was observed. A similar degree of stimulation, compared to incubator controls, was also detected after sham treatment. No significant difference existed between changes in total CL or stimulation indices of the MW and sham-exposed groups. Exposure to MW radiation, under normothermic (37 + or - 0.03 C) conditions, appears to have no effect on the oxidative metabolic activity of human peripheral mononuclear leukocytes. However, the significant differences between MW or sham-exposed cells and their respective incubator controls occurred because the temperature of the incubator did not exceed 35.9 C, and 39 minutes were required for the temperature to rise from 22 to 35.9 C. Slow heating of incubator controls must be accounted for in thermal and redio-frequency radiation studies in vitro.

  5. Final Progress Report: FRACTURE AND SUBCRITICAL DEBONDING IN THIN LAYERED STRUCTURES: EXPERIMENTS AND MULTI-SCALE MODELING

    SciTech Connect

    Reinhold H. Dauskardt

    2005-08-30

    Final technical report detailing unique experimental and multi-scale computational modeling capabilities developed to study fracture and subcritical cracking in thin-film structures. Our program to date at Stanford has studied the mechanisms of fracture and fatigue crack-growth in structural ceramics at high temperature, bulk and thin-film glasses in selected moist environments where we demonstrated the presence of a true mechanical fatigue effect in some glass compositions. We also reported on the effects of complex environments and fatigue loading on subcritical cracking that effects the reliability of MEMS and other micro-devices using novel micro-machined silicon specimens and nanomaterial layers.

  6. Organization of the R chromosome region in maize: Final progress report, June 1, 1983--May 31, 1986

    SciTech Connect

    Kermicle, J.

    1989-02-01

    For the present study, insertional mutagenesis using transposable sequences proved the most effective means of producing /und R/ variants for fine structure study. Considerable effort was directed toward developing this means of mutagenesis. It was also necessary to describe the pattern of recombination that prevailed in this region when insertions were present. Thus some of the topics considered as separate items in the following discussion concern transposable element behavior and recombination as such. Until recently, genetic analysis had been the principal means of investigating /und R/ structure and function. With the advent of molecular cloning of maize genes by transposon tagging, a more direct means of investigating /und R/ structure was envisioned. This possibility was realized. We are now collaborating with these investigators to integrate genetic and molecular sources of evidence. This document summarizes publications of research sponsored by this grant, and recent findings that appear to be major advances but concerning which further experiments are in progress. 12 refs.

  7. Progressive Inhibition by Water Deficit of Cell Wall Extensibility and Growth along the Elongation Zone of Maize Roots Is Related to Increased Lignin Metabolism and Progressive Stelar Accumulation of Wall Phenolics1

    PubMed Central

    Fan, Ling; Linker, Raphael; Gepstein, Shimon; Tanimoto, Eiichi; Yamamoto, Ryoichi; Neumann, Peter M.

    2006-01-01

    Water deficit caused by addition of polyethylene glycol 6000 at −0.5 MPa water potential to well-aerated nutrient solution for 48 h inhibited the elongation of maize (Zea mays) seedling primary roots. Segmental growth rates in the root elongation zone were maintained 0 to 3 mm behind the tip, but in comparison with well-watered control roots, progressive growth inhibition was initiated by water deficit as expanding cells crossed the region 3 to 9 mm behind the tip. The mechanical extensibility of the cell walls was also progressively inhibited. We investigated the possible involvement in root growth inhibition by water deficit of alterations in metabolism and accumulation of wall-linked phenolic substances. Water deficit increased expression in the root elongation zone of transcripts of two genes involved in lignin biosynthesis, cinnamoyl-CoA reductase 1 and 2, after only 1 h, i.e. before decreases in wall extensibility. Further increases in transcript expression and increased lignin staining were detected after 48 h. Progressive stress-induced increases in wall-linked phenolics at 3 to 6 and 6 to 9 mm behind the root tip were detected by comparing Fourier transform infrared spectra and UV-fluorescence images of isolated cell walls from water deficit and control roots. Increased UV fluorescence and lignin staining colocated to vascular tissues in the stele. Longitudinal bisection of the elongation zone resulted in inward curvature, suggesting that inner, stelar tissues were also rate limiting for root growth. We suggest that spatially localized changes in wall-phenolic metabolism are involved in the progressive inhibition of wall extensibility and root growth and may facilitate root acclimation to drying environments. PMID:16384904

  8. Progressive inhibition by water deficit of cell wall extensibility and growth along the elongation zone of maize roots is related to increased lignin metabolism and progressive stelar accumulation of wall phenolics.

    PubMed

    Fan, Ling; Linker, Raphael; Gepstein, Shimon; Tanimoto, Eiichi; Yamamoto, Ryoichi; Neumann, Peter M

    2006-02-01

    Water deficit caused by addition of polyethylene glycol 6000 at -0.5 MPa water potential to well-aerated nutrient solution for 48 h inhibited the elongation of maize (Zea mays) seedling primary roots. Segmental growth rates in the root elongation zone were maintained 0 to 3 mm behind the tip, but in comparison with well-watered control roots, progressive growth inhibition was initiated by water deficit as expanding cells crossed the region 3 to 9 mm behind the tip. The mechanical extensibility of the cell walls was also progressively inhibited. We investigated the possible involvement in root growth inhibition by water deficit of alterations in metabolism and accumulation of wall-linked phenolic substances. Water deficit increased expression in the root elongation zone of transcripts of two genes involved in lignin biosynthesis, cinnamoyl-CoA reductase 1 and 2, after only 1 h, i.e. before decreases in wall extensibility. Further increases in transcript expression and increased lignin staining were detected after 48 h. Progressive stress-induced increases in wall-linked phenolics at 3 to 6 and 6 to 9 mm behind the root tip were detected by comparing Fourier transform infrared spectra and UV-fluorescence images of isolated cell walls from water deficit and control roots. Increased UV fluorescence and lignin staining colocated to vascular tissues in the stele. Longitudinal bisection of the elongation zone resulted in inward curvature, suggesting that inner, stelar tissues were also rate limiting for root growth. We suggest that spatially localized changes in wall-phenolic metabolism are involved in the progressive inhibition of wall extensibility and root growth and may facilitate root acclimation to drying environments.

  9. Positron tomographic imaging of tumors using monoclonal antibodies. Final progress report, April 15, 1989--October 31, 1995

    SciTech Connect

    Zalutsky, M.R.

    1997-02-01

    The overall objective of this research is to develop methods for utilizing positron emission tomography (PET) to increase the clinical potential of radiolabeled monoclonal antibodies (MAbs). Enhancement of MAb tumor localization by hyperthermia also was proposed. Studies were to have been performed with both {sup 18}F and {sup 124}I; however, the lack of its availability (until quite recently) prevented experiments with {sup 124}I. Instead, two additional lines of inquiry were initiated in which they utilized aspects of the radiofluorination chemistries originally developed for MAbs for labeling chemotactic peptides and meta-iodobenzylguanidine (MIBG) analogues with {sup 18}F. This final report summarizes the original specific aims and the main research accomplishments in studies of mouse, dog and human models.

  10. Regulation and genetic organization of hydrogenase: Final progress report for the period June 1, 1985--July 31, 1988

    SciTech Connect

    Krasna, A.I.

    1988-10-01

    Hydrogenase is an enzyme which plays an important role in the anaerobic metabolism of many bacteria. The objectives of the research were to elucidate the regulation and genetic organization of hydrogenase in microorganisms. A mutation in the E. coli hydE gene leads to loss of all hydrogenase activities and isoenzymes as well as all formate-related activities. A 0.9 kb DNA fragment has been cloned from an E. coli genomic DNA library which restored all hydrogenase and formate activities to a hydE mutant strain. This gene coded for a polypeptide of subunit mw 36 kDa which is required for hydrogenase synthesis. It is involved in incorporation of nickel into hydrogenase. A mutation in the E coli hupB gene leads to the loss of the uptake of H/sub 2/ by dyes and the ability to grow on fumarate plus H/sub 2/, but expresses normal levels of hydrogenase when assayed by deuterium exchange. This mutation also leads to loss of all formate-related activities. The mutation mapped near minute 17 and a single mutation was responsible for loss of both activities. A 1.4 kb DNA fragment was isolated which restored the hydrogen uptake activities and coded for a polypeptide of subunit mw 30 kDa. Dna fragments have been isolated from Chromatium vinosum and Proteus vulgaris which restored hydrogenase activities to E. coli strains with mutations in the hydA or hydB regulatory genes and which lack all hydrogenase activities. 6 refs., 12 figs.

  11. Measurement and apportionment of radon source terms for modeling indoor environments. Final progress report, March 1990--August 1992

    SciTech Connect

    Harley, N.H.

    1992-12-31

    During the present 2 1/2 year contract period, we have made significant Progress in modeling the source apportionment of indoor {sup 222}Rn and in {sup 222}Rn decay product dosimetry. Two additional areas were worked on which we believe are useful for the DOE Radon research Program. One involved an analysis of the research house data, grouping the hourly house {sup 222}Rn measurements into 2 day, 7 day and 90 day intervals to simulate the response of passive monitors. Another area requiring some attention resulted in a publication of 3 years of our indoor/outdoor measurements in a high-rise apartment. Little interest has been evinced in apartment measurements yet 20% of the US population lives in multiple-family dwellings, not in contact with the ground. These data together with a summary of all other published data on apartments showed that apartments have only about 50% greater {sup 222}Rn concentration than the measured outdoor {sup 222}Rn. Apartment dwellers generally represent a low risk group regarding {sup 222}Rn exposure. The following sections describe the main projects in some detail.

  12. Parallel logic programming and parallel systems software and hardware. Progress report (Final), 1 April 1988-31 March 1989

    SciTech Connect

    Minker, J.

    1989-07-29

    This progress report summarizes work performed under AFOSR-88-0152 on parallel logic programming, problem solving, and deductive data bases. A parallel problem-solving system, PRISM (Parallel Inference System), that was implemented on McMOB was ported to the BBN Butterfly machine. Two versions of PRISM were developed and are operational on the Butterfly: a message-passing ring-structure system and a shared-memory system. Experimental testing of PRISM on McMOB continued, while experiments were also conducted on the Butterfly systems. Three enhancements were made and completed during the grant period. These are: a capability to handle negated queries and a capability to assert and retract statements. In addition to the above, work continued in the area of informative answers to queries in deductive data bases. A thesis was completed on the subject. An interpreter was developed and is running, that can take restricted natural language as input and can respond with a cooperative natural language output. In the area of parallel software development, the following were accomplished. Theoretical work on slicing/splicing was completed. Tools were provided for software development using artificial-intelligence techniques. AI software for massively parallel architectures was started.

  13. Bioconversion of coal derived synthesis gas to liquid fuels. Final quarterly technical progress report, July 1, 1993--September 30, 1993

    SciTech Connect

    Jain, M.K.; Worden, R.M.; Grethlein, H.

    1993-10-25

    The overall objective of the project is to develop an integrated two stage fermentation process for conversion of coal-derived synthesis gas to a mixture of alcohols. This is achieved in two steps. In the first step, Butyribacterium methylotrophicum converts carbon monoxide (CO) to butyric and acetic acids. Subsequent fermentation of the acids by Clostridium acetobutylicum leads to the production of butanol and ethanol. The tasks for this quarter were: (1) development/isolation of superior strains for fermentation of syngas, (2) optimization of process conditions for fermentation of syngas, (3) evaluation of bioreactor configuration for improved mass transfer of syngas, (4) development of a membrane-based pervaporation system, (5) optimization of process conditions for reducing carbon and electron loss by H{sub 2}-CO{sub 2} fermentation, and (6) synthesis gas fermentation in single-stage by co-culture. Progress is reported in isolation of CO utilizing anaerobic strains; investigating the product profile for the fermentation of syngas by B. methylotrophicum; and determining the effect of carbon monoxide on growth of C. acetobutylicum.

  14. Chemical and geochemical studies off the coast of Washington. Final report of progress, July 1983-July 1985

    SciTech Connect

    Carpenter, R.

    1985-07-01

    This report summarizes progress from July 1983 through conclusion in July 1985 of a series of marine chemical and geochemical investigations involving both laboratory studies and field studies off the coast of Washington. Most of our field work the past few years has been on the Washington continental shelf, slope, and the submarine canyons indenting the shelf north of the Columbia River. Our aim has been to provide basic data required to characterize underlying chemical and physical processes and their rates which control the distribution, concentrations, and ultimate fate of some of the potentially hazardous agents associated with fossil fuel and/or nuclear power production or transportation. We concentrated on several processes which we feel are of special importance in the sea, and developed methodologies and expertise to study them. Laboratory and field experiments and theories derived from them were used iteratively to investigate: (1) vertical transfer of trace chemicals from surface seawaters to underlying waters and sediments; (2) processes which may transfer certain chemicals from sediments back into the overlying water column; (3) redox processes which besides changing valence states of certain chemicals may alter their precipitation/dissolution tendencies, their biological availability and/or toxicity; and (4) accumulation histories of potentially hazardous chemicals in sediments during the past 100 years.

  15. Loss of ovarian function in the VCD mouse-model of menopause leads to insulin resistance and a rapid progression into the metabolic syndrome.

    PubMed

    Romero-Aleshire, Melissa J; Diamond-Stanic, Maggie K; Hasty, Alyssa H; Hoyer, Patricia B; Brooks, Heddwen L

    2009-09-01

    Factors comprising the metabolic syndrome occur with increased incidence in postmenopausal women. To investigate the effects of ovarian failure on the progression of the metabolic syndrome, female B(6)C(3)F(1) mice were treated with 4-vinylcyclohexene diepoxide (VCD) and fed a high-fat (HF) diet for 16 wk. VCD destroys preantral follicles, causing early ovarian failure and is a well-characterized model for the gradual onset of menopause. After 12 wk on a HF diet, VCD-treated mice had developed an impaired glucose tolerance, whereas cycling controls were unaffected [12 wk AUC HF mice 13,455 +/- 643 vs. HF/VCD 17,378 +/- 1140 mg/dl/min, P < 0.05]. After 16 wk on a HF diet, VCD-treated mice had significantly higher fasting insulin levels (HF 5.4 +/- 1.3 vs. HF/VCD 10.1 +/- 1.4 ng/ml, P < 0.05) and were significantly more insulin resistant (HOMA-IR) than cycling controls on a HF diet (HF 56.2 +/- 16.7 vs. HF/VCD 113.1 +/- 19.6 mg/dl x microU/ml, P < 0.05). All mice on a HF diet gained more weight than mice on a standard diet, and weight gain in HF/VCD mice was significantly increased compared with HF cycling controls. Interestingly, even without a HF diet, progression into VCD-induced menopause caused a significant increase in cholesterol and free fatty acids. Furthermore, in mice fed a standard diet (6% fat), insulin resistance developed 4 mo after VCD-induced ovarian failure. Insulin resistance following ovarian failure (menopause) was prevented by estrogen replacement. Studies here demonstrate that ovarian failure (menopause) accelerates progression into the metabolic syndrome and that estrogen replacement prevents the onset of insulin resistance in VCD-treated mice. Thus, the VCD model of menopause provides a physiologically relevant means of studying how sex hormones influence the progression of the metabolic syndrome.

  16. Progressive metabolic changes underlying the chronic reorganization of brain circuits during the silent phase of the lithium-pilocarpine model of epilepsy in the immature and adult Rat.

    PubMed

    Dubé, C; Boyet, S; Marescaux, C; Nehlig, A

    2000-03-01

    The lithium-pilocarpine (Li-Pilo) model of epilepsy reproduces most of the features of human temporal lobe epilepsy. In the present study, we explored the correlation between metabolic changes, neuronal damage, and epileptogenesis during the silent phase following status epilepticus (SE) induced by Li-Pilo in 10- (P10) and 21-day-old (P21) and adult rats. Cerebral metabolic rates for glucose (CMR(glcs)) were measured at 14 and 60 days after SE by the 2-[(14)C]deoxyglucose method and neurodegeneration was assessed by the silver staining and cresyl violet techniques. In P10 rats, there was no damage and no metabolic consequences at any time after SE. In P21 rats, metabolic decreases were recorded at 14 days after SE, mainly in damaged forebrain regions. Conversely at 60 days after SE, P21 rats exhibited metabolic increases in both forebrain-damaged and brain-stem-intact areas. Finally, in adult rats studied at 14 days after SE, CMR(glcs) decreased in damaged forebrain areas involved in the circuitry of spontaneous seizures and increased in nondamaged brain-stem areas involved in the remote control of epilepsy. The increase in CMR(glcs) in damaged forebrain areas of P21 rats at 60 days after SE may reflect the genesis of a new circuitry underlying the occurrence of spontaneous seizures. The metabolic increase recorded in nondamaged brain-stem areas of P21 and adult rats occurs in regions involved in the remote control of seizures and might underlie a process of protection against the occurrence of seizures. Copyright 2000 Academic Press.

  17. The effect of variable calcium and very low calcium diets on human calcium metabolism. Ph.D. Thesis. Final Report

    NASA Technical Reports Server (NTRS)

    Chu, J.

    1971-01-01

    The effects of a very low calcium diet, with variable high and low protein intake, on the dynamics of calcium metabolism and the mechanism of calciuretics, are examined. The experiment, using male subjects, was designed to study the role of intestinal calcium absorption on urinary calcium excretion, and the rate of production of endogeneously secreted calcium in the gastrointestinal tract. The study showed an average of 70% fractional absorption rate during very low calcium intake, and that a decrease in renal tubular reabsorption of calcium is responsible for calciuretic effects of high protein intake. The study also indicates that there is a tendency to develop osteoporosis after long periods of low calcium intake, especially with a concurrent high protein intake.

  18. Construction of a genome-wide human BAC-Unigene resource. Final progress report, 1989--1996

    SciTech Connect

    Lim, C.S.; Xu, R.X.; Wang, M.

    1996-12-31

    Currently, over 30,000 mapped STSs and 27,000 mapped Unigenes (non-redundant, unigene sets of cDNA representing EST clusters) are available for human alone. A total of 44,000 Unigene cDNA clones have been supplied by Research Genetics. Unigenes, or cDNAs are excellent resource for map building for two reasons. Firstly, they exist in two alternative forms -- as both sequence information for PCR primer pairs, and cDNA clones -- thus making library screening by colony hybridization as well as pooled library PCR possible. The authors have developed an efficient and robust procedure to screen genomic libraries with large number of DNA probes. Secondly, the linkage and order of expressed sequences, or genes are highly conserved among human, mouse and other mammalian species. Therefore, mapping with cDNA markers rather than random anonymous STSs will greatly facilitate comparative, evolutionary studies as well as physical map building. They have currently deconvoluted over 10,000 Unigene probes against a 4X coverage human BAC clones from the approved library D by high density colony hybridization method. 10,000 batches of Unigenes are arrayed in an imaginary 100 X 100 matrix from which 100 row pools and 100 column pools are obtained. Library filters are hybridized with pooled probes, thus reducing the number of hybridization required for addressing the positives for each Unigene from 10,000 to 200. Details on the experimental scheme as well as daily progress report is posted on the Web site (http://www.tree.caltech.edu).

  19. Highly nucleophilic acetylide, vinyl, and vinylidene complexes. Final progress report, 1 January 1991--31 March 1994

    SciTech Connect

    Geoffroy, G.L.

    1994-10-04

    In the course of this research the authors found that the anionic alkynyl complex [Cp{prime}(CO)(PPh{sub 3})Mn-C{triple_bond}C-CH{sub 3}]{sup {minus}} can be generated in situ by the addition of two equivalents of n-BuLi to a solution of the carbene complex Cp{prime}(CO)(PPh{sub 3})Mn{double_bond}C(OMe)CH{sub 2}CH{sub 3}. It was also found that the highly nucleophilic propynyl complex [Cp(CO)(PPh{sub 3})Mn-C{triple_bond}C-Me]{sup {minus}} reacts with a variety of aldehydes and ketones in the presence of BF{sub 3}{center_dot}Et{sub 2}O to give, after quenching with MeOH, a series of cationic vinylcarbyne complexes of the general form [Cp(CO)(PPh{sub 3})Mn{triple_bond}C-C(Me){double_bond}C(R)(R{prime})]BF{sub 4}. The cationic alkylidyne complexes [Cp(CO){sub 2}M{triple_bond}C-CH{sub 2}R]{sup +} [M = Re, R = H, M = Mn, R = H, Me, Ph] have been found to undergo facile deprotonation to give the corresponding neutral vinylidene complexes Cp(CO){sub 2}M{double_bond}C{double_bond}C(H)R. The authors have also investigated reactions relevant to the halide promoted Fe and Ru catalyzed carbonylation of nitroaromatics. The final part of this work has involved investigations of metal-oxo complexes.

  20. Final design and progress of WEAVE: the next generation wide-field spectroscopy facility for the William Herschel Telescope

    NASA Astrophysics Data System (ADS)

    Dalton, Gavin; Trager, Scott; Abrams, Don Carlos; Bonifacio, Piercarlo; Aguerri, J. Alfonso L.; Middleton, Kevin; Benn, Chris; Dee, Kevin; Sayède, Frédéric; Lewis, Ian; Pragt, Johannes; Pico, Sergio; Walton, Nic; Rey, Jeurg; Allende Prieto, Carlos; Peñate, José; Lhome, Emilie; Agócs, Tibor; Alonso, José; Terrett, David; Brock, Matthew; Gilbert, James; Schallig, Ellen; Ridings, Andy; Guinouard, Isabelle; Verheijen, Marc; Tosh, Ian; Rogers, Kevin; Lee, Martin; Steele, Iain; Stuik, Remko; Tromp, Niels; Jaskó, Attila; Carrasco, Esperanza; Farcas, Szigfrid; Kragt, Jan; Lesman, Dirk; Kroes, Gabby; Mottram, Chris; Bates, Stuart; Rodriguez, Luis Fernando; Gribbin, Frank; Delgado, José Miguel; Herreros, José Miguel; Martin, Carlos; Cano, Diego; Navarro, Ramon; Irwin, Mike; Lewis, Jim; Gonzalez Solares, Eduardo; Murphy, David; Worley, Clare; Bassom, Richard; O'Mahoney, Neil; Bianco, Andrea; Zurita, Christina; ter Horst, Rik; Molinari, Emilio; Lodi, Marcello; Guerra, José; Martin, Adrian; Vallenari, Antonella; Salasnich, Bernardo; Baruffolo, Andrea; Jin, Shoko; Hill, Vanessa; Smith, Dan; Drew, Janet; Poggianti, Bianca; Pieri, Mat; Dominquez Palmero, Lillian; Farina, Cecilia

    2016-08-01

    We present the Final Design of the WEAVE next-generation spectroscopy facility for the William Herschel Telescope (WHT), together with a status update on the details of manufacturing, integration and the overall project schedule now that all the major fabrication contracts are in place. We also present a summary of the current planning behind the 5-year initial phase of survey operations. WEAVE will provide optical ground-based follow up of ground-based (LOFAR) and space-based (Gaia) surveys. WEAVE is a multi-object and multi-IFU facility utilizing a new 2-degree prime focus field of view at the WHT, with a buffered pick-and-place positioner system hosting 1000 multi-object (MOS) fibres, 20 integral field units, or a single large IFU for each observation. The fibres are fed to a single (dual-beam) spectrograph, with total of 16k spectral pixels, located within the WHT GHRIL enclosure on the telescope Nasmyth platform, supporting observations at R 5000 over the full 370-1000nm wavelength range in a single exposure, or a high resolution mode with limited coverage in each arm at R 20000. The project is now in the manufacturing and integration phase with first light expected for early of 2018.

  1. The oncogenic action of ionizing radiation on rat skin. Final progress report, May 1, 1990--April 30, 1992

    SciTech Connect

    Burns, F.J.; Garte, S.J.

    1992-12-31

    The multistage theory of carcinogenesis specifies that cells progress to cancer through a series of discrete, irreversible genetic alterations, but data on radiation-induced cancer incidence in rat skin suggests that an intermediate repairable alteration may occur. Data are presented on cancer induction in rat skin exposed to an electron beam (LET=0.34 keV/{mu}), a neon ion beam (LET=45) or an argon ion beam (LET=125). The rats were observed for tumors at least 78 weeks with squamous and basal cell carcinomas observed. The total cancer yield was fitted by the quadratic equation, and the equation parameters were estimated by linear regression for each type of radiation. Analysis of the DNA from the electron-induced carcinomas indicated that K-ras and/or c-myc oncogenes were activated. In situ hybridization indicated that the cancers contain subpopulations of cells with differing amounts of c-myc and H-ras amplification. The results are consistent with the idea that ionizing radiation produces stable, carcinogenically relevant lesions via 2 repairable events at low LET and via a non-repairable linked event pathway at high LET; either pathway may advance the cell by 1 stage. The proliferative response of rat epidermis following exposure to ionizing radiation was quantified by injection of {sup 14}C-thymidine. The return of these cells to S-phase a second time was detected by a second label ({sup 3}H). When the labeled cells were in G1-phase, the dorsal skin was irradiated with X-rays. All labeling indices were determined. The {sup 14}C labeling index was constant and unaffected by the radiation. The proportion of all cells entering S-phase averaged 3.5% at 18 hr and increased after 44, 52 and 75 hr to average levels of 11.8%, 5. 3%, and 6.6% at 0, 10 and 25 Gy respectively. The proportion of S-phase cells labeled with {sup 14}C increased after 42 hr and remained relatively constant thereafter.

  2. Hybrid solar thermal-photovoltaic systems demonstration, Phase I and II. Final technical progress report, July 5, 1979-December 1982

    SciTech Connect

    Loferski, J.J.

    1983-12-01

    The purpose of the project is to investigate a system based on combined photovoltaic/thermal (PV/T) panels to supply the energy needs of a small single family residence. The system finally selected and constructed uses PV/T panels which utilize air as the heat transfer medium. Optimization of thermal performance was accomplished by attaching metal fins to the back surface of each cell which significantly increased the heat transfer coefficient from the solar cells to the air stream. The other major components of the selected system are an air-to-air heat pump, a rock bin thermal energy storage bin, a synchronous dc-to-ac converter, a microprocessor to control the system, a heat exchanger for the domestic hot water system and of course the building itself which is a one story, well insulated structure having a floor area of 1200 ft/sup 2/. A prototype collector was constructed and tested. Based on this experience, twenty collectors, containing 2860 four inch diameter solar cells, were constructed and installed on the building. Performance of the system was simulated using a TRNSYS-derived program, modified to accommodate PV/T panels and to include the particular components included in the selected system. Simulation of the performance showed that about 65 percent of the total annual energy needs of the building would be provided by the PV/T system. Of this total, about one half is produced at a time when it can be used in the building and one half must be sold back to the utility.

  3. Effects of a selenium-laden soil amendment on grapevine metabolism and progression of Pierce’s disease

    USDA-ARS?s Scientific Manuscript database

    Selenium containing soil amendments might be beneficial to growers as selenium may increase resistance to certain plant pathogens and pests. Therefore, grapevines growing in soil with different amounts of selenium-laden amendment were evaluated for metabolism and susceptibility to Pierce’s disease (...

  4. Monola oil versus canola oil as a fish oil replacer in rainbow trout feeds: effects on growth, fatty acid metabolism and final eating quality.

    PubMed

    Turchini, G M; Moretti, V M; Hermon, K; Caprino, F; Busetto, M L; Bellagamba, F; Rankin, T; Keast, R S J; Francis, D S

    2013-11-15

    Monola oil, a high oleic acid canola cultivar, and canola oil were evaluated as replacers of fish oil at three levels of inclusion (60%, 75% and 90%) in rainbow trout diets. After a 27-week grow-out cycle, the diet-induced effects on growth, fatty acid metabolism and final eating quality were assessed. Overall, no effects were noted for growth, feed utilisation or fish biometry, and the fatty acid composition of fish fillets mirrored that of the diets. Dietary treatments affected fillet lipid oxidation (free malondialdehyde), pigmentation and flavour volatile compounds, but only minor effects on sensorial attributes were detected. Ultimately, both oils were demonstrated to possess, to differing extents, suitable qualities to adequately replace fish oil from the perspective of fish performance and final product quality. However, further research is required to alleviate on-going issues associated with the loss of health promoting attributes (n-3 long chain polyunsaturated fatty acids) of final farmed products. Copyright © 2013 Elsevier Ltd. All rights reserved.

  5. Assessment of chimeric mice with humanized livers in new drug development: generation of pharmacokinetics, metabolism and toxicity data for selecting the final candidate compound.

    PubMed

    Kamimura, Hidetaka; Ito, Satoshi

    2016-01-01

    1. Chimeric mice with humanized livers are expected to be a novel tool for new drug development. This review discusses four applications where these animals can be used efficiently to collect supportive data for selecting the best compound in the final stage of drug discovery. 2. The first application is selection of the final compound based on estimated pharmacokinetic parameters in humans. Since chimeric mouse livers are highly repopulated with human hepatocytes, hepatic clearance values in vivo could be used preferentially to estimate pharmacokinetic profiles for humans. 3. The second is prediction of human-specific or disproportionate metabolites. Chimeric mice reproduce human-specific metabolites of drugs under development to conform to ICH guidance M3(R2), except for compounds that were extensively eliminated by co-existing mouse hepatocytes. 4. The third is identifying metabolites with distinct pharmacokinetic profiles in humans. Slow metabolite elimination specifically in humans increases its exposure level, but if its elimination is faster in laboratory animals, the animal exposure level might not satisfy ICH guidance M3(R2). 5. Finally, two examples of reproducing acute liver toxicity in chimeric mice are introduced. Integrated pharmacokinetics, metabolism and toxicity information are expected to assist pharmaceutical scientists in selecting the best candidate compound in new drug development.

  6. Large experiment data analysis collaboration. Final annual progress report for period November 15, 2000 - April 30, 2002

    SciTech Connect

    Callen, J. D.

    2002-01-14

    Because of the good agreement between theory and experiment (on a number of tokamak experiments) on the nonlinear development, saturation of neoclassical tearing modes (NTMs), the study of NTMs is becoming a mature subject. Thus, our contributions to studies of neoclassical (and regular classical) tearing modes over the past year have focused on a number of particular, more detailed issues: flow shear effects on linear tearing modes, exploring the possibility of NTMs in spherical tokamaks such as NSTX, assisting with classical tearing mode explorations in DIII-D, and fast ion effects on NTMs. In addition, a collaboration with the Institute for Plasma Research group in India was initiated due to their interest in using the NEAR code (developed in part under this grant) to explore neoclassical tearing modes. Finally, a number of talks have been given on basic, current frontier and future extensions of neoclassical tearing mode theory. Our previous identification of the disruption precursor in DIII-D shot 87009 as being due to a global ideal MHD interchange-type instability being driven slowly though its threshold was featured prominently in the DIII-D MHD theory paper at the 2000 IAEA Sorrento meeting. We have also stimulated the application of the NIMROD code to this particular DIII-D disruption precursor and continued to support this code exploration of it. To facilitate quicker evaluations of global-type ideal MHD growth rates and eigenmodes, we have continued our development of a new method for using perturbed equilibria to ''maneuver in delta-W'' space. Since this basic concept for efficiently finding trends in ideal MHD stability using perturbed equilibria has been proven using a screw-pinch geometry, we are now beginning to implement and test the procedure in the GAT0 code for specific DIII-D high beta equilibria. In addition, to analytically explore the ultimate nonlinear evolution of these types of modes, we have begun (primarily on our DOE ''Nonlinear and

  7. Lipidomics to analyze the influence of diets with different EPA:DHA ratios in the progression of Metabolic Syndrome using SHROB rats as a model.

    PubMed

    Dasilva, Gabriel; Pazos, Manuel; García-Egido, Eduardo; Pérez-Jiménez, Jara; Torres, Josep Lluis; Giralt, Montserrat; Nogués, María-Rosa; Medina, Isabel

    2016-08-15

    The role of specific proportions of ω-3 EPA and DHA, in the modulation of inflammation and oxidative stress markers associated to the progression of Metabolic Syndrome was investigated. Potential inflammatory eicosanoids and docosanoids were discussed together to biomarkers of CVD, obesity, inflammation and oxidative stress in an animal model of metabolic disorders. Results evidenced a noteworthy health effect of 1:1 and 2:1 EPA:DHA proportions over 1:2 EPA:DHA based diets through a down-regulation in the production of strong pro-inflammatory ω-6 eicosanoids, a decrement of biomarkers of oxidative stress, and a modulation of fatty acid desaturase activities and plasma and membrane PUFAs towards greater anti-inflammatory profiles. Outcomes contribute to the general knowledge on the health benefits of marine lipids and their role on the progress of MetS, inflammation and oxidative stress. Results shed light on controversial protective mechanisms of EPA and DHA to better design dietary interventions aimed at reducing MetS. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Neuron-Glia Crosstalk in the Autonomic Nervous System and Its Possible Role in the Progression of Metabolic Syndrome: A New Hypothesis

    PubMed Central

    Del Rio, Rodrigo; Quintanilla, Rodrigo A.; Orellana, Juan A.; Retamal, Mauricio A.

    2015-01-01

    Metabolic syndrome (MS) is characterized by the following physiological alterations: increase in abdominal fat, insulin resistance, high concentration of triglycerides, low levels of HDL, high blood pressure, and a generalized inflammatory state. One of the pathophysiological hallmarks of this syndrome is the presence of neurohumoral activation, which involve autonomic imbalance associated to hyperactivation of the sympathetic nervous system. Indeed, enhanced sympathetic drive has been linked to the development of endothelial dysfunction, hypertension, stroke, myocardial infarct, and obstructive sleep apnea. Glial cells, the most abundant cells in the central nervous system, control synaptic transmission, and regulate neuronal function by releasing bioactive molecules called gliotransmitters. Recently, a new family of plasma membrane channels called hemichannels has been described to allow the release of gliotransmitters and modulate neuronal firing rate. Moreover, a growing amount of evidence indicates that uncontrolled hemichannel opening could impair glial cell functions, affecting synaptic transmission and neuronal survival. Given that glial cell functions are disturbed in various metabolic diseases, we hypothesize that progression of MS may relies on hemichannel-dependent impairment of glial-to-neuron communication by a mechanism related to dysfunction of inflammatory response and mitochondrial metabolism of glial cells. In this manuscript, we discuss how glial cells may contribute to the enhanced sympathetic drive observed in MS, and shed light about the possible role of hemichannels in this process. PMID:26648871

  9. Brain Cholesterol Synthesis and Metabolism is Progressively Disturbed in the R6/1 Mouse Model of Huntington's Disease: A Targeted GC-MS/MS Sterol Analysis.

    PubMed

    Kreilaus, Fabian; Spiro, Adena S; Hannan, Anthony J; Garner, Brett; Jenner, Andrew M

    2015-01-01

    Cholesterol has essential functions in neurological processes that require tight regulation of synthesis and metabolism. Perturbed cholesterol homeostasis has been demonstrated in Huntington's disease, however the exact role of these changes in disease pathogenesis is not fully understood. This study aimed to comprehensively examine changes in cholesterol biosynthetic precursors, metabolites and oxidation products in the striatum and cortex of the R6/1 transgenic mouse model of Huntington's disease. We also aimed to characterise the progression of the physical phenotype in these mice. GC-MS/MS was used to quantify a broad range of sterols in the striatum and cortex of R6/1 and wild type mice at 6, 12, 20, 24 and 28 weeks of age. Motor dysfunction was assessed over 28 weeks using the RotaRod and the hind-paw clasping tests. 24(S)-Hydroxycholesterol and 27-hydroxycholesterol were the major cholesterol metabolites that significantly changed in R6/1 mice. These changes were specifically localised to the striatum and were detected at the end stages of the disease. Cholesterol synthetic precursors (lathosterol and lanosterol) were significantly reduced in the cortex and striatum by 6 weeks of age, prior to the onset of motor dysfunction, as well as the cognitive and affective abnormalities previously reported. Elevated levels of desmosterol, a substrate of delta(24)-sterol reductase (DHCR24), were also detected in R6/1 mice at the end time-point. Female R6/1 mice exhibited a milder weight loss and hind paw clasping phenotype compared to male R6/1 mice, however, no difference in the brain sterol profile was detected between sexes. Several steps in cholesterol biosynthetic and metabolic pathways are differentially altered in the R6/1 mouse brain as the disease progresses and this is most severe in the striatum. This provides further insights into early molecular mediators of HD onset and disease progression and identifies candidate molecular targets for novel therapeutic

  10. Pharmacokinetics, metabolism, and excretion of (14)C-labeled belinostat in patients with recurrent or progressive malignancies.

    PubMed

    Calvo, Emiliano; Reddy, Guru; Boni, Valentina; García-Cañamaque, Lina; Song, Tao; Tjornelund, Jette; Choi, Mi Rim; Allen, Lee F

    2016-04-01

    Belinostat, a potent pan-inhibitor of histone deacetylase (HDAC) enzymes, is approved in the United States (US) for relapsed/refractory peripheral T-cell lymphoma. In nonclinical studies, bile and feces were identified as the predominant elimination routes (50-70%), with renal excretion accounting for ~30-50%. A Phase 1 human mass balance study was conducted to identify species-dependent variations in belinostat metabolism and elimination. Patients received a single 30-min intravenous (i.v.) infusion of (14)C-labeled belinostat (1500 mg). Venous blood samples and pooled urine and fecal samples were evaluated using liquid chromatography-tandem mass spectroscopy for belinostat and metabolite concentrations pre-infusion through 7 days post-infusion. Total radioactivity was determined using liquid scintillation counting. Continued treatment with nonradiolabled belinostat (1000 mg/m(2) on Days 1-5 every 21 days) was permitted. Belinostat was extensively metabolized and mostly cleared from plasma within 8 h (N = 6), indicating that metabolism is the primary route of elimination. Systemic exposure for the 5 major metabolites was >20% of parent, with belinostat glucuronide the predominant metabolite. Mean recovery of radioactive belinostat was 94.5% ± 4.0%, with the majority excreted within 48 and 96 h in urine and feces, respectively. Renal elimination was the principal excretion route (mean 84.8% ± 9.8% of total dose); fecal excretion accounted for 9.7% ± 6.5%. Belinostat was well tolerated, with mostly mild to moderate adverse events and no treatment-related severe/serious events. Mass balance was achieved (~95% mean recovery), with metabolism identified as the primary route of elimination. Radioactivity was predominantly excreted renally as belinostat metabolites.

  11. The Influence of Metabolic Syndrome on Prostate Cancer Progression and Risk of Recurrence in African American and European American Men

    DTIC Science & Technology

    2012-10-01

    MetSyn: 1) abdominal obesity ( waist circumference of> 102cm in men or> 88 em in women); 2) hypertriglyceridemia (<: 150mg/dl); 3)1ow high-density...possess at least three of the following five features are classified as having metabolic syndrome: l) abdominal obesity ( waist circumference of> 102...measured through the use of measured waist circumference was more prevalent in white patients (62%) compared to black patients ( 48% ). Approximately

  12. Metabolic Syndrome as a Risk Factor for Cardiovascular Disease, Mortality, and Progression of Diabetic Nephropathy in Type 1 Diabetes

    PubMed Central

    Thorn, Lena M.; Forsblom, Carol; Wadén, Johan; Saraheimo, Markku; Tolonen, Nina; Hietala, Kustaa; Groop, Per-Henrik

    2009-01-01

    OBJECTIVE To assess the predictive value of the metabolic syndrome in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS Patients were from the prospective Finnish Diabetic Nephropathy (FinnDiane) Study (n = 3,783): mean age 37 ± 12 years and diabetes duration 23 ± 12 years. Metabolic syndrome was defined according to World Health Organization (WHO), National Cholesterol Education Program (NCEP), and International Diabetes Federation (IDF) definitions. Follow-up time was median 5.5 years (interquartile range 3.7–6.7). Mortality data were complete, whereas morbidity data were available in 69% of the patients. RESULTS The WHO definition was associated with a 2.1-fold increased risk of cardiovascular events and a 2.5-fold increased risk of cardiovascular- and diabetes-related mortality, after adjustment for traditional risk factors and diabetic nephropathy. The NCEP definition did not predict outcomes when adjusted for nephropathy but markedly added to the risk associated with elevated albuminuria alone (P < 0.001). The IDF definition did not predict outcomes. CONCLUSIONS The metabolic syndrome is a risk factor, beyond albuminuria, for cardiovascular morbidity and diabetes-related mortality in type 1 diabetes. PMID:19196885

  13. Filling Knowledge Gaps in Biological Networks: integrating global approaches to understand H2 metabolism in Chlamydomonas reinhardtii - Final Report

    SciTech Connect

    Posewitz, Matthew C

    2011-06-30

    The green alga Chlamydomonas reinhardtii (Chlamydomonas) has numerous genes encoding enzymes that function in fermentative pathways. Among these genes, are the [FeFe]-hydrogenases, pyruvate formate lyase, pyruvate ferredoxin oxidoreductase, acetate kinase, and phosphotransacetylase. We have systematically undertaken a series of targeted mutagenesis approaches to disrupt each of these key genes and omics techniques to characterize alterations in metabolic flux. Funds from DE-FG02-07ER64423 were specifically leveraged to generate mutants with disruptions in the genes encoding the [FeFe]-hydrogenases HYDA1 and HYDA2, pyruvate formate lyase (PFL1), and in bifunctional alcohol/aldehyde alcohol dehydrogenase (ADH1). Additionally funds were used to conduct global transcript profiling experiments of wildtype Chlamydomonas cells, as well as of the hydEF-1 mutant, which is unable to make H2 due to a lesion in the [FeFe]-hydrogenase biosynthetic pathway. In the wildtype cells, formate, acetate and ethanol are the dominant fermentation products with traces of CO2 and H2 also being produced. In the hydEF-1 mutant, succinate production is increased to offset the loss of protons as a terminal electron acceptor. In the pfl-1 mutant, lactate offsets the loss of formate production, and in the adh1-1 mutant glycerol is made instead of ethanol. To further probe the system, we generated a double mutant (pfl1-1 adh1) that is unable to synthesize both formate and ethanol. This strain, like the pfl1 mutants, secreted lactate, but also exhibited a significant increase in the levels of extracellular glycerol, acetate, and intracellular reduced sugars, and a decline in dark, fermentative H2 production. Whereas wild-type Chlamydomonas fermentation primarily produces formate and ethanol, the double mutant performs a complete rerouting of the glycolytic carbon to lactate and glycerol. Lastly, transcriptome data have been analysed for both the wildtype and hydEF-1, that correlate with our

  14. The progression from a lower to a higher invasive stage of bladder cancer is associated with severe alterations in glucose and pyruvate metabolism.

    PubMed

    Conde, Vanessa R; Oliveira, Pedro F; Nunes, Ana R; Rocha, Cátia S; Ramalhosa, Elsa; Pereira, José A; Alves, Marco G; Silva, Branca M

    2015-07-01

    Cancer cells present a particular metabolic behavior. We hypothesized that the progression of bladder cancer could be accompanied by changes in cells glycolytic profile. We studied two human bladder cancer cells, RT4 and TCCSUP, in which the latter represents a more invasive stage. The levels of glucose, pyruvate, alanine and lactate in the extracellular media were measured by Proton Nuclear Magnetic Resonance. The protein expression levels of glucose transporters 1 (GLUT1) and 3 (GLUT3), monocarboxylate transporter 4 (MCT4), phosphofructokinase-1 (PFK1), glutamic-pyruvate transaminase (GPT) and lactate dehydrogenase (LDH) were determined. Our data showed that glucose consumption and GLUT3 levels were similar in both cell lines, but TCCSUP cells displayed lower levels of GLUT1 and PFK expression. An increase in pyruvate consumption, concordant with the higher levels of lactate and alanine production, was also detected in TCCSUP cells. Moreover, TCCSUP cells presented lower protein expression levels of GPT and LDH. These results illustrate that bladder cancer progression is associated with alterations in cells glycolytic profile, namely the switch from glucose to pyruvate consumption in the more aggressive stage. This may be useful to develop new therapies and to identify biomarkers for cancer progression.

  15. Summer investigations into the metabolic diversity of the microbial world. Progress report, May 5, 1992--April 30, 1993

    SciTech Connect

    Breznak, J.; Dworkin, M.

    1993-05-17

    The philosophy of the course described here is to underscore the essence of microbiology which is diversity>: diversity of morphology and cellular development, behavior, and metabolic and physiological functions. Emphasis is on microbes other than those customarily covered in conventional microbiology courses and includes: the archaebacteria, extremophiles, and array of obligate anaerobes, various phototrophs, and those microbes exhibiting complex developmental cycles. Also included are microbes carrying out a variety of transformations of organic and inorganic compounds, as well as those which normally occur in symbiotic association with other microbes or with higher forms of life.

  16. Relationship of metabolic syndrome with incident aortic valve calcium and aortic valve calcium progression: the Multi-Ethnic Study of Atherosclerosis (MESA).

    PubMed

    Katz, Ronit; Budoff, Matthew J; Takasu, Junichiro; Shavelle, David M; Bertoni, Alain; Blumenthal, Roger S; Ouyang, Pamela; Wong, Nathan D; O'Brien, Kevin D

    2009-04-01

    Metabolic syndrome (MetS) has been associated with increased prevalence of aortic valve calcium (AVC) and with increased progression of aortic stenosis. The purpose of this study was to determine whether MetS is associated with increased risks for the development of new ("incident") AVC or for progression of established AVC as assessed by CT. The relationships of MetS or its components as well as of diabetes to risks for incident AVC or AVC progression were studied among participants with CT scans performed at baseline and at either year 2 or year 3 examinations in the Multi-Ethnic Study of Atherosclerosis (MESA). Of 5,723 MESA participants meeting criteria for inclusion, 1,674 had MetS by Adult Treatment Panel III criteria, whereas 761 had diabetes. Among the 5,123 participants without baseline AVC, risks for incident AVC, adjusted for time between scans, age, sex, race/ethnicity, LDL cholesterol, lipid-lowering medications, and smoking, were increased significantly for MetS (odds ratio [OR] 1.67 [95% CI 1.21-2.31]) or diabetes (2.06 [1.39-3.06]). In addition, there was an increase in incident AVC risk with increasing number of MetS components. Similar results were found using the International Diabetes Federation MetS criteria. Among the 600 participants (10.5%) with baseline AVC, neither MetS nor diabetes was associated with AVC progression. In the MESA cohort, MetS was associated with a significant increase in incident ("new") AVC, raising the possibility that MetS may be a potential therapeutic target to prevent AVC development.

  17. Organometallic Chemistry. Final Progress Report

    SciTech Connect

    2003-07-14

    The Gordon Research Conference (GRC) on Organometallic Chemistry was held at Salve Regina, Newport, Rhode Island, 7/21-26/02. Emphasis was placed on current unpublished research and discussion of the future target areas in this field.

  18. ROCK DEFORMATION. Final Progress Report

    SciTech Connect

    2002-05-24

    The Gordon Research Conference (GRC) on ROCK DEFORMATION was held at II Ciocco from 5/19/02 thru 5/24/02. Emphasis was placed on current unpublished research and discussion of the future target areas in this field.

  19. A proliferative probiotic Bifidobacterium strain in the gut ameliorates progression of metabolic disorders via microbiota modulation and acetate elevation.

    PubMed

    Aoki, Ryo; Kamikado, Kohei; Suda, Wataru; Takii, Hiroshi; Mikami, Yumiko; Suganuma, Natsuki; Hattori, Masahira; Koga, Yasuhiro

    2017-03-02

    The gut microbiota is an important contributor to the worldwide prevalence of metabolic syndrome (MS), which includes obesity and diabetes. The anti-MS effects exerted by Bifidobacterium animalis ssp. lactis GCL2505 (BlaG), a highly proliferative Bifidobacterium strain in the gut, and B. longum ssp. longum JCM1217(T) (BloJ) were comparatively examined. BlaG treatment reduced visceral fat accumulation and improved glucose tolerance, whereas BloJ had no effect on these parameters. Gut microbial analysis revealed that BlaG exerted stronger effects on the overall bacterial structure of the gut microbiota than BloJ, including enrichment of the genus Bifidobacterium. The levels of acetate and glucagon-like peptide-1 were increased by BlaG treatment in both the gut and plasma, but not by BloJ treatment. Correlation analysis suggested that the elevation of gut acetate levels by BlaG treatment plays a pivotal role in the BlaG-induced anti-MS effects. These findings indicated that BlaG, a highly viable and proliferative probiotic, improves metabolic disorders by modulating gut microbiota, which results in the elevation of SCFAs, especially acetate.

  20. A proliferative probiotic Bifidobacterium strain in the gut ameliorates progression of metabolic disorders via microbiota modulation and acetate elevation

    PubMed Central

    Aoki, Ryo; Kamikado, Kohei; Suda, Wataru; Takii, Hiroshi; Mikami, Yumiko; Suganuma, Natsuki; Hattori, Masahira; Koga, Yasuhiro

    2017-01-01

    The gut microbiota is an important contributor to the worldwide prevalence of metabolic syndrome (MS), which includes obesity and diabetes. The anti-MS effects exerted by Bifidobacterium animalis ssp. lactis GCL2505 (BlaG), a highly proliferative Bifidobacterium strain in the gut, and B. longum ssp. longum JCM1217T (BloJ) were comparatively examined. BlaG treatment reduced visceral fat accumulation and improved glucose tolerance, whereas BloJ had no effect on these parameters. Gut microbial analysis revealed that BlaG exerted stronger effects on the overall bacterial structure of the gut microbiota than BloJ, including enrichment of the genus Bifidobacterium. The levels of acetate and glucagon-like peptide-1 were increased by BlaG treatment in both the gut and plasma, but not by BloJ treatment. Correlation analysis suggested that the elevation of gut acetate levels by BlaG treatment plays a pivotal role in the BlaG-induced anti-MS effects. These findings indicated that BlaG, a highly viable and proliferative probiotic, improves metabolic disorders by modulating gut microbiota, which results in the elevation of SCFAs, especially acetate. PMID:28252037

  1. [Progress in microbial production of succinic acid].

    PubMed

    Liu, Rongming; Liang, Liya; Wu, Mingke; Jiang, Min

    2013-10-01

    Succinic acid is one of the key intermediates in the tricarboxylic acid cycle (TCA)and has huge potentials in biopolymer, food, medicine applications. This article reviews recent research progress in the production of succinic acid by microbial fermentation, including discovery and screening of the succinic-acid-producing microbes, the progress of genetic engineering strategy and metabolic engineering technology for construction of succinic acid-producing strains, and fermentation process control and optimization. Finally, we discussed the limitation of current progress and proposed the future research needs for microbial production of succinic acid.

  2. Metabolic syndrome-associated osteoarthritis.

    PubMed

    Courties, Alice; Sellam, Jérémie; Berenbaum, Francis

    2017-03-01

    Interest in the metabolic syndrome-associated osteoarthritis phenotype is increasing. Here, we summarize recently published significant findings. Meta-analyses confirmed an association between type 2 diabetes and osteoarthritis and between cardiovascular diseases and osteoarthritis. Recent advances in the study of metabolic syndrome-associated osteoarthritis have focused on a better understanding of the role of metabolic diseases in inducing or aggravating joint damage. In-vivo models of obesity, diabetes, or dyslipidemia have helped to better decipher this association. They give emerging evidence that, beyond the role of common pathogenic mechanisms for metabolic diseases and osteoarthritis (i.e., low-grade inflammation and oxidative stress), metabolic diseases have a direct systemic effect on joints. In addition to the impact of weight, obesity-associated inflammation is associated with osteoarthritis severity and may modulate osteoarthritis progression in mouse models. As well, osteoarthritis synovium from type 2 diabetic patients shows insulin-resistant features, which may participate in joint catabolism. Finally, exciting data are emerging on the association of gut microbiota and circadian rhythm and metabolic syndrome-associated osteoarthritis. The systemic role of metabolic syndrome in osteoarthritis pathophysiology is now better understood, but new avenues of research are being pursued to better decipher the metabolic syndrome-associated osteoarthritis phenotype.

  3. Analysis of Global and Absorption, Distribution, Metabolism, and Elimination Gene Expression in the Progressive Stages of Human Nonalcoholic Fatty Liver DiseaseS⃞

    PubMed Central

    Lake, April D.; Novak, Petr; Fisher, Craig D.; Jackson, Jonathan P.; Hardwick, Rhiannon N.; Billheimer, D. Dean; Klimecki, Walter T.

    2011-01-01

    Nonalcoholic fatty liver disease (NAFLD) is characterized by a series of pathological changes that range from simple fatty liver to nonalcoholic steatohepatitis (NASH). The objective of this study is to describe changes in global gene expression associated with the progression of human NAFLD. This study is focused on the expression levels of genes responsible for the absorption, distribution, metabolism, and elimination (ADME) of drugs. Differential gene expression between three clinically defined pathological groups—normal, steatosis, and NASH—was analyzed. Genome-wide mRNA levels in samples of human liver tissue were assayed with Affymetrix GeneChip Human 1.0ST arrays. A total of 11,633 genes exhibited altered expression out of 33,252 genes at a 5% false discovery rate. Most gene expression changes occurred in the progression from steatosis to NASH. Principal component analysis revealed that hepatic disease status was the major determinant of differential ADME gene expression rather than age or sex of sample donors. Among the 515 drug transporters and 258 drug-metabolizing enzymes (DMEs) examined, uptake transporters but not efflux transporters or DMEs were significantly over-represented in the number of genes down-regulated. These results suggest that uptake transporter genes are coordinately targeted for down-regulation at the global level during the pathological development of NASH and that these patients may have decreased drug uptake capacity. This coordinated regulation of uptake transporter genes is indicative of a hepatoprotective mechanism acting to prevent accumulation of toxic intermediates in disease-compromised hepatocytes. PMID:21737566

  4. Genetic and metabolic signals during acute enteric bacterial infection alter the microbiota and drive progression to chronic inflammatory disease

    SciTech Connect

    Kamdar, Karishma; Khakpour, Samira; Chen, Jingyu; Leone, Vanessa; Brulc, Jennifer; Mangatu, Thomas; Antonopoulos, Dionysios A.; Chang, Eugene B; Kahn, Stacy A.; Kirschner, Barbara S; Young, Glenn; DePaolo, R. William

    2016-01-13

    Chronic inflammatory disorders are thought to arise due to an interplay between predisposing host genetics and environmental factors. For example, the onset of inflammatory bowel disease is associated with enteric proteobacterial infection, yet the mechanistic basis for this association is unclear. We have shown previously that genetic defiency in TLR1 promotes acute enteric infection by the proteobacteria Yersinia enterocolitica. Examining that model further, we uncovered an altered cellular immune response that promotes the recruitment of neutrophils which in turn increases metabolism of the respiratory electron acceptor tetrathionate by Yersinia. These events drive permanent alterations in anti-commensal immunity, microbiota composition, and chronic inflammation, which persist long after Yersinia clearence. Deletion of the bacterial genes involved in tetrathionate respiration or treatment using targeted probiotics could prevent microbiota alterations and inflammation. Thus, acute infection can drive long term immune and microbiota alterations leading to chronic inflammatory disease in genetically predisposed individuals.

  5. Human CHCHD4 mitochondrial proteins regulate cellular oxygen consumption rate and metabolism and provide a critical role in hypoxia signaling and tumor progression.

    PubMed

    Yang, Jun; Staples, Oliver; Thomas, Luke W; Briston, Thomas; Robson, Mathew; Poon, Evon; Simões, Maria L; El-Emir, Ethaar; Buffa, Francesca M; Ahmed, Afshan; Annear, Nicholas P; Shukla, Deepa; Pedley, Barbara R; Maxwell, Patrick H; Harris, Adrian L; Ashcroft, Margaret

    2012-02-01

    Increased expression of the regulatory subunit of HIFs (HIF-1α or HIF-2α) is associated with metabolic adaptation, angiogenesis, and tumor progression. Understanding how HIFs are regulated is of intense interest. Intriguingly, the molecular mechanisms that link mitochondrial function with the HIF-regulated response to hypoxia remain to be unraveled. Here we describe what we believe to be novel functions of the human gene CHCHD4 in this context. We found that CHCHD4 encodes 2 alternatively spliced, differentially expressed isoforms (CHCHD4.1 and CHCHD4.2). CHCHD4.1 is identical to MIA40, the homolog of yeast Mia40, a key component of the mitochondrial disulfide relay system that regulates electron transfer to cytochrome c. Further analysis revealed that CHCHD4 proteins contain an evolutionarily conserved coiled-coil-helix-coiled-coil-helix (CHCH) domain important for mitochondrial localization. Modulation of CHCHD4 protein expression in tumor cells regulated cellular oxygen consumption rate and metabolism. Targeting CHCHD4 expression blocked HIF-1α induction and function in hypoxia and resulted in inhibition of tumor growth and angiogenesis in vivo. Overexpression of CHCHD4 proteins in tumor cells enhanced HIF-1α protein stabilization in hypoxic conditions, an effect insensitive to antioxidant treatment. In human cancers, increased CHCHD4 expression was found to correlate with the hypoxia gene expression signature, increasing tumor grade, and reduced patient survival. Thus, our study identifies a mitochondrial mechanism that is critical for regulating the hypoxic response in tumors.

  6. Human CHCHD4 mitochondrial proteins regulate cellular oxygen consumption rate and metabolism and provide a critical role in hypoxia signaling and tumor progression

    PubMed Central

    Yang, Jun; Staples, Oliver; Thomas, Luke W.; Briston, Thomas; Robson, Mathew; Poon, Evon; Simões, Maria L.; El-Emir, Ethaar; Buffa, Francesca M.; Ahmed, Afshan; Annear, Nicholas P.; Shukla, Deepa; Pedley, Barbara R.; Maxwell, Patrick H.; Harris, Adrian L.; Ashcroft, Margaret

    2012-01-01

    Increased expression of the regulatory subunit of HIFs (HIF-1α or HIF-2α) is associated with metabolic adaptation, angiogenesis, and tumor progression. Understanding how HIFs are regulated is of intense interest. Intriguingly, the molecular mechanisms that link mitochondrial function with the HIF-regulated response to hypoxia remain to be unraveled. Here we describe what we believe to be novel functions of the human gene CHCHD4 in this context. We found that CHCHD4 encodes 2 alternatively spliced, differentially expressed isoforms (CHCHD4.1 and CHCHD4.2). CHCHD4.1 is identical to MIA40, the homolog of yeast Mia40, a key component of the mitochondrial disulfide relay system that regulates electron transfer to cytochrome c. Further analysis revealed that CHCHD4 proteins contain an evolutionarily conserved coiled-coil-helix-coiled-coil-helix (CHCH) domain important for mitochondrial localization. Modulation of CHCHD4 protein expression in tumor cells regulated cellular oxygen consumption rate and metabolism. Targeting CHCHD4 expression blocked HIF-1α induction and function in hypoxia and resulted in inhibition of tumor growth and angiogenesis in vivo. Overexpression of CHCHD4 proteins in tumor cells enhanced HIF-1α protein stabilization in hypoxic conditions, an effect insensitive to antioxidant treatment. In human cancers, increased CHCHD4 expression was found to correlate with the hypoxia gene expression signature, increasing tumor grade, and reduced patient survival. Thus, our study identifies a mitochondrial mechanism that is critical for regulating the hypoxic response in tumors. PMID:22214851

  7. Impact of Gentamicin Coadministration along with High Fructose Feeding on Progression of Renal Failure and Metabolic Syndrome in Sprague-Dawley Rats

    PubMed Central

    Ibraheem, Zaid O.; Basir, Rusliza; Aljobory, Ahmad Kh.; Ibrahim, Omar E.; Alsumaidaee, Ajwad; Yam, Mun Fee

    2014-01-01

    The current study evaluates the impact of high fructose feeding in rat model of gentamicin induced nephrotoxicity. Sprague-Dawley rats weighing 180–200 g were randomized into four groups; (C) received standard rodents chow with free access to ad libitum drinking water for 8 weeks and was considered as control, (F) received standard rodents chow with free access to drinking water supplemented with 20% (W/V) fructose for the same abovementioned period, (FG) was fed as group F and was given 80 mg/kg (body weight)/day gentamicin sulphate intraperitoneally during the last 20 days of the feeding period, and (G) was given gentamicin as above and fed as group C. Renal function was assessed at the end of the treatment period through measuring serum creatinine, uric acid and albumin, creatinine clearance, absolute and fractional excretion of both sodium and potassium, twenty-four-hour urinary excretion of albumin, and renal histology. For metabolic syndrome assessment, fasting plasma glucose and insulin were measured and oral glucose tolerance test was performed throughout the treatment period. Results showed that gentamicin enhances progression of fructose induced metabolic syndrome. On the other hand, fructose pretreatment before gentamicin injection produced a comparable degree of renal dysfunction to those which were given fructose-free water but the picture of nephrotoxicity was somewhat altered as it was characterized by higher extent of glomerular congestion and protein urea. Overall, more vigilance is required when nephrotoxic drugs are prescribed for patients with fructose induced metabolic syndrome. PMID:25045706

  8. Beneficial effects of silibinin against the progression of metabolic syndrome, increased oxidative stress, and liver steatosis in Psammomys obesus, a relevant animal model of human obesity and diabetes.

    PubMed

    Bouderba, Saida; Sanchez-Martin, Carlos; Villanueva, Gloria R; Detaille, Dominique; Koceïr, E Ahmed

    2014-03-01

    Insulin resistance and oxidative stress are major pathogenic mechanisms leading to chronic liver diseases in diabetic subjects. The gerbil Psammomys obesus is a unique model of nutritional diabetes resembling the disease in humans. This study investigated whether the natural ingredient silibinin, known as hepatoprotective, could decrease oxidative stress and reduce liver damage in obese gerbils. Control animals were fed their vegetable-based low caloric diet while two other rat groups ingested a high calorie diet for 14 weeks. Silibinin, or its vehicle, was administrated by gastric intubation (100 mg/kg per day) from the 7th week of treatment, which corresponds to an established insulin resistance state. At the end of the experiments, the hepatic biochemical profile, markers of oxidative stress in either plasma or liver tissue, and histological alterations were examined. Diabetic P. obesus displayed many metabolic disturbances (hyperinsulinemia, hyperglycemia, dyslipidemia), which were aggravated for the last 8 weeks. These events were coupled with greater oxidative stress (decline in glutathione, rise in lipoperoxidation). In addition, glutathione peroxidase activity was reduced while the level of superoxide dismutase was elevated. Interestingly, treatment with silibinin alleviated most of the metabolic defects, especially high triglyceride levels, reduced insulin resistance and largely restored antioxidant status. Also, Masson's trichrome staining revealed distinct steatosis, yet silibinin partially reversed this manifestation. Silibinin affords substantial protection against the progression of insulin resistance in Type 2 diabetes mellitus for P. obesus by hampering the oxidative process and improving hepatic metabolism. © 2013 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

  9. The Role of Sarcosine, Uracil, and Kynurenic Acid Metabolism in Urine for Diagnosis and Progression Monitoring of Prostate Cancer.

    PubMed

    Gkotsos, Georgios; Virgiliou, Christina; Lagoudaki, Ioanna; Sardeli, Chrysanthi; Raikos, Nikolaos; Theodoridis, Georgios; Dimitriadis, Georgios

    2017-02-23

    The aim of this pilot study is to evaluate sarcosine, uracil, and kynurenic acid in urine as potential biomarkers in prostate cancer detection and progression monitoring. Sarcosine, uracil, and kynurenic acid were measured in urine samples of 32 prostate cancer patients prior to radical prostatectomy, 101 patients with increased prostate-specific antigen prior to ultrasonographically-guided prostatic biopsy collected before and after prostatic massage, and 15 healthy volunteers (controls). The results were related to histopathologic data, Gleason score, and PSA (Prostate Specific Antigen). Metabolites were measured after analysis of urine samples with Ultra-High Performance Liquid Chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) instrumentation. Multivariate, nonparametric statistical tests including receiver operating characteristics analyses, one-way analysis of variance (Kruskal-Wallis test), parametric statistical analysis, and Pearson correlation, were performed to evaluate diagnostic performance. Decreased median sarcosine and kynurenic acid and increased uracil concentrations were observed for patients with prostate cancer compared to participants without malignancy. Results showed that there was no correlation between the concentration of the studied metabolites and the cancer grade (Gleason score <7 vs. ≥7) and the age of the patients. Evaluation of biomarkers by ROC (Receiving Operating Characteristics) curve analysis showed that differentiation of prostate cancer patients from participants without malignancy was not enhanced by sarcosine or uracil levels in urine. In contrast to total PSA values, kynurenic acid was found a promising biomarker for the detection of prostate cancer particularly in cases where collection of urine samples was performed after prostatic massage. Sarcosine and uracil in urine samples of patients with prostate cancer were not found as significant biomarkers for the diagnosis of prostate cancer. None of the three

  10. The Role of Sarcosine, Uracil, and Kynurenic Acid Metabolism in Urine for Diagnosis and Progression Monitoring of Prostate Cancer

    PubMed Central

    Gkotsos, Georgios; Virgiliou, Christina; Lagoudaki, Ioanna; Sardeli, Chrysanthi; Raikos, Nikolaos; Theodoridis, Georgios; Dimitriadis, Georgios

    2017-01-01

    The aim of this pilot study is to evaluate sarcosine, uracil, and kynurenic acid in urine as potential biomarkers in prostate cancer detection and progression monitoring. Sarcosine, uracil, and kynurenic acid were measured in urine samples of 32 prostate cancer patients prior to radical prostatectomy, 101 patients with increased prostate-specific antigen prior to ultrasonographically-guided prostatic biopsy collected before and after prostatic massage, and 15 healthy volunteers (controls). The results were related to histopathologic data, Gleason score, and PSA (Prostate Specific Antigen). Metabolites were measured after analysis of urine samples with Ultra-High Performance Liquid Chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) instrumentation. Multivariate, nonparametric statistical tests including receiver operating characteristics analyses, one-way analysis of variance (Kruskal–Wallis test), parametric statistical analysis, and Pearson correlation, were performed to evaluate diagnostic performance. Decreased median sarcosine and kynurenic acid and increased uracil concentrations were observed for patients with prostate cancer compared to participants without malignancy. Results showed that there was no correlation between the concentration of the studied metabolites and the cancer grade (Gleason score <7 vs. ≥7) and the age of the patients. Evaluation of biomarkers by ROC (Receiving Operating Characteristics) curve analysis showed that differentiation of prostate cancer patients from participants without malignancy was not enhanced by sarcosine or uracil levels in urine. In contrast to total PSA values, kynurenic acid was found a promising biomarker for the detection of prostate cancer particularly in cases where collection of urine samples was performed after prostatic massage. Sarcosine and uracil in urine samples of patients with prostate cancer were not found as significant biomarkers for the diagnosis of prostate cancer. None of the

  11. Altered glutamate metabolism contributes to antiepileptogenic effects in the progression from focal seizure to generalized seizure by low-frequency stimulation in the ventral hippocampus.

    PubMed

    Sun, Hong-Liu; Zhu, Wei; Zhang, Yu-Rong; Pan, Xiao-Hong; Zhang, Jun-Ru; Chen, Xiang-Ming; Liu, Yu-Xia; Li, Shu-Cui; Wang, Qiao-Yun; Deng, Da-Ping

    2017-03-01

    As a promising method for treating intractable epilepsy, the inhibitory effect of low-frequency stimulation (LFS) is well known, although its mechanisms remain unclear. Excessive levels of cerebral glutamate are considered a crucial factor for epilepsy. Therefore, we designed experiments to investigate the crucial parts of the glutamate cycle. We evaluated glutamine synthetase (GS, metabolizes glutamate), glutaminase (synthesizes glutamate), and glutamic acid decarboxylase (GAD, a γ-aminobutyric acid [GABA] synthetase) in different regions of the brain, including the dentate gyrus (DG), CA3, and CA1 subregions of the hippocampus, and the cortex, using western blots, immunohistochemistry, and enzyme activity assays. Additionally, the concentrations of glutamate, GABA, and glutamine (a product of GS) were measured using high-performance liquid chromatography (HPLC) in the same subregions. The results indicated that a transiently promoted glutamate cycle was closely involved in the progression from focal to generalized seizure. Low-frequency stimulation (LFS) delivered to the ventral hippocampus had an antiepileptogenic effect in rats exposed to amygdaloid-kindling stimulation. Simultaneously, LFS could partly reverse the effects of the promoted glutamate cycle, including increased GS function, accelerated glutamate-glutamine cycling, and an unbalanced glutamate/GABA ratio, all of which were induced by amygdaloid kindling in the DG when seizures progressed to stage 4. Moreover, glutamine treatment reversed the antiepileptic effect of LFS with regard to both epileptic severity and susceptibility. Our results suggest that the effects of LFS on the glutamate cycle may contribute to the antiepileptogenic role of LFS in the progression from focal to generalized seizure.

  12. (Summer investigations into the isolation, cultivation and metabolism of anaerobes involved in biodegradation): Progress report, year 4, summer 1988

    SciTech Connect

    Not Available

    1988-01-01

    In the laboratory our students were trained in modern techniques for the isolation and study of a wide variety of microbes from marine and brackish environments. Special emphasis was placed on anaerobes and archaebacteria. Microbial groups that were studied included the propionic bacteria, clostridia, methanogens, acetogens, hydrogen oxidizing anaerobes and aerobes, sulfate-reducing bacteria and sulfur-reducing bacteria, anoxic photosynthetic bacteria, cyanobacteria, spirochetes, symbiotic and non-symbiotic nitrogen fixing bacteria, luminescent bacteria, iron bacteria, magnetic bacteria, and sulfur oxidizing bacteria. The permanent staff led discussions and presented lectures on the metabolism, physiology and biochemistry of the groups listed above. Material was also presented on motility and chemotaxis of bacteria, and particular emphasis was given to molecular approaches to studying evolution of bacteria. We also had five successful Microbiology Mini-symposia (see attached schedule). These one-day symposia involved lecture/seminar presentations by investigators involved in state-of-the-art working particularly exciting areas within the scope of our course.

  13. Establishing Performance Indicators To Assess Progress toward Meeting the Goals of "The Illinois Commitment": Final Recommendations. Report of the Performance Indicator Advisory Committee to the Illinois Board of Higher Education.

    ERIC Educational Resources Information Center

    Illinois State Board of Higher Education, Springfield.

    This report presents the final recommendations of the Performance Indicator Advisory Committee to the Illinois Board of Higher Education with regard to statewide and common institutional indicators that can be used to assess progress toward meeting the goals of "The Illinois Commitment" for higher education. Also addressed are the…

  14. Randomized controlled trial to evaluate the effects of combined progressive exercise on metabolic syndrome in breast cancer survivors: rationale, design, and methods.

    PubMed

    Dieli-Conwright, Christina M; Mortimer, Joanne E; Schroeder, E Todd; Courneya, Kerry; Demark-Wahnefried, Wendy; Buchanan, Thomas A; Tripathy, Debu; Bernstein, Leslie

    2014-04-03

    Metabolic syndrome (MetS) is increasingly present in breast cancer survivors, possibly worsened by cancer-related treatments, such as chemotherapy. MetS greatly increases risk of cardiovascular disease and diabetes, co-morbidities that could impair the survivorship experience, and possibly lead to cancer recurrence. Exercise has been shown to positively influence quality of life (QOL), physical function, muscular strength and endurance, reduce fatigue, and improve emotional well-being; however, the impact on MetS components (visceral adiposity, hyperglycemia, low serum high-density lipoprotein cholesterol, hypertriglyceridemia, and hypertension) remains largely unknown. In this trial, we aim to assess the effects of combined (aerobic and resistance) exercise on components of MetS, as well as on physical fitness and QOL, in breast cancer survivors soon after completing cancer-related treatments. This study is a prospective randomized controlled trial (RCT) investigating the effects of a 16-week supervised progressive aerobic and resistance exercise training intervention on MetS in 100 breast cancer survivors. Main inclusion criteria are histologically-confirmed breast cancer stage I-III, completion of chemotherapy and/or radiation within 6 months prior to initiation of the study, sedentary, and free from musculoskeletal disorders. The primary endpoint is MetS; secondary endpoints include: muscle strength, shoulder function, cardiorespiratory fitness, body composition, bone mineral density, and QOL. Participants randomized to the Exercise group participate in 3 supervised weekly exercise sessions for 16 weeks. Participants randomized to the Control group are offered the same intervention after the 16-week period of observation. This is the one of few RCTs examining the effects of exercise on MetS in breast cancer survivors. Results will contribute a better understanding of metabolic disease-related effects of resistance and aerobic exercise training and inform

  15. Long-term omega-3 fatty acid supplementation prevents expression changes in cochlear homocysteine metabolism and ameliorates progressive hearing loss in C57BL/6J mice.

    PubMed

    Martínez-Vega, Raquel; Partearroyo, Teresa; Vallecillo, Néstor; Varela-Moreiras, Gregorio; Pajares, María A; Varela-Nieto, Isabel

    2015-12-01

    Omega-3 polyunsaturated fatty acids (PUFAs) are essential nutrients well known for their beneficial effects, among others on cognitive development and maintenance, inflammation and oxidative stress. Previous studies have shown an inverse association between high plasma levels of PUFAs and age-related hearing loss, and the relationship between low serum folate and elevated plasma homocysteine levels and hearing loss. Therefore, we used C57BL/6J mice and long-term omega-3 supplementation to evaluate the impact on hearing by analyzing their auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) thresholds. The omega-3 group showed significantly lower ABR hearing thresholds (~25 dB sound pressure level) and higher DPOAE amplitudes in mid-high frequencies when compared to the control group. These changes did not correlate with alterations between groups in plasma homocysteine or serum folate levels as measured by high-performance liquid chromatography and a microbiological method, respectively. Aging in the control group was associated with imbalanced cytokine expression toward increased proinflammatory cytokines as determined by quantitative reverse transcriptase polymerase chain reaction; these changes were prevented by omega-3 supplementation. Genes involved in homocysteine metabolism showed decreased expression during aging of control animals, and only alterations in Bhmt and Cbs were significantly prevented by omega-3 feeding. Western blotting showed that omega-3 supplementation precluded the CBS protein increase detected in 10-month-old controls but also produced an increase in BHMT protein levels. Altogether, the results obtained suggest a long-term protective role of omega-3 supplementation on cochlear metabolism and progression of hearing loss.

  16. Involvement of alcohol and aldehyde dehydrogenase activities on hepatic retinoid metabolism and its possible participation in the progression of rat liver regeneration.

    PubMed

    López-Valencia, Verónica; Rangel, Pablo; Rodríguez, Sandra; Hernández-Muñoz, Rolando

    2007-02-15

    Liver alcohol dehydrogenase (ADH) activity is decreased towards exogenous substrates after partial hepatectomy (PH), probably due to putative endogenous substrates acting as ADH inhibitors. Hence, retinoids could be suitable candidates as such endogenous substrates. Therefore, cytosolic ADH kinetic analysis using several substrates, liver cytosolic and mitochondrial aldehyde dehydrogenase (ALDH) activities, retinal and retinol content, as well as expression of proteins for ADH and CRBPI (a retinol carrier protein) were determined in liver samples, at two stages of liver regeneration (one- or two-thirds PH). The effect of inhibiting in vivo liver ADH by 4-methylpyrazole (4-MP) was also evaluated after 70%-PH. With 70%-PH, in vitro ADH activity towards exogenous alcohols and aldehydes was diminished, but retinol oxidation was increased and retinal reduction was decreased. These activities that be due to the participation of an ADH type which did not correlate with the amount of immunoreactive ADH protein. Cytosolic and mitochondrial ALDH activities oxidized actively retinal, whereas retinol and CBRP-I expression were reduced in these animals. With 30%-PH, these changes were less evident and sometimes opposite to those found with 70%-PH. In addition, retinol readily inhibited ADH-mediated ethanol oxidation. Interestingly, in vivo 4-MP administration inhibited ADH activity in a dose-dependent manner correlating with a progressive inhibition of liver regeneration. In conclusion, PH-induced inhibition of ADH (mainly type I) seems to be related to ADH-mediated retinoid metabolism during liver proliferation. Thus, results suggest a role of ADH in retinoid metabolism, which is apparently required during rat liver regeneration.

  17. Dose-dependent effects of calorie restriction on gene expression, metabolism, and tumor progression are partially mediated by insulin-like growth factor-1.

    PubMed

    Nogueira, Leticia M; Lavigne, Jackie A; Chandramouli, Gadisetti V R; Lui, Huaitian; Barrett, J Carl; Hursting, Stephen D

    2012-10-01

    The prevalence of obesity, an established risk and progression factor for breast and many other cancer types, remains very high in the United States and throughout the world. Calorie restriction (CR), a reduced-calorie dietary regimen typically involving a 20-40% reduction in calorie consumption, prevents or reverses obesity, and inhibits mammary and other types of cancer in multiple tumor model systems. Unfortunately, the mechanisms underlying the tumor inhibitory effects of CR are poorly understood, and a better understanding of these mechanisms may lead to new intervention targets and strategies for preventing or controlling cancer. We have previously shown that the anticancer effects of CR are associated with decreased systemic levels of insulin-like growth factor-1 (IGF-1), the primary source of which is liver. We have also reported that CR strongly suppresses tumor development and growth in multiple mammary cancer models. To identify CR-responsive genes and pathways, and to further characterize the role of IGF-1 as a mediator of the anticancer effects of CR, we assessed hepatic and mammary gland gene expression, hormone levels and growth of orthotopically transplanted mammary tumors in control and CR mice with and without exogenous IGF-1. C57BL/6 mice were fed either control AIN-76A diet ad libitum (AL), subjected to 20%, 30%, or 40% CR plus placebo timed-release pellets, or subjected to 30% or 40% CR plus timed-release pellets delivering murine IGF-1 (mIGF-1, 20 μg/day). Compared with AL-fed controls, body weights were decreased 14.3% in the 20% CR group, 18.5% in the 30% CR group, and 38% in the 40% CR group; IGF-1 infusion had no effect on body weight. Hepatic transcriptome analyses indicated that compared with 20% CR, 30% CR significantly modulated more than twice the number of genes and 40% CR more than seven times the number of genes. Many of the genes specific to the 40% CR regimen were hepatic stress-related and/or DNA damage-related genes. Exogenous

  18. Final Report: Filling Knowledge Gaps in Biological Networks: Integrated Global Approaches to Understand H{sub 2} Metabolism in Chlamydomonas Reinhardtii

    SciTech Connect

    Grossman, Arthur

    2012-05-01

    The major goal of our part of this project has been to generate mutants in fermentation metabolism and begin to decipher how lesions in the pathways associated with fermentation metabolism impact both H{sub 2} production and the production of other metabolites that accumulate as cells become anoxic. We are also trying to understand how metabolic pathways are regulated as O{sub 2} in the environment becomes depleted.

  19. The effects of age on associations between markers of HIV progression and markers of metabolic function including albumin, haemoglobin and lipid concentrations

    PubMed Central

    Samuel, M; Jose, S; Winston, A; Nelson, M; Johnson, M; Chadwick, D; Fisher, M; Leen, C; Gompels, M; Gilson, R; Post, FA; Hay, P; Sabin, CA; for the UK Collaborative HIV Cohort Study (UK CHIC)

    2014-01-01

    Objectives We investigated whether age modified associations between markers of HIV progression, CD4 T lymphocyte count and HIV RNA viral load (VL), and the following markers of metabolic function: albumin, haemoglobin, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC). Methods A retrospective analysis of data from the United Kingdom Collaborative HIV Cohort was carried out. Analyses were limited to antiretroviral-naïve subjects to focus on the impact of HIV disease itself. A total of 16670 subjects were included in the analysis. Multilevel linear regression models assessed associations between CD4 count/VL and each of the outcomes. Statistical tests for interactions assessed whether associations differed among age groups. Results After adjustment for gender and ethnicity, there was evidence that lower CD4 count and higher VL were associated with lower TC, LDL-C, haemoglobin and albumin concentrations but higher triglyceride concentrations. Age modified associations between CD4 count and albumin (P < 0.001) and haemoglobin (P = 0.001), but not between CD4 count and HDL-C, LDL-C and TC, or VL and any outcome. Among participants aged < 30, 30–50 and > 50 years, a 50 cells/μL lower CD4 count correlated with a 2.4 [95% confidence interval (CI) 1.7–3.0], 3.6 (95% CI 3.2–4.0) and 5.1 (95% CI 4.0–6.1) g/L lower haemoglobin concentration and a 0.09 (95% CI 0.07–0.11), 0.12 (95% CI 0.11–0.13) and 0.16 (95% CI 0.13–0.19) g/L lower albumin concentration, respectively. Conclusions We present evidence that age modifies associations between CD4 count and plasma albumin and haemoglobin levels. A given reduction in CD4 count was associated with a greater reduction in haemoglobin and albumin concentrations among older people living with HIV. These findings increase our understanding of how the metabolic impact of HIV is influenced by age. PMID:24245861

  20. Randomized controlled trial to evaluate the effects of combined progressive exercise on metabolic syndrome in breast cancer survivors: rationale, design, and methods

    PubMed Central

    2014-01-01

    Background Metabolic syndrome (MetS) is increasingly present in breast cancer survivors, possibly worsened by cancer-related treatments, such as chemotherapy. MetS greatly increases risk of cardiovascular disease and diabetes, co-morbidities that could impair the survivorship experience, and possibly lead to cancer recurrence. Exercise has been shown to positively influence quality of life (QOL), physical function, muscular strength and endurance, reduce fatigue, and improve emotional well-being; however, the impact on MetS components (visceral adiposity, hyperglycemia, low serum high-density lipoprotein cholesterol, hypertriglyceridemia, and hypertension) remains largely unknown. In this trial, we aim to assess the effects of combined (aerobic and resistance) exercise on components of MetS, as well as on physical fitness and QOL, in breast cancer survivors soon after completing cancer-related treatments. Methods/Design This study is a prospective randomized controlled trial (RCT) investigating the effects of a 16-week supervised progressive aerobic and resistance exercise training intervention on MetS in 100 breast cancer survivors. Main inclusion criteria are histologically-confirmed breast cancer stage I-III, completion of chemotherapy and/or radiation within 6 months prior to initiation of the study, sedentary, and free from musculoskeletal disorders. The primary endpoint is MetS; secondary endpoints include: muscle strength, shoulder function, cardiorespiratory fitness, body composition, bone mineral density, and QOL. Participants randomized to the Exercise group participate in 3 supervised weekly exercise sessions for 16 weeks. Participants randomized to the Control group are offered the same intervention after the 16-week period of observation. Discussion This is the one of few RCTs examining the effects of exercise on MetS in breast cancer survivors. Results will contribute a better understanding of metabolic disease-related effects of resistance and

  1. The effects of age on associations between markers of HIV progression and markers of metabolic function including albumin, haemoglobin and lipid concentrations.

    PubMed

    Samuel, M; Jose, S; Winston, A; Nelson, M; Johnson, M; Chadwick, D; Fisher, M; Leen, C; Gompels, M; Gilson, R; Post, F A; Hay, P; Sabin, C A

    2014-05-01

    We investigated whether age modified associations between markers of HIV progression, CD4 T lymphocyte count and HIV RNA viral load (VL), and the following markers of metabolic function: albumin, haemoglobin, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC). A retrospective analysis of data from the United Kingdom Collaborative HIV Cohort was carried out. Analyses were limited to antiretroviral-naïve subjects to focus on the impact of HIV disease itself. A total of 16670 subjects were included in the analysis. Multilevel linear regression models assessed associations between CD4 count/VL and each of the outcomes. Statistical tests for interactions assessed whether associations differed among age groups. After adjustment for gender and ethnicity, there was evidence that lower CD4 count and higher VL were associated with lower TC, LDL-C, haemoglobin and albumin concentrations but higher triglyceride concentrations. Age modified associations between CD4 count and albumin (P < 0.001) and haemoglobin (P = 0.001), but not between CD4 count and HDL-C, LDL-C and TC, or VL and any outcome. Among participants aged < 30, 30-50 and > 50 years, a 50 cells/μL lower CD4 count correlated with a 2.4 [95% confidence interval (CI) 1.7-3.0], 3.6 (95% CI 3.2-4.0) and 5.1 (95% CI 4.0-6.1) g/L lower haemoglobin concentration and a 0.09 (95% CI 0.07-0.11), 0.12 (95% CI 0.11-0.13) and 0.16 (95% CI 0.13-0.19) g/L lower albumin concentration, respectively. We present evidence that age modifies associations between CD4 count and plasma albumin and haemoglobin levels. A given reduction in CD4 count was associated with a greater reduction in haemoglobin and albumin concentrations among older people living with HIV. These findings increase our understanding of how the metabolic impact of HIV is influenced by age. © 2013 The Authors. HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.

  2. Detection of minimal residual disease following induction immunochemotherapy predicts progression free survival in mantle cell lymphoma: final results of CALGB 59909.

    PubMed

    Liu, Hongtao; Johnson, Jeffrey L; Koval, Greg; Malnassy, Greg; Sher, Dorie; Damon, Lloyd E; Hsi, Eric D; Bucci, Donna Marie; Linker, Charles A; Cheson, Bruce D; Stock, Wendy

    2012-04-01

    In the present study, the prognostic impact of minimal residual disease during treatment on time to progression and overall survival was analyzed prospectively in patients with mantle cell lymphoma treated on the Cancer and Leukemia Group B 59909 clinical trial. Peripheral blood and bone marrow samples were collected during different phases of the Cancer and Leukemia Group B 59909 study for minimal residual disease analysis. Minimal residual disease status was determined by quantitative polymerase chain reaction of IgH and/or BCL-1/JH gene rearrangement. Correlation of minimal residual disease status with time to progression and overall survival was determined. In multivariable analysis, minimal residual disease, and other risk factors were correlated with time to progression. Thirty-nine patients had evaluable, sequential peripheral blood and bone marrow samples for minimal residual disease analysis. Using peripheral blood monitoring, 18 of 39 (46%) achieved molecular remission following induction therapy. The molecular remission rate increased from 46 to 74% after one course of intensification therapy. Twelve of 21 minimal residual disease positive patients (57%) progressed within three years of follow up compared to 4 of 18 (22%) molecular remission patients (P=0.049). Detection of minimal residual disease following induction therapy predicted disease progression with a hazard ratio of 3.7 (P=0.016). The 3-year probability of time to progression among those who were in molecular remission after induction chemotherapy was 82% compared to 48% in patients with detectable minimal residual disease. The prediction of time to progression by post-induction minimal residual disease was independent of other prognostic factors in multivariable analysis. Detection of minimal residual disease following induction immunochemotherapy was an independent predictor of time to progression following immunochemotherapy and autologous stem cell transplantation for mantle cell lymphoma.

  3. Detection of minimal residual disease following induction immunochemotherapy predicts progression free survival in mantle cell lymphoma: final results of CALGB 59909

    PubMed Central

    Liu, Hongtao; Johnson, Jeffrey L.; Koval, Greg; Malnassy, Greg; Sher, Dorie; Damon, Lloyd E.; Hsi, Eric D.; Bucci, Donna Marie; Linker, Charles A.; Cheson, Bruce D.; Stock, Wendy

    2012-01-01

    Background In the present study, the prognostic impact of minimal residual disease during treatment on time to progression and overall survival was analyzed prospectively in patients with mantle cell lymphoma treated on the Cancer and Leukemia Group B 59909 clinical trial. Design and Methods Peripheral blood and bone marrow samples were collected during different phases of the Cancer and Leukemia Group B 59909 study for minimal residual disease analysis. Minimal residual disease status was determined by quantitative polymerase chain reaction of IgH and/or BCL-1/JH gene rearrangement. Correlation of minimal residual disease status with time to progression and overall survival was determined. In multivariable analysis, minimal residual disease, and other risk factors were correlated with time to progression. Results Thirty-nine patients had evaluable, sequential peripheral blood and bone marrow samples for minimal residual disease analysis. Using peripheral blood monitoring, 18 of 39 (46%) achieved molecular remission following induction therapy. The molecular remission rate increased from 46 to 74% after one course of intensification therapy. Twelve of 21 minimal residual disease positive patients (57%) progressed within three years of follow up compared to 4 of 18 (22%) molecular remission patients (P=0.049). Detection of minimal residual disease following induction therapy predicted disease progression with a hazard ratio of 3.7 (P=0.016). The 3-year probability of time to progression among those who were in molecular remission after induction chemotherapy was 82% compared to 48% in patients with detectable minimal residual disease. The prediction of time to progression by post-induction minimal residual disease was independent of other prognostic factors in multivariable analysis. Conclusions Detection of minimal residual disease following induction immunochemotherapy was an independent predictor of time to progression following immunochemotherapy and autologous

  4. Drug target identification in sphingolipid metabolism by computational systems biology tools: metabolic control analysis and metabolic pathway analysis.

    PubMed

    Ozbayraktar, F Betül Kavun; Ulgen, Kutlu O

    2010-08-01

    Sphingolipids regulate cellular processes that are critically important in cell's fate and function in cancer development and progression. This fact underlies the basics of the novel cancer therapy approach. The pharmacological manipulation of the sphingolipid metabolism in cancer therapeutics necessitates the detailed understanding of the pathway. Two computational systems biology tools are used to identify potential drug target enzymes among sphingolipid pathway that can be further utilized in drug design studies for cancer therapy. The enzymes in sphingolipid pathway were ranked according to their roles in controlling the metabolic network by metabolic control analysis. The physiologically connected reactions, i.e. biologically significant and functional modules of network, were identified by metabolic pathway analysis. The final set of candidate drug target enzymes are selected such that their manipulation leads to ceramide accumulation and long chain base phosphates depletion. The mathematical tools' efficiency for drug target identification performed in this study is validated by clinically available drugs. Copyright 2010 Elsevier Inc. All rights reserved.

  5. Long-term effects intensive medical therapy on the development and progression of subclinical atherosclerosis and the metabolic syndrome in Chinese patients with type 2 diabetes mellitus

    PubMed Central

    Liu, Zhiwen; Zhou, Zhiguang; Huang, Gan; Xiao, Yang; Li, Zhen; Liu, Cong; Na, Risu

    2016-01-01

    Abstract Background: Few studies have investigated the progression of subclinical atherosclerosis and metabolic syndrome (MetS) in Chinese patients with type 2 diabetes mellitus (T2DM). This study was to compare the long-term effects of intensive medical therapy on the development and progression of subclinical atherosclerosis and MetS in Chinese T2DM patients with that of a conventional treatment regimen. Methods: A total of 316 T2DM patients were randomized to receive conventional pharmacological treatment or intensive medical therapy, consisting of diet and exercise counseling, from 2002 to 2014 at our hospital in Changsha, China. Clinical indicators of subclinical atherosclerosis and MetS were evaluated over the 12-year follow-up period. A χ2 analysis or t tests was used to compare the data between the 2 groups. Risk factors for subclinical atherosclerosis were identified using Cox proportional hazard models. Results: The incidence of subclinical atherosclerosis increased in both groups over time, and did not differ significantly between the 2 groups at the end of the study. However, after 6 years of treatment, the risk of subclinical atherosclerosis was significantly lower in the intensive medical therapy group, based on intima-media thickness (IMT) measurements, compared with that in the conventional treatment (44.2% vs. 69.7%; P < 0.01). Age, creatinine, and IMT of the common iliac artery were significantly associated with subclinical atherosclerosis. Although the indicators of MetS did not differ significantly at the end of study, the success rate for the management of MetS in the intensive medical therapy group was significantly higher than that in the conventional treatment group in 2006, 2008, 2010, and 2012. Conclusions: The incidence of atherosclerosis in the intensive medical therapy group was significantly lower than that in the conventional treatment group from 2006 to 2010 (P < 0.05), and the incidence of MetS in the intensive medical

  6. Increased expression of the retinoic acid-metabolizing enzyme CYP26A1 during the progression of cervical squamous neoplasia and head and neck cancer.

    PubMed

    Osanai, Makoto; Lee, Gang-Hong

    2014-10-07

    Retinoic acid (RA) is a critical regulator of cell differentiation, proliferation, and apoptosis in various cell types. Recently, the RA-metabolizing enzyme CYP26A1 (cytochrome P450, family 26, subfamily A, polypeptide 1) has been shown to have an oncogenic function in breast carcinogenesis. However, the relevance of elevated CYP26A1 expression in human cancers remains to be clarified. We immunohistochemically examined the expression of CYP26A1 in cervical squamous cell carcinoma (SCC) and its precursors, including low- and high-grade squamous intraepithelial lesions (LSIL and HSIL, respectively), as well as head and neck cancer (HNC). The association between CYP26A1 expression and a number of clinicopathological parameters was also evaluated. CYP26A1 was not expressed in normal cervical epithelium. CYP26A1 expression was present in LSIL but limited to basal and parabasal cells. HSIL cases exhibited strong nuclear expression of CYP26A1 and mixed cytoplasmic expression patterns with widely distributed expression toward the epithelial surface. Importantly, strong cytoplasmic staining of CYP26A1 was observed in 19 of 50 (38%) patients with cervical SCC. Elevated expression of CYP26A1 was significantly associated with younger age (<50 years) and lymph node involvement (pN). Similarly, CYP26A1 was not expressed in non-neoplastic tissues of the head and neck, but strong cytoplasmic staining of CYP26A1 was observed in 52 of 128 (41%) HNC cases. Such strong CYP26A1 expression was significantly associated with the primary tumor stage of carcinomas (pT) and the pathological tumor-node-metastasis (pTNM) stage in HNC. Our results indicated an elevated CYP26A1 expression in malignant and precancerous dysplastic lesions of the human cervix, which also increased with the progression of cervical squamous neoplasia. In addition, this report is the first to demonstrate the increased expression of CYP26A1 in HNC and its significant correlation with primary tumor growth. These data

  7. Predicting the accumulation of well-metabolized chemicals by fish from measured rates of in vitro intrinsic clearance: Progress made and challenges ahead

    EPA Science Inventory

    Several groups have extrapolated in vitro metabolism data for fish to the intact animal and used this information as an input to models of chemical bioconcentration. These “proof of concept” studies show that incorporating in vitro metabolism data into the models sub...

  8. Metabolic support for a lunar base

    NASA Technical Reports Server (NTRS)

    Sauer, R. L.

    1985-01-01

    A review of the metabolic support systems used and the metabolic support requirements provided on past and current spaceflight programs is presented. This review will provide familiarization with unique constraints of space flight and technology as it relates to inflight metabolic support of astronauts. This information, along with a general review of the NASA effort to develop a Controlled Ecological Life Support System (CELSS) will define the general scenario of metabolic support for a lunar base. A phased program of metabolic support for a lunar base will be elucidated. Included will be discussion of the CELSS water reclamation and food recycling technology as it now exists and how it could be expected to be progressively incorporated into the lunar base. This transition would be from a relatively open system in the initial development period, when mechanical phase change water reclamation and minimal plant growth are incorporated, to the final period when practically total closure of the life support system will be proved through physicochemical and biological processes. Finally, a review of the estimated metabolic intake requirements for the occupants of a lunar base will be presented.

  9. Computational and Mathematical Methods to Estimate the Basic Reproduction Number and Final Size for Single-Stage and Multistage Progression Disease Models for Zika with Preventative Measures

    PubMed Central

    2017-01-01

    We present new mathematical models that include the impact of using selected preventative measures such as insecticide treated nets (ITN) in controlling or ameliorating the spread of the Zika virus. For these models, we derive the basic reproduction number and sharp estimates for the final size relation. We first present a single-stage model which is later extended to a new multistage model for Zika that incorporates more realistic incubation stages for both the humans and vectors. For each of these models, we derive a basic reproduction number and a final size relation estimate. We observe that the basic reproduction number for the multistage model converges to expected values for a standard Zika epidemic model with fixed incubation periods in both hosts and vectors. Finally, we also perform several computational experiments to validate the theoretical results obtained in this work and study the influence of various parameters on the models. PMID:28894473

  10. Computational and Mathematical Methods to Estimate the Basic Reproduction Number and Final Size for Single-Stage and Multistage Progression Disease Models for Zika with Preventative Measures.

    PubMed

    Padmanabhan, P; Seshaiyer, P

    2017-01-01

    We present new mathematical models that include the impact of using selected preventative measures such as insecticide treated nets (ITN) in controlling or ameliorating the spread of the Zika virus. For these models, we derive the basic reproduction number and sharp estimates for the final size relation. We first present a single-stage model which is later extended to a new multistage model for Zika that incorporates more realistic incubation stages for both the humans and vectors. For each of these models, we derive a basic reproduction number and a final size relation estimate. We observe that the basic reproduction number for the multistage model converges to expected values for a standard Zika epidemic model with fixed incubation periods in both hosts and vectors. Finally, we also perform several computational experiments to validate the theoretical results obtained in this work and study the influence of various parameters on the models.

  11. Experimental verification of a progressive damage model for composite laminates based on continuum damage mechanics. M.S. Thesis Final Report

    NASA Technical Reports Server (NTRS)

    Coats, Timothy William

    1994-01-01

    Progressive failure is a crucial concern when using laminated composites in structural design. Therefore the ability to model damage and predict the life of laminated composites is vital. The purpose of this research was to experimentally verify the application of the continuum damage model, a progressive failure theory utilizing continuum damage mechanics, to a toughened material system. Damage due to tension-tension fatigue was documented for the IM7/5260 composite laminates. Crack density and delamination surface area were used to calculate matrix cracking and delamination internal state variables, respectively, to predict stiffness loss. A damage dependent finite element code qualitatively predicted trends in transverse matrix cracking, axial splits and local stress-strain distributions for notched quasi-isotropic laminates. The predictions were similar to the experimental data and it was concluded that the continuum damage model provided a good prediction of stiffness loss while qualitatively predicting damage growth in notched laminates.

  12. Kansas Services for Children and Youth with Dual Sensory Impairments Project. Final Four Year Progress Report. October 1, 1995 to September 30, 1999.

    ERIC Educational Resources Information Center

    Kansas State Board of Education, Topeka.

    This final report describes the process and steps the Kansas Services Project for Children and Youth with Dual Sensory Impairments Project (KSDSIP) has taken to provide services and technical assistance for infants, toddlers, children and youth with deaf-blindness. The 4-year federally funded project met federally-set priorities through…

  13. Federal Assistance Program Quarterly Project Progress Report. Geothermal Energy Program: Information Dissemination, Public Outreach, and Technical Analysis Activities. Reporting Period: January 1 - March 31, 2001 [Final report

    SciTech Connect

    Lund, John W.

    2002-03-22

    The final report of the accomplishments of the geothermal energy program: information dissemination, public outreach and technical analysis activities by the project team consisting of the Geo-Heat Center, Geothermal Resources Council, Geothermal Education Office, Geothermal Energy Association and the Washington State University Energy Program.

  14. Two dimensional and zero field NMR studies of coal structure: Final progress report, including the period July 1, 1987 to September 30, 1987

    SciTech Connect

    Zilm, K.W.

    1987-12-01

    This report covers the progress made on the title project during the last quarter and summarizes the accomplishments for the project period. During the last three months we have completed a full analysis of the limitations of our ADIPSHIFT 2D NMR experiment that we have developed to determine the distribution of functional types of carbon in coals. This is an extensive piece of work and will provide a firm foundation for the application of the method to complex organic solids in the future. A particularly useful graphical analysis is described for use with unknowns such as coals. 17 refs.

  15. Mercuric iodide research and development in support of DOE historically black colleges and university program. Final technical progress report, May 4, 1994--January 31, 1997

    SciTech Connect

    George, M.A.; Chen, K.T.; Burger, A.

    1996-07-31

    This report describes the progress achieved during the period May 1, 1994 through July 31, 1996. During this period, the different subjects studied were: (a) Improvements in zone refining experiments to establish optimum refining parameters; (b) Development of surface reflection spectroscopy as a method to measure crystal surface temperature; preliminary results on applicability on CdTe material; (c) Atomic Force Microscopy studies in the contact mode; (d) Optical Methods for Measuring Iodine Vapor During Physical Vapor Transport of HgI{sub 2}; and (e) Establishment of a Brigman melt growth facility at Fisk University.

  16. Summary of activities and accomplishments. Volume IV. A proposal to develop a method for the detection of HE employing chemiluminescence reactions. Final progress report

    SciTech Connect

    Neary, M.P.

    1981-01-01

    This is the final and fourth quarter report for the study of high explosive (HE) detection by coupling the chemistry of HE with that of luminol reaction, a well-known chemiluminescence (CL) reaction. Our accomplishments include: success in coupling HE and CL chemistry reliably; the capability to use a micellized solvent to concentrate HE; and the basis for design instrumentation that may exhibit better sensitivity and lower levels of detection than that exhibited by the laboratory apparatus used for this study. On the basis of these results we are prepared to recommend further study.

  17. Recovery of valuable chlorosilane intermediates by a novel waste conversion process. Technical report for phase IIIA (final) and phase IIIB (progress)

    SciTech Connect

    Anderson, K.E.

    1998-10-01

    From July 1994 through May 1998, direct process residue (DPR) hydrogenolysis has been studied in the laboratory, at a small Pilot Plant, and finally at a larger Pilot Plant within Dow Corning`s Carrollton, Kentucky plant. The system reacts filtered DPR with monomer at high temperature and pressure. The process demonstrates DPR conversion up to 86%. The reaction product contains high concentrations of valuable monomers such as dimethyldichlorosilane and methyldichlorosilane. A larger DPR hydrogenolysis reactor based on these results is being designed for operation in Europe at Dow Corning`s Barry, Wales site.

  18. Field evaluation of gas-lift and progressive-cavity pumps as effective dewatering methods for coalbed methane wells. Final report, April 1984-December 1985

    SciTech Connect

    Graves, S.L.; Hollingsworth, F.C.; Beavers, W.M.

    1986-03-01

    Field evaluations of gas-lift and progressive-cavity pumps were conducted to determine their effectiveness as dewatering techniques for coalbed-methane wells in the Warrior Coal Field. AMPCO installed a gas-lift system in AMPCO Well No. 6. Problems included poor performance of all gas-lift valve designs and higher instantaneous water production rates than anticipated due to heading and unloading. The test provided the conclusion that gas lift is an effective start-up dewatering tool for initial removal of large amounts of water and solids but that in use as a long-term dewatering tool, needs additional evaluation relative to capital cost, valve design, and extended performance.

  19. Metabolism disrupting chemicals and metabolic disorders.

    PubMed

    Heindel, Jerrold J; Blumberg, Bruce; Cave, Mathew; Machtinger, Ronit; Mantovani, Alberto; Mendez, Michelle A; Nadal, Angel; Palanza, Paola; Panzica, Giancarlo; Sargis, Robert; Vandenberg, Laura N; Vom Saal, Frederick

    2017-03-01

    The recent epidemics of metabolic diseases, obesity, type 2 diabetes(T2D), liver lipid disorders and metabolic syndrome have largely been attributed to genetic background and changes in diet, exercise and aging. However, there is now considerable evidence that other environmental factors may contribute to the rapid increase in the incidence of these metabolic diseases. This review will examine changes to the incidence of obesity, T2D and non-alcoholic fatty liver disease (NAFLD), the contribution of genetics to these disorders and describe the role of the endocrine system in these metabolic disorders. It will then specifically focus on the role of endocrine disrupting chemicals (EDCs) in the etiology of obesity, T2D and NAFLD while finally integrating the information on EDCs on multiple metabolic disorders that could lead to metabolic syndrome. We will specifically examine evidence linking EDC exposures during critical periods of development with metabolic diseases that manifest later in life and across generations.

  20. Nuclear Island Engineering MHTGR [Modular High-Temperature Gas-cooled Reactor] preliminary and final designs. Technical progress report, December 12, 1988--September 30, 1989

    SciTech Connect

    1989-12-01

    This report summarizes the Department of Energy (DOE)-funded work performed by General Atomics (GA) under the Nuclear Island Engineering (NIE)-Modular High-Temperature Gas-cooled Reactor (MHTGR) Preliminary and Final Designs Contract DE-AC03-89SF17885 for the period December 12, 1988 through September 30, 1989. This reporting period is the first (partial) fiscal year of the 5-year contract performance period. The objective of DOE`s MHTGR program is to advance the design from the conceptual design phase into preliminary design and then on to final design in support of the Nuclear Regulatory Commission`s (NRC`s) design review and approval of the MHTGR Design Team, is focused on the Nuclear Island portion of the technology and design, primarily in the areas of the reactor and internals, fuel characteristics and fuel fabrication, helium services systems, reactor protection, shutdown cooling, circulator design, and refueling system. Maintenance and implementation of the functional methodology, plant-level analysis, support for probabilistic risk assessment, quality assurance, operations, and reliability/availability assessments are included in GA`s scope of work.

  1. Pelletizing/reslurrying as a means of distributing and firing clean coal. Final quarterly technical progress report No. 7, January 1, 1992-- March 31, 1992

    SciTech Connect

    Conkle, H.N.

    1992-06-09

    Work in this quarter focused on completing (1) the final batch of pilot-scale disk pellets, (2) storage, handling, and transportation evaluation, (3) pellet reslurrying and atomization studies, and (4) cost estimation for pellet and slurry production. Disk pelletization of Elkhorn coal was completed this quarter. Pellets were approximately 1/2- to 3/4-in. in diameter. Pellets, after thermal curing were strong and durable and exceeded the pellet acceptance criteria. Storage and handling tests indicate a strong, durable pellet can be prepared from all coals, and these pellets (with the appropriate binder) can withstand outdoor, exposed storage for at least 4 weeks. Pellets in unexposed storage show no deterioration in pellet properties. Real and simulated transportation tests indicate truck transportation should generate less than 5 percent fines during transport. Continuous reslurrying testing and subsequent atomization evaluation were performed this quarter in association with University of Alabama and Jim Walter Resources. Four different slurries of approximately 55-percent-solids with viscosities below 500 cP (at 100 sec{sup {minus}1}) were prepared. Both continuous pellet-to-slurry production and atomization testing was successfully demonstrated. Finally, an in depth evaluation of the cost to prepare pellets, transport, handle, store, and convert the pellet into Coal Water Fuel (CWF) slurries was completed. Cost of the pellet-CWF option are compared with the cost to directly convert clean coal filter cake into slurry and transport, handle and store it at the user site. Findings indicate that in many circumstances, the pellet-CWF option would be the preferred choice. The decision depends on the plant size and transportation distance, and to a lesser degree on the pelletization technique and the coal selected.

  2. Engineering development of coal-fired high performance power systems, Phases 2 and 3. Quarterly progress report, October 1--December 31, 1996. Final report

    SciTech Connect

    1996-12-31

    The goals of this program are to develop a coal-fired high performance power generation system (HIPPS) by the year 2000 that is capable of: {gt} 47% efficiency (HHV); NO{sub x}, SO{sub x}, and particulates {gt} 10% NSPS; coal providing {ge} 65% of heat input; all sold wastes benign; and cost of electricity 90% of present plant. Work reported herein is from Task 1.3 HIPPS Commercial Plant Design, Task 2,2 HITAF Air Heater, and Task 2.4 Duct Heater Design. The impact on cycle efficiency from the integration of various technology advances is presented. The criteria associated with a commercial HIPPS plant design as well as possible environmental control options are presented. The design of the HITAF air heaters, both radiative and convective, is the most critical task in the program. In this report, a summary of the effort associated with the radiative air heater designs that have been considered is provided. The primary testing of the air heater design will be carried out in the UND/EERC pilot-scale furnace; progress to date on the design and construction of the furnace is a major part of this report. The results of laboratory and bench scale activities associated with defining slag properties are presented. Correct material selection is critical for the success of the concept; the materials, both ceramic and metallic, being considered for radiant air heater are presented. The activities associated with the duct heater are also presented.

  3. Simultaneous metabolism of chloro- and methyl-aromatic compounds by selected bacterial strains. Final report, 20 August 1991-19 August 1992

    SciTech Connect

    Focht, D.D.

    1993-05-27

    Microorganisms are frequently able to degrade anthropogenic materials using pathways that evolved for the assimilation of related naturally-occurring compounds. Complications can arise, however, during the metabolism of mixtures when incompatible intermediates are formed from different components. The breakdown of chloro- and methyl-aromatics, for example, produces catechols which are oxidized differently: chlorocatechols are normally cleaved by ortho fission and methylcatechols by meta fission. If both systems act simultaneously, suicide substrates or dead-end metabolites are usually formed. Nevertheless, bacteria differ in their, ability to cope with such mixtures. A unique bacterium, Pseudomonas cepacia MB2 was isolated by selective enrichment on 2-methylbenzoate, yet was also able to fortuitously utilize 3-chloro-2-methylbenzoate as a sole carbon source. This strain is unique in its ability to utilize an aromatic acid containing both a methyl and chloro substituent via the metafission pathway without the production of suicidal products.

  4. Mitochondrial metabolism in cancer metastasis

    PubMed Central

    Whitaker-Menezes, Diana; Martinez-Outschoorn, Ubaldo E; Flomenberg, Neal; Birbe, Ruth C; Witkiewicz, Agnieszka K; Howell, Anthony; Philp, Nancy J; Pestell, Richard G

    2012-01-01

    We have recently proposed a new two-compartment model for understanding the Warburg effect in tumor metabolism. In this model, glycolytic stromal cells produce mitochondrial fuels (L-lactate and ketone bodies) that are then transferred to oxidative epithelial cancer cells, driving OXPHOS and mitochondrial metabolism. Thus, stromal catabolism fuels anabolic tumor growth via energy transfer. We have termed this new cancer paradigm the “reverse Warburg effect,” because stromal cells undergo aerobic glycolysis, rather than tumor cells. To assess whether this mechanism also applies during cancer cell metastasis, we analyzed the bioenergetic status of breast cancer lymph node metastases, by employing a series of metabolic protein markers. For this purpose, we used MCT4 to identify glycolytic cells. Similarly, we used TOMM20 and COX staining as markers of mitochondrial mass and OXPHOS activity, respectively. Consistent with the “reverse Warburg effect,” our results indicate that metastatic breast cancer cells amplify oxidative mitochondrial metabolism (OXPHOS) and that adjacent stromal cells are glycolytic and lack detectable mitochondria. Glycolytic stromal cells included cancer-associated fibroblasts, adipocytes and inflammatory cells. Double labeling experiments with glycolytic (MCT4) and oxidative (TOMM20 or COX) markers directly shows that at least two different metabolic compartments co-exist, side-by-side, within primary tumors and their metastases. Since cancer-associated immune cells appeared glycolytic, this observation may also explain how inflammation literally “fuels” tumor progression and metastatic dissemination, by “feeding” mitochondrial metabolism in cancer cells. Finally, MCT4(+) and TOMM20(-) “glycolytic” cancer cells were rarely observed, indicating that the conventional “Warburg effect” does not frequently occur in cancer-positive lymph node metastases. PMID:22395432

  5. Metabolic studies of neptunium in the adult baboon: retention, distribution, kinetics, and enhanced excretion by chelation therapy. Technical progress report summary

    SciTech Connect

    Not Available

    1984-01-01

    These investigations provided additional data on the uptake, distribution, retention and excretion of Np-237, Np-239 and Pa-233 in baboons following single intravenous or gavage administration. The influence of oxidation state, chemical medium, pH, mass, etc. on the metabolism of these radionuclides is related.

  6. Development and testing of a commercial scale coal-fired combustion system -- Phase 3. Final technical progress report, September 26, 1990--August 31, 1994

    SciTech Connect

    Litka, A.; Breault, R.

    1994-10-01

    This report summarizes the results of work performed in the development and testing of a coal-fired space heating system for the commercial market sector. Although coal is the most plentiful energy resource in the US, its use since World War II has been largely restricted to utility power generation for environmental and economic reasons. Within the commercial sector, oil and natural gas are the predominant heating fuels for office buildings, apartment complexes, and similar structures. Generally, these buildings require firing rates of 1 to 10 million Btu/hr. The objective of this program was to design, build, and test a coal-based heating system for this sector, and determine the economic viability and market potential for the system. Coal water slurry (CWS) fuel was chosen as the fuel form for this development effort. CWS eliminates the need to use dry pulverized coal with its attendant handling, metering, and dusting problems, as well as its explosive potential. A brief description of the overall system design is given in this report, as well as a discussion of the unique features of the system configuration and key components. This is followed by a summary of the testing performed, including a comparison between system performance and program goals. Finally, the results of the economic evaluation are presented, along with a commercialization plan for the technology. A key issue in the eventual commercialization of the technology is the availability of a competitively priced coal water slurry fuel. Predicted prices and availability of CWS are discussed.

  7. Intelligent distributed control for nuclear power plants. Final (third annual) technical progress report, September 1991--June 1993 (September 1989--June 1993): Includes no-cost extension period from September 1992--June 1993

    SciTech Connect

    Klevans, E.H.

    1993-12-31

    This project was initiated in September 1989 as a three year project to develop and demonstrate Intelligent Distributed Control (IDC) for Nuclear Power Plants. There were two primary goals of this research project. The first goal was to combine diagnostics and control to achieve a highly automated power plant as described by M.A. Schultz. The second goal was to apply this research to develop a prototype demonstration on an actual power plant system, the EBR-2 steam plant. Described in this Final (Third Annual) Technical Progress Report is the accomplishment of the project`s final milestone, an in-plant intelligent control experiment conducted on April 1, 1993. The development of the experiment included: simulation validation, experiment formulation and final programming, procedure development and approval, and experimental results. Other third year developments summarized in this report are: (1) a theoretical foundation for Reconfigurable Hybrid Supervisory Control, (2) a steam plant diagnostic system, (3) control console design tools and (4) other advanced and intelligent control.

  8. Niacin plus Simvastatin Reduces Coronary Stenosis Progression Among Patients with Metabolic Syndrome Despite a Modest Increase in Insulin Resistance: A Subgroup Analysis of the HDL-Atherosclerosis Treatment Study (HATS)

    PubMed Central

    Vittone, Francesca; Chait, Alan; Morse, Josh S.; Fish, Brian; Brown, B. Greg; Zhao, Xue-Qiao

    2007-01-01

    , insulin resistance, and to a lesser extent in patients with dysglycemia in the N+S group compared to PL. Conclusions These data indicate that, in CAD patients with low HDL, treating the atherogenic dyslipidemia with a combination of N+S leads to substantial benefits in terms of stenosis progression and clinical events, independently of whether the patient has the metabolic syndrome or is insulin resistant. Over a 3 year period, the beneficial effect of niacin in combination with simvastatin appears to offset the modest adverse effect of niacin on glucose metabolism and insulin resistance in at higher risk patients, as long as careful attention is paid to glycemic control. PMID:18591993

  9. Systems Biology of Metabolism.

    PubMed

    Nielsen, Jens

    2017-06-20

    Metabolism is highly complex and involves thousands of different connected reactions; it is therefore necessary to use mathematical models for holistic studies. The use of mathematical models in biology is referred to as systems biology. In this review, the principles of systems biology are described, and two different types of mathematical models used for studying metabolism are discussed: kinetic models and genome-scale metabolic models. The use of different omics technologies, including transcriptomics, proteomics, metabolomics, and fluxomics, for studying metabolism is presented. Finally, the application of systems biology for analyzing global regulatory structures, engineering the metabolism of cell factories, and analyzing human diseases is discussed.

  10. Studies of transport pathways of Th, U, rare earths, Ra-228, and Ra-226 from soil to plants and farm animals: Final progress report, 1983-1988

    SciTech Connect

    Linsalata, P

    1988-07-01

    This report consists of three parts. Part 1 discusses a field study conducted in an area of enhanced, natural radioactivity to assess the soil to edible vegetable concentration ratios (CR = concentration in dry vegetable/concentration in dry soil) of Th-232, Th-230, Ra-226, Ra-228, and the light rare earth elements (REE's), La, Ce, and Nd. Twenty-eight soil, and approximately 42 vegetable samples consisting of relatively equal numbers of seven varieties, were obtained from 11 farms on the Pocos de Caldas Plateau in the state of Minas Gerais, Brazil. This region is the site of a major natural analogue study to assess the mobilization and retardation processes affecting thorium and the REE's at the Morro do Ferro ore body, and uranium series radionuclides at the Osamu Utsumi open pit uranium mine. Thorium (IV) serves as a chemical analogue for quadrivalent plutonium, the light REE's (III) as chemical analogues for trivalent americium and curium, and uranium (VI) as an analogue for transuranics with stable oxidation states above IV, e.g., Pu(VI). Part 2 includes our final measurement results for naturally occurring light rare earth elements (REE's include La, Ce, Nd, and SM), U-series and Th-series radionuclides in adult farm animal tissues, feeds and soils. Our findings on soil-to-tissue concentration ratios (CR's) and the comparative behavior of these elements in farm animals raised under natural conditions by local farmers are presented. Part 3 summarizes our findings to date on the distribution and mobilization of Th-232, light rare earth elements (LREE), U-238 and Ra-228 in the MF basin. Estimates of first order, present day, mobilization rate constants resulting from ground water solubilization and seepage/stream transport are calculated using revised inventory estimates for the occurrence of these elements in the ore body and annual flux estimates for the transport of these elements away from the ore body. 151 refs., 20 figs., 40 tabs.

  11. Biophysical techniques for examining metabolic, proliferative, and genetic effects of microwave radiation. Final report, 1 Oct 89-30 Aug 90

    SciTech Connect

    Meltz, M.L.

    1991-09-01

    This project was undertaken to prepare for a comprehensive research effort examining metabolic, proliferative, and genetic effects of microwave radiation. To accomplish this task, preliminary studies have been performed with 4 cells systems; Chinese hamster ovary (CHO) cells, AS52 Chinese hamster cells (heterozygous at the xanthine-guanine phosphoribosyl transferase (XGPRT) locus), 244B proliferating human lymphoblastoid cells, and freshly isolated peripheral lymphocytes. The thermal response of the 244B cells has been carefully examined, and an initial characterization of the membrane markers, membrane permeability, and cell cycle distribution of these cells undertaken. The absence of the induction of chromosome aberrations in CHO cells, after exposure to 850 MHz pulsed wave (PW), 18mW/cm2 (specific absorption rate (SAR) 14.4 W/kg) radiofrequency radiation (RFR), or after exposure to 1,200 MHz PW (220 W -300 W) net forward power; SAR 24.33 W/kg RFR, is reported. The survival response of the AS52 cells, after simultaneous treatment at 37 C or 40 C, with and without mitomycin or adriamycin, is described. The survival of the AS52 cells after X-ray exposure at low and high dose rates is also described.

  12. Dissolved organic matter and lake metabolism: biogeochemistry and controls of nutrient flux dynamics in lakes. Technical progress report, 1 July 1980-1 June 1981

    SciTech Connect

    Wetzel, R.G.

    1981-01-01

    These continuing investigations focus on integrated studies of the qualitative and quantitative cycling and metabolism of particulate and dissolved organic carbon in lakes and their inflow sources (surface and subsurface). Emphasis is placed on the sources, fates, and interactions of dissolved and particulate organic matter in relation to: inorganic chemical cycling, allochthonous loading to the lake system, and the coupled nutrient physiology and metabolism of phytoplankton, bacterial populations, macrophytes, and attendant sessile algal-bacterial communities. Regulatory mechanisms of growth and rates of carbon and nutrient cycling are being evaluated among the inorganic-organic influxes of allochthonous sources as they are controlled by wetland-littoral communities, the littoral photosynthetic producer-decomposer complex, and the microflora of the pelagial zone. The integrated studies addressing these multifaceted objectives are summarized in a detailed outline.

  13. Dissolved organic matter and lake metabolism: Biogeochemistry and controls of nutrient flux dynamics to fresh waters. Technical progress report, January 1, 1990--December 31, 1991

    SciTech Connect

    Wetzel, R.G.

    1992-12-31

    The land-water interface region consists of two major components: the wetland, and the down-gradient adjacent littoral floating-leaved and submersed, macrophyte communities. Because of the importance of very high production and nutrient turnover of attached microbiota, a major emphasis of this investigation was placed upon these biota and their metabolic capacities for assimilation and release of organic compounds and nutrient retention and cycling. Examination of the capacities of wetland littoral communities to regulate fluxes of nutrients and organic compounds often has been limited to input-output analyses. These input-output data are an integral part of these investigations, but most of the research effort concentrated on the biotic and metabolic mechanisms that control fluxes and retention capacities and their effects upon biota in the down-gradient waters. The important regulatory capacities of dissolved organic compounds on enzyme reactivity was examined experimentally and coupled to the wetland-littoral organic carbon flux budgets.

  14. Pulmonary metabolism of dibenz(a,j)acridine: a carcinogenic heterocyclic aromatic. Technical progress report, September 1, 1982-September 30, 1983

    SciTech Connect

    Warshawsky, D.

    1983-10-31

    Dibenz(a,j)acridine (D(a,j)A) is metabolized by rat liver microsomes which results in the formation of seven major metabolites. Under the present conditions of the microsomal assay, 55% of D(a,j)A is metabolized by corn oil induced microsomes in 30 minutes, whereas 80% of D(a,j)A is metabolized by 3MC induced microsomes in 60 minutes. In the presence of the 3MC induced microsomes, a metabolite in fraction 19 is produced very rapidly and disappears linearly over 60 minutes. Of the major metabolites of D(a,j)A produced by microsomal incubations metabolites in fractions 11-12, 13 and 19 are possibly the 5,6-dihydrodiol of D(a,j)A, definitely the 3,4-dihydrodiol of D(a,j)A and a phenol or epoxide respectively. BaP pretreatment of the New Zealand white rabbits doubles the rate of appearance of the metabolites of D(a,j)A in the blood in the IPL. With or without pretreatment, the major metabolites are found in fractions 13 and 19 with 70 to 80% of the activity present in the nonextractable fraction. At the end of the perfusion 50% of the D(a,j)A remains in the IPL following BaP pretreatment as compared to 72% without pretreatment. This increased rate of metabolism due to BaP pretreatment results in the appearance of more conjugated metabolites at the end of the perfusion in the mercaptan fraction.

  15. Final report, Feedback limitations of photosynthesis

    SciTech Connect

    Sharkey, Thomas D.

    1999-07-22

    Final report of research on carbon metabolism of photosynthesis. The feedback from carbon metabolism to primary photosynthetic processes is summarized, and a comprehensive list of published scientific papers is provided.

  16. Final Report

    SciTech Connect

    Callis, Judy

    2016-11-30

    This report summarizes our research activities. In the award period, we have made significant progress on the first aim, with new discoveries reported in one published paper (1) and in one submitted manuscript (2) currently under review. The published manuscript reports on our discovery of plant ribokinase and the metabolic pathway in which it functions; the submitted manuscript is identification and characterization of the plant fructokinase family of enzymes from expression studies, sequence comparisons, subcellular localizations and enzymatic activities of recombinant proteins. Our study of loss-of-function mutants in the fructokinase family members (2) revealed that there were no phenotypic differences observed for the five genes analyzed, so we have adopted the Crispr/Cas9 system to isolate mutants in the two genes for which there are no currently available insertion mutants, and we are generating higher order mutants (double, triples, etc) to discern the relative roles and significance for each fructokinase. These mutants will be an important resource to understand regulation of carbohydrate movement and catabolism in plants. As studies from others indicate, alteration of fructokinases results in changes in cell walls and vasculatures, which have importance relative to biofuel yield and quality. In the second aim, we have characterized the protein-protein interactions for the pkfB proteins FLN1 and FLN2 that are localized to chloroplast transcriptional complexes and have proposed a new model for how chloroplast transcription is regulated. This work has been submitted for publication, been revised and will be re-submitted in December 2016

  17. New paradigms for metabolic modeling of human cells.

    PubMed

    Mardinoglu, Adil; Nielsen, Jens

    2015-08-01

    Abnormalities in cellular functions are associated with the progression of human diseases, often resulting in metabolic reprogramming. GEnome-scale metabolic Models (GEMs) have enabled studying global metabolic reprogramming in connection with disease development in a systematic manner. Here we review recent work on reconstruction of GEMs for human cell/tissue types and cancer, and the use of GEMs for identification of metabolic changes occurring in response to disease development. We further discuss how GEMs can be used for the development of efficient therapeutic strategies. Finally, challenges in integration of cell/tissue models for simulation of whole body functions as well as integration of GEMs with other biological networks for generating complete cell/tissue models are presented. Copyright © 2014 Elsevier Ltd. All rights reserved.

  18. Similar Progression of Morphological and Metabolic Phenotype in R6/2 Mice with Different CAG Repeats Revealed by In Vivo Magnetic Resonance Imaging and Spectroscopy.

    PubMed

    Sawiak, Stephen J; Wood, Nigel I; Morton, A Jennifer

    2016-10-01

    Huntington's disease (HD) is caused by an unstable polyglutamine (CAG) repeat in the HD gene, whereby a CAG repeat length greater than ∼36 leads to the disease. In HD patients, longer repeats correlate with more severe disease and earlier death. This is also seen in R6/2 mice carrying repeat lengths up to ∼200. Paradoxically, R6/2 mice with repeat lengths >300 have a less aggressive phenotype and longer lifespan than those with shorter repeats. The mechanism underlying this phenomenon is unknown. To investigate the consequences of longer repeat lengths on structural changes in the brains of R6/2 mice, especially with regard to progressive atrophy. We used longitudinal in vivo magnetic resonance imaging (MRI) and spectroscopy (MRS) to compare pathological changes in two strains of R6/2 mice, one with a rapidly progressing disease (250 CAG repeats), and the other with a less aggressive phenotype (350 CAG repeats). We found significant progressive brain atrophy in both 250 and 350 CAG repeat mice, as well as changes in metabolites (glutamine/glutamate, choline and aspartate). Although similar in magnitude, atrophy in the brains of 350 CAG R6/2 mice progressed more slowly than that seen in 250 CAG mice, in line with the milder phenotype and longer lifespan. Interestingly, significant atrophy was detectable in 350 CAG mice as early as 8-12 weeks of age, although behavioural abnormalities in these mice are not apparent before 25-30 weeks. This finding fits well with human data from the PREDICT-HD and TRACK-HD project, where reductions in brain volume were found 10 years in advance of the onset of symptoms. The similar brain atrophy with a mismatch between onset of brain atrophy and behavioural phenotype in HD mice with 350 repeats will make this mouse particularly useful for modelling early stages of HD pathology.

  19. Intimal redox stress: Accelerated atherosclerosis in metabolic syndrome and type 2 diabetes mellitus. Atheroscleropathy

    PubMed Central

    Hayden, Melvin R; Tyagi, Suresh C

    2002-01-01

    Metabolic syndrome, insulin resistance, prediabetes, and overt type 2 diabetes mellitus are associated with an accelerated atherosclerosis (atheroscleropathy). This quartet is also associated with multiple metabolic toxicities resulting in the production of reactive oxygen species. The redox stress associated with these reactive oxygen species contribute to the development, progression, and the final fate of the arterial vessel wall in prediabetic and diabetic atheroscleropathy. The prevention of morbidity and mortality of these intersecting metabolic diseases can be approached through comprehensive global risk reduction. PMID:12392600

  20. Year in review 2009: Critical Care - metabolism

    PubMed Central

    2010-01-01

    Novel insights into the metabolic alterations of critical illness were published in Critical Care in 2009. The association between early hypoglycaemia/high glycemic variability and poor outcome was confirmed. Improvements in the understanding of the pathophysiological mechanisms of stress hyperglycemia and potential progress in the bedside management of glucose control were presented. With regard to enteral nutrition, some alterations of gastrointestinal physiology were better delineated. The relationship between the achievement of nutritional goals and outcomes was further investigated. Finally, understanding of some critical-illness-related endocrine and neuromuscular disorders improved through new experimental and clinical findings. PMID:21122170

  1. Structure related effects of flavonoid aglycones on cell cycle progression of HepG2 cells: Metabolic activation of fisetin and quercetin by catechol-O-methyltransferase (COMT).

    PubMed

    Poór, Miklós; Zrínyi, Zita; Kőszegi, Tamás

    2016-10-01

    Dietary flavonoids are abundant in the Plant Kingdom and they are extensively studied because of their manifold pharmacological activities. Recent studies highlighted that cell cycle arrest plays a key role in their antiproliferative effect in different tumor cells. However, structure-activity relationship of flavonoids is poorly characterized. In our study the influence of 18 flavonoid aglycones (as well as two metabolites) on cell cycle distribution was investigated. Since flavonoids are extensively metabolized by liver cells, HepG2 tumor cell line was applied, considering the potential metabolic activation/inactivation of flavonoids. Our major observations are the followings: (1) Among the tested compounds diosmetin, fisetin, apigenin, lutelin, and quercetin provoked spectacular extent of G2/M phase cell cycle arrest. (2) Inhibition of catechol-O-methyltransferase enzyme by entacapone decreased the antiproliferative effects of fisetin and quercetin. (3) Geraldol and isorhamnetin (3'-O-methylated metabolites of fisetin and quercetin, respectively) demonstrated significantly higher antiproliferative effect on HepG2 cells compared to the parent compounds. Based on these results, O-methylated flavonoid metabolites or their chemically modified derivatives may be suitable candidates of tumor therapy in the future.

  2. Metabolism throughout follicle and oocyte development in mammals.

    PubMed

    Collado-Fernandez, Esther; Picton, Helen M; Dumollard, Rémi

    2012-01-01

    Metabolic studies of mammalian embryos started with the development of in vitro culture systems more than 40 years ago. More recently, metabolic studies have begun to shed light on the requirements of growing oocytes/follicles from the earliest stages of folliculogenesis. While growing oocytes preferentially metabolise pyruvate over glucose, the somatic compartment of ovarian follicles is more glycolytic. The metabolic preferences of the oocyte are reflected in the early zygote, which becomes increasingly dependent on glycolytic energy production as development progresses to the blastocyst stage. Furthermore, the intricate metabolic relationship between each oocyte and its somatic surroundings is critical for oocyte growth and developmental competence. Measurements of amino acid turnover in bovine oocytes indicate that glutamine, arginine and leucine are consistently depleted, while alanine is produced, showing similarities with amino acid turnover in preimplantation embryos. Amino acid profiling is a good predictor of embryo quality and might also turn out to be a predictor of oocyte developmental competence. Finally, recent studies have uncovered lipid metabolism in oocytes and early embryos, suggesting that endogenous fatty acids might be used for energy production. Together, metabolic studies have revealed the multiplicity of energetic substrates used by oocytes and early embryos, and suggest that the versatility of the metabolic pathways available for energy production is key for high developmental potential. Metabolic studies of early embryos are now being applied to follicle culture, and the goal of describing the metabolome of the growing oocyte in its follicle is now very attainable.

  3. miRNA-133a-UCP2 pathway regulates inflammatory bowel disease progress by influencing inflammation, oxidative stress and energy metabolism

    PubMed Central

    Jin, Xi; Chen, Dong; Zheng, Ruo-Heng; Zhang, Hong; Chen, Yi-Peng; Xiang, Zun

    2017-01-01

    AIM To investigate the role of the miR-133a-UCP2 pathway in the pathogenesis of inflammatory bowel disease (IBD) and to explore the potential downstream mechanisms with respect to inflammation, oxidative stress and energy metabolism. METHODS C57BL/6 mice were fed dextran sulfate sodium (DSS) liquid for 7 consecutive days, followed by the administration of saline to the DSS group, UCP2 siRNA to the UCP2 group and a miR-133a mimic to the miR-133a group on days 8 and 11. Body weight, stool consistency and rectal bleeding were recorded daily, and these composed the disease activity index (DAI) score for the assessment of disease severity. After cervical dislocation was performed on day 14, the length of the colon in each mouse was measured, and colonic tissue was collected for further study, which included the following: haematoxylin and eosin staining, UCP2 and miR-133a detection by immunohistochemical staining, western blot and quantitative real-time PCR, measurement of apoptosis by TUNEL assay, and the assessment of inflammation (TNF-α, IL-1β, IL-6 and MCP1), oxidative stress (H2O2 and MDA) and metabolic parameters (ATP) by ELISA and colorimetric methods. RESULTS An animal model of IBD was successfully established, as shown by an increased DAI score, shortened colon length and specific pathologic changes, along with significantly increased UCP2 and decreased miR-133a levels. Compared with the DSS group, the severity of IBD was alleviated in the UCP2 and the miR-133a groups after successful UCP2 knockdown and miR-133a overexpression. The extent of apoptosis, as well as the levels of TNF-α, IL-1β, MDA and ATP, were significantly increased in both the UCP2 and miR-133a groups compared with the DSS group. CONCLUSION The miR-133a-UCP2 pathway participates in IBD by altering downstream inflammation, oxidative stress and markers of energy metabolism, which provides novel clues and potential therapeutic targets for IBD. PMID:28104982

  4. LncRNA ANRIL is up-regulated in nasopharyngeal carcinoma and promotes the cancer progression via increasing proliferation, reprograming cell glucose metabolism and inducing side-population stem-like cancer cells

    PubMed Central

    Zou, Zhen Wei; Ma, Charlie; Medoro, Lorraine; Chen, Lili; Wang, Bin; Gupta, Roohi; Liu, Ting; Yang, Xian Zi; Chen, Tian Tian; Wang, Ruo Zhen; Zhang, Wen Jie; Li, Pin Dong

    2016-01-01

    Long noncoding RNAs play a vital role in diverse biological processes such as embryonic development, cell growth, and tumorigenesis. In this study, we report that LncRNA ANRIL, which encodes a 3834-nt RNA that contains 19 exons at the antisense orientation of the INK4B-ARF-INK4A gene cluster, generally up-regulated in nasopharyngeal carcinoma [1]. In a cohort of 88 NPC patients, ANRIL was highly expressed in advanced-stage cancer. Multivariate analyses revealed that ANRIL expression could serve as an independent predictor of overall survival (P = 0.027) and disease-free survival (P = 0.033). Further investigation showed that knockdown of ANRIL significantly repressed NPC cell proliferation and transformation. We also found that ANRIL could induce the percentage of side population cells (SP cells) in NPC. To meet the urgent needs of energy provision, ANRIL can also reprogram glucose metabolism via increasing glucose uptake for glycolysis, which was regulated by the mTOR signal pathway to affect the expression of essential genes in glycolysis. We concluded that ANRIL could promote NPC progression via increasing cell proliferation, reprograming cell glucose metabolism and inducing side-population stem-like cancer cells. Our results also suggested that ANRIL may serve as a novel diagnostic or prognostic biomarker and a candidate target for new therapies in NPC. PMID:27557514

  5. Studies in genetic discrimination. Final progress report

    SciTech Connect

    Not Available

    1994-06-01

    We have screened 1006 respondents in a study of genetic discrimination. Analysis of these responses has produced evidence of the range of institutions engaged in genetic discrimination and demonstrates the impact of this discrimination on the respondents to the study. We have found that both ignorance and policy underlie genetic discrimination and that anti-discrimination laws are being violated.

  6. ESG-CET Final Progress Title

    SciTech Connect

    Don Middleton

    2011-10-06

    Drawing to a close after five years of funding from DOE's ASCR and BER program offices, the SciDAC-2 project called the Earth System Grid (ESG) Center for Enabling Technologies has successfully established a new capability for serving data from distributed centers. The system enables users to access, analyze, and visualize data using a globally federated collection of networks, computers and software. The ESG software - now known as the Earth System Grid Federation (ESGF) - has attracted a broad developer base and has been widely adopted so that it is now being utilized in serving the most comprehensive multi-model climate data sets in the world. The system is used to support international climate model intercomparison activities as well as high profile U.S. DOE, NOAA, NASA, and NSF projects. It currently provides more than 25,000 users access to more than half a petabyte of climate data (from models and from observations) and has enabled over a 1,000 scientific publications.

  7. Comprehensive Offender Program Effort. Final Progress Report.

    ERIC Educational Resources Information Center

    Bagley, Carole A.

    This report summarizes the year's activities of a project at two adult correctional institutions which utilized computers in their educational programs to supplement the existing GED, basic math, language arts, reading, and vocational skills and awareness curriculums. The computer is used as a supplement to the educational programs by providing…

  8. Biorefinery Demonstration Project Final Progress Report

    SciTech Connect

    Lee, David

    2015-10-20

    In this project we focused on various aspects of biorefinery technology development including algal-biorefinery technology, thermochemical conversion of biomass to bio-oils and biochar; we tested characteristics and applications of biochars and evaluated nutrient cycling with wastewater treatment by the coupling of algal culture systems and anaerobic digestion. Key results include a method for reducing water content of bio-oil through atomized alcohol addition. The effect included increasing the pH and reducing the viscosity and cloud point of the bio-oil. Low input biochar production systems were evaluated via literature reviews and direct experimental work. Additionally, emissions were evaluated and three biochar systems were compared via a life cycle analysis. Attached growth systems for both algal cultivation and algal harvesting were found to be superior to suspended growth cultures. Nutrient requirements for algal cultivation could be obtained by the recycling of anaerobic digester effluents, thus experimentally showing that these two systems could be directly coupled. Twenty-two journal articles and six intellectual property applications resulted from the cumulative work that this project contributed to programmatically.

  9. Innovative conservation housing. Final progress report

    SciTech Connect

    Nuttle, D.A.

    1983-01-01

    A new passive solar thermal storage brick was developed and tested. A new insulating curtain concept was developed to assist in passive solar heating and cooling. A steel truss was designed to replace the wood truss in solar attic applications where the wood truss typically suffers some 50% loss of structural strength. Improvements were made of the dry composting toilet and grey water recycling for homes. An algae cultivation system was created for production of food, feed, fertilizer, or biomass as needed for home, farm, or industry. New concepts were explored in the areas of economy shelter, solar hot water heating, home generation of electricity, edible landscapes and other home food production, growing of fiber crops for cottage industry, storage, insulation, solar cooking, and solar refrigeration. (LEW)

  10. Water & Aqueous Solutions. Final Progress Report

    SciTech Connect

    2002-08-09

    The Gordon Research Conference (GRC) on Water & Aqueous Solutions was held at Holderness School, New Hampshire, 8/4/02 thru 8/9/02. Emphasis was placed on current unpublished research and discussion of the future target areas in this field.

  11. Electron Donor Acceptor Interactions. Final Progress Report

    SciTech Connect

    2002-08-16

    The Gordon Research Conference (GRC) on Electron Donor Acceptor Interactions was held at Salve Regina University, Newport, Rhode Island, 8/11-16/02. Emphasis was placed on current unpublished research and discussion of the future target areas in this field.

  12. Chemical Reactions at Surfaces. Final Progress Report

    SciTech Connect

    2003-02-21

    The Gordon Research Conference (GRC) on Chemical Reactions at Surfaces was held at Holiday Inn, Ventura, California, 2/16-21/03. Emphasis was placed on current unpublished research and discussion of the future target areas in this field.

  13. White coat hypertension in definition of metabolic syndrome.

    PubMed

    Helvaci, Mehmet Rami; Kaya, Hasan; Seyhanli, Mahmut; Yalcin, Atilla

    2008-07-01

    Although white coat hypertension (WCH) is believed to have an effect on health, there is no term defining WCH in metabolic syndrome. Consecutive patients 20 years old or older who underwent a check-up were included. The study included 1068 cases. The prevalences of hyperbetalipoproteinemia, hypertriglyceridemia, dyslipidemia, impaired glucose tolerance (IGT), and WCH were similar to excess weight in that they increased significantly until the seventh decade of life and decreased thereafter significantly (P < 0.05 in most steps). On the other hand, the prevalences of hypertension (HT), diabetes mellitus (DM), and coronary heart disease (CHD) always increased significantly with age without any decrease (P < 0.05 in most steps), indicating their irreversibility in contrast to the reversibility of excess weight, hyperbetalipoproteinemia, hypertriglyceridemia, dyslipidemia, IGT, and WCH. Metabolic syndrome is a reversible progression step between health and irreversible final diseases terminating with increased mortality and disabilities. Thus, the definition of metabolic syndrome should include reversible metabolic risk factors such as excess weight (overweight and obesity), hyperbetalipoproteinemia, hypertriglyceridemia, dyslipidemia, IGT, and WCH, instead of irrevesible diseases such as DM, HT, CHD, and stroke that have already developed and require drug therapy. After development of one of the final metabolic diseases, the term metabolic syndrome probably loses most of its significance, since from that point on, nonpharmaceutical approaches such as lifestyle changes, diet, and exercise will provide little benefit to prevent development of the others, most likely due to the cumulative effects of the risk factors on body systems over a long period of time.

  14. Epigenetics and Cellular Metabolism

    PubMed Central

    Xu, Wenyi; Wang, Fengzhong; Yu, Zhongsheng; Xin, Fengjiao

    2016-01-01

    Living eukaryotic systems evolve delicate cellular mechanisms for responding to various environmental signals. Among them, epigenetic machinery (DNA methylation, histone modifications, microRNAs, etc.) is the hub in transducing external stimuli into transcriptional response. Emerging evidence reveals the concept that epigenetic signatures are essential for the proper maintenance of cellular metabolism. On the other hand, the metabolite, a main environmental input, can also influence the processing of epigenetic memory. Here, we summarize the recent research progress in the epigenetic regulation of cellular metabolism and discuss how the dysfunction of epigenetic machineries influences the development of metabolic disorders such as diabetes and obesity; then, we focus on discussing the notion that manipulating metabolites, the fuel of cell metabolism, can function as a strategy for interfering epigenetic machinery and its related disease progression as well. PMID:27695375

  15. Rapidly Progressive Dementia

    PubMed Central

    Geschwind, Michael D.; Shu, Huidy; Haman, Aissa; Sejvar, James J.; Miller, Bruce L.

    2009-01-01

    In contrast with more common dementing conditions that typically develop over years, rapidly progressive dementias can develop subacutely over months, weeks, or even days and be quickly fatal. Because many rapidly progressive dementias are treatable, it is paramount to evaluate and diagnose these patients quickly. This review summarizes recent advances in the understanding of the major categories of RPD and outlines efficient approaches to the diagnosis of the various neurodegenerative, toxic-metabolic, infectious, autoimmune, neoplastic, and other conditions that may progress rapidly. PMID:18668637

  16. Rosetta: The Final Furlong

    NASA Astrophysics Data System (ADS)

    Wright, I. P.; Andrews, D. J.; Barber, S. J.; Sheridan, S.; Morgan, G. H.; Morse, A. D.

    2014-09-01

    By the time of the meeting, the Rosetta spacecraft will have formally arrived at its target comet, and final landing site selection will be in progress. One of the instruments that will be sent down to the surface of the comet is Ptolemy (a GC-MS).

  17. Lipid metabolic reprogramming in cancer cells

    PubMed Central

    Beloribi-Djefaflia, S; Vasseur, S; Guillaumond, F

    2016-01-01

    Many human diseases, including metabolic, immune and central nervous system disorders, as well as cancer, are the consequence of an alteration in lipid metabolic enzymes and their pathways. This illustrates the fundamental role played by lipids in maintaining membrane homeostasis and normal function in healthy cells. We reviewed the major lipid dysfunctions occurring during tumor development, as determined using systems biology approaches. In it, we provide detailed insight into the essential roles exerted by specific lipids in mediating intracellular oncogenic signaling, endoplasmic reticulum stress and bidirectional crosstalk between cells of the tumor microenvironment and cancer cells. Finally, we summarize the advances in ongoing research aimed at exploiting the dependency of cancer cells on lipids to abolish tumor progression. PMID:26807644

  18. Energetics of end product excretion in anaerobic bacteria and the metabolism of fatty acids by Syntrophomonas wolfei: Progress report, November 16, 1986-November 15, 1987

    SciTech Connect

    McInerney, M.J.

    1987-01-01

    We have studied the growth and metabolism of Syntrophomonas wolfei in pure culture with crotonate as the energy source. S. wolfei grows in crotonate mineral salts medium without rumen fluid with cobalamin, thymine, lipoic acid and biotin added. However, after four to six transfers in this medium, growth ceases, indicating that another vitamin is required. The chemically defined medium allows large batches of S. wolfei to be grown for enzyme purification. All the enzymes involved in the oxidation of crotonyl-CoA to acetate have been detected. The pure culture of S. wolfei or coculture of S. wolfei grown with crotonate contain high activities of a crotonate: acetyl-CoA CoA-transferase activity. This activity is not detected in cocultures grown with butyrate. Thus, we believe that the reason why S. wolfei can now grow with crotonate is that an alteration or mutation occurred which allows the organism to activate this crotonate. S. wolfei also makes small amounts of H/sub 2/ when grown in pure culture with crotonate. A methyl viologen-dependent hydrogenase activity was found. We have also demonstrated the production of H/sub 2/ from 3-hydroxybutyryl-CoA in cell-free extracts of S. wolfei by coupling H/sub 2/ production to CH/sub 4/ production with the addition of Methanobacterium bryantii and directly using a hydrogen electrode. These results clearly show that S. wolfei makes H/sub 2/. S. wolfei does not contain formate dehydrogenase or CO dehydrogenase activities.

  19. The male sterility 8 mutation of maize disrupts the temporal progression of the transcriptome and results in mis-regulation of metabolic functions

    PubMed Central

    Wang, Dongxue; Oses-Prieto, Juan A.; Li, Kathy H.; Fernandes, John F.; Burlingame, Alma L.; Walbot, Virginia

    2010-01-01

    SUMMARY Maize anther ontogeny is complex with expression of more than 30,000 genes over four days of cell proliferation, cell fate acquisition, and the start of meiosis. Although many male-sterile mutants disrupt these key steps, few have been investigated in detail. The terminal phenotypes of maize male-sterile 8 (ms8) are small anthers exhibiting meiotic failure. Here we document much earlier defects: ms8 epidermal cells are normal in number but fail to elongate, and there are fewer, larger tapetal cells that retain rather than secrete their contents. ms8 meiocytes separate early, have extra space between them occupied by excess callose, and the meiotic dyads abort. Thousands of transcriptome changes occur in ms8 including ectopic activation of genes not expressed in fertile siblings, failure to express some genes, differential expression compared to fertile siblings and about 40% of the differentially expressed transcripts appear precociously. There is a high correlation between mRNA accumulation assessed by microarray hybridization and qRT-PCR. Sixty-three differentially expressed proteins were identified after 2-D gel electrophoresis followed by LC/MS/MS (liquid chromatography tandem mass spectroscopy), including those involved in metabolism, plasmodesmatal remodeling, and cell division. The majority of these were not identified by differential RNA expression demonstrating the importance of proteomics to define developmental mutants. PMID:20626649

  20. Energetics of end product excretion in anaerobic bacteria and the metabolism of fatty acids by Syntrophomonas wolfei. Progress report, January 31-December 15, 1985

    SciTech Connect

    McInerney, M.J.

    1985-01-01

    This work addresses the metabolism of fatty acids and the energetics of growth of the anaerobic, syntrophic, fatty acid-degrading bacterium, Syntrophomonas wolfei. S. wolfei degrades C/sub 4/ to C/sub 8/ straight chain fatty acids to acetate and H/sub 2/ or acetate, propionate and H/sub 2/; isoheptanoate is degraded to isovalerate, acetate, and H/sub 2/. S. wolfei can not use any common bacterial energy source that will allow it to grow in pure culture. A significant breakthrough in the cultivation of S. wolfei was achieved. Long term (3 months) incubation of S. wolfei cocultures in medium with crotonate selects for a population of S. wolfei cells that can use this compound. These cultures contain large numbers of S. wolfei cells and very few cells of the methanogen. Pure cultures of S. wolfei do not use butyrate. However, when pure cultures of S. wolfei are incubated in the presence of H/sub 2/-using bacteria, butyrate is degraded to acetate and H/sub 2/. These data show that the cells present in the pure cultures are in fact S. wolfei. Growth of S. wolfei with crotonate is faster and much higher cell densities are obtained. Thus, large amounts of cell material will be available for biochemical studies. 3 refs.

  1. Hepatic diseases related to triglyceride metabolism.

    PubMed

    Aguilera-Méndez, Asdrubal; Álvarez-Delgado, Carolina; Hernández-Godinez, Daniel; Fernandez-Mejia, Cristina

    2013-10-01

    Triglycerides participate in key metabolic functions such as energy storage, thermal insulation and as deposit for essential and non-essential fatty acids that can be used as precursors for the synthesis of structural and functional phospholipids. The liver is a central organ in the regulation of triglyceride metabolism, and it participates in triglyceride synthesis, export, uptake and oxidation. The metabolic syndrome and associated diseases are among the main concerns of public health worldwide. One of the metabolic syndrome components is impaired triglyceride metabolism. Diseases associated with the metabolic syndrome promote the appearance of hepatic alterations e.g., non-alcoholic steatosis, steatohepatitis, fibrosis, cirrhosis and cancer. In this article, we review the molecular actions involved in impaired triglyceride metabolism and its association with hepatic diseases. We discuss mechanisms that reconcile the chronic inflammation and insulin resistance, and new concepts on the role of intestinal micro-flora permeability and proliferation in fatty liver etiology. We also describe the participation of oxidative stress in the progression of events leading from steatosis to steatohepatitis and fibrosis. Finally, we provide information regarding the mechanisms that link fatty acid accumulation during steatosis with changes in growth factors and cytokines that lead to the development of neoplastic cells. One of the main medical concerns vis-a-vis hepatic diseases is the lack of symptoms at the onset of the illness and, as result, its late diagnosis. The understandings of the molecular mechanisms that underlie hepatic diseases could help design strategies towards establishing markers for their accurate and timely diagnosis.

  2. Fundamentals of cancer metabolism

    PubMed Central

    DeBerardinis, Ralph J.; Chandel, Navdeep S.

    2016-01-01

    Tumors reprogram pathways of nutrient acquisition and metabolism to meet the bioenergetic, biosynthetic, and redox demands of malignant cells. These reprogrammed activities are now recognized as hallmarks of cancer, and recent work has uncovered remarkable flexibility in the specific pathways activated by tumor cells to support these key functions. In this perspective, we provide a conceptual framework to understand how and why metabolic reprogramming occurs in tumor cells, and the mechanisms linking altered metabolism to tumorigenesis and metastasis. Understanding these concepts will progressively support the development of new strategies to treat human cancer. PMID:27386546

  3. Fundamentals of cancer metabolism.

    PubMed

    DeBerardinis, Ralph J; Chandel, Navdeep S

    2016-05-01

    Tumors reprogram pathways of nutrient acquisition and metabolism to meet the bioenergetic, biosynthetic, and redox demands of malignant cells. These reprogrammed activities are now recognized as hallmarks of cancer, and recent work has uncovered remarkable flexibility in the specific pathways activated by tumor cells to support these key functions. In this perspective, we provide a conceptual framework to understand how and why metabolic reprogramming occurs in tumor cells, and the mechanisms linking altered metabolism to tumorigenesis and metastasis. Understanding these concepts will progressively support the development of new strategies to treat human cancer.

  4. Cell signalling and phospholipid metabolism. Final report

    SciTech Connect

    Boss, W.F.

    1990-12-31

    These studies explored whether phosphoinositide (PI) has a role in plants analogous to its role in animal cells. Although no parallel activity of PI in signal transduction was found in plant cells, activity of inositol phospholipid kinase was found to be modulated by light and by cell wall degrading enzymes. These studies indicate a major role for inositol phospholipids in plant growth and development as membrane effectors but not as a source of second messengers.

  5. Metabolic Networks of Sodalis glossinidius: A Systems Biology Approach to Reductive Evolution

    PubMed Central

    Belda, Eugeni; Silva, Francisco J.; Peretó, Juli; Moya, Andrés

    2012-01-01

    Background Genome reduction is a common evolutionary process affecting bacterial lineages that establish symbiotic or pathogenic associations with eukaryotic hosts. Such associations yield highly reduced genomes with greatly streamlined metabolic abilities shaped by the type of ecological association with the host. Sodalis glossinidius, the secondary endosymbiont of tsetse flies, represents one of the few complete genomes available of a bacterium at the initial stages of this process. In the present study, genome reduction is studied from a systems biology perspective through the reconstruction and functional analysis of genome-scale metabolic networks of S. glossinidius. Results The functional profile of ancestral and extant metabolic networks sheds light on the evolutionary events underlying transition to a host-dependent lifestyle. Meanwhile, reductive evolution simulations on the extant metabolic network can predict possible future evolution of S. glossinidius in the context of genome reduction. Finally, knockout simulations in different metabolic systems reveal a gradual decrease in network robustness to different mutational events for bacterial endosymbionts at different stages of the symbiotic association. Conclusions Stoichiometric analysis reveals few gene inactivation events whose effects on the functionality of S. glossinidius metabolic systems are drastic enough to account for the ecological transition from a free-living to host-dependent lifestyle. The decrease in network robustness across different metabolic systems may be associated with the progressive integration in the more stable environment provided by the insect host. Finally, reductive evolution simulations reveal the strong influence that external conditions exert on the evolvability of metabolic systems. PMID:22292008

  6. How does cancer cell metabolism affect tumor migration and invasion?

    PubMed

    Han, Tianyu; Kang, De; Ji, Daokun; Wang, Xiaoyu; Zhan, Weihua; Fu, Minggui; Xin, Hong-Bo; Wang, Jian-Bin

    2013-01-01

    Cancer metastasis is the major cause of cancer-associated death. Accordingly, identification of the regulatory mechanisms that control whether or not tumor cells become "directed walkers" is a crucial issue of cancer research. The deregulation of cell migration during cancer progression determines the capacity of tumor cells to escape from the primary tumors and invade adjacent tissues to finally form metastases. The ability to switch from a predominantly oxidative metabolism to glycolysis and the production of lactate even when oxygen is plentiful is a key characteristic of cancer cells. This metabolic switch, known as the Warburg effect, was first described in 1920s, and affected not only tumor cell growth but also tumor cell migration. In this review, we will focus on the recent studies on how cancer cell metabolism affects tumor cell migration and invasion. Understanding the new aspects on molecular mechanisms and signaling pathways controlling tumor cell migration is critical for development of therapeutic strategies for cancer patients.

  7. Final Results of the IELSG-19 Randomized Trial of Mucosa-Associated Lymphoid Tissue Lymphoma: Improved Event-Free and Progression-Free Survival With Rituximab Plus Chlorambucil Versus Either Chlorambucil or Rituximab Monotherapy.

    PubMed

    Zucca, Emanuele; Conconi, Annarita; Martinelli, Giovanni; Bouabdallah, Reda; Tucci, Alessandra; Vitolo, Umberto; Martelli, Maurizio; Pettengell, Ruth; Salles, Gilles; Sebban, Catherine; Guillermo, Armando Lopez; Pinotti, Graziella; Devizzi, Liliana; Morschhauser, Franck; Tilly, Hervé; Torri, Valter; Hohaus, Stefan; Ferreri, Andrés J M; Zachée, Pierre; Bosly, André; Haioun, Corinne; Stelitano, Caterina; Bellei, Monica; Ponzoni, Maurilio; Copie-Bergman, Christiane; Jack, Andrew; Campo, Elias; Mazzucchelli, Luca; Cavalli, Franco; Johnson, Peter; Thieblemont, Catherine

    2017-03-29

    Purpose There is no consensus on the optimal systemic treatment of patients with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue. The IELSG-19 phase III study, to our knowledge, was the first such study to address the question of first-line treatment in a randomized trial. Patients and Methods Eligible patients were initially randomly assigned (1:1 ratio) to receive either chlorambucil monotherapy (6 mg/m(2)/d orally on weeks 1 to 6, 9 to 10, 13 to 14, 17 to 18, and 21 to 22) or a combination of chlorambucil (same schedule as above) and rituximab (375 mg/m(2) intravenously on day 1 of weeks 1, 2, 3, 4, 9, 13, 17, and 21). After the planned enrollment of 252 patients, the protocol was amended to continue with a three-arm design (1:1:6 ratio), with a new arm that included rituximab alone (same schedule as the combination arm) and with a final sample size of 454 patients. The main end point was event-free survival (EFS). Analysis of chlorambucil versus the combination arm was performed and reported separately before any analysis of the third arm. Results At a median follow-up of 7.4 years, addition of rituximab to chlorambucil led to significantly better EFS (hazard ratio, 0.54; 95% CI, 0.38 to 0.77). EFS at 5 years was 51% (95% CI, 42 to 60) with chlorambucil alone, 50% (95% CI, 42 to 59) with rituximab alone, and 68% (95% CI, 60 to 76) with the combination ( P = .0009). Progression-free survival was also significantly better with the combination ( P = .0119). Five-year overall survival was approximately 90% in each arm. All treatments were well tolerated. No unexpected toxicities were recorded. Conclusion Rituximab in combination with chlorambucil demonstrated superior efficacy in mucosa-associated lymphoid tissue lymphoma; however, improvements in EFS and progression-free survival did not translate into longer overall survival.

  8. Synthetic metabolism: metabolic engineering meets enzyme design.

    PubMed

    Erb, Tobias J; Jones, Patrik R; Bar-Even, Arren

    2017-04-01

    Metabolic engineering aims at modifying the endogenous metabolic network of an organism to harness it for a useful biotechnological task, for example, production of a value-added compound. Several levels of metabolic engineering can be defined and are the topic of this review. Basic 'copy, paste and fine-tuning' approaches are limited to the structure of naturally existing pathways. 'Mix and match' approaches freely recombine the repertoire of existing enzymes to create synthetic metabolic networks that are able to outcompete naturally evolved pathways or redirect flux toward non-natural products. The space of possible metabolic solution can be further increased through approaches including 'new enzyme reactions', which are engineered on the basis of known enzyme mechanisms. Finally, by considering completely 'novel enzyme chemistries' with de novo enzyme design, the limits of nature can be breached to derive the most advanced form of synthetic pathways. We discuss the challenges and promises associated with these different metabolic engineering approaches and illuminate how enzyme engineering is expected to take a prime role in synthetic metabolic engineering for biotechnology, chemical industry and agriculture of the future. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  9. Progressive hemifacial atrophy

    PubMed Central

    Sande, Abhijeet; Risbud, Mukund; Kshar, Avinash; Paranjpe, Arati Oka

    2013-01-01

    Progressive hemifacial atrophy, also known as Parry-Romberg Syndrome, is an uncommon degenerative and poorly understood condition. It is characterized by a slow and progressive but self-limited atrophy affecting one side of the face. The incidence and the cause of this alteration are unknown. A cerebral disturbance of fat metabolism has been proposed as a primary cause. Possible factors that are involved in the pathogenesis include trauma, viral infections, heredity, endocrine disturbances and auto-immunity. The most common complications that appear in association to this disorder are: trigeminal neuralgia, facial paresthesia, severe headache and epilepsy. Characteristically, the atrophy progresses slowly for several years and, it becomes stable. The objective of this work is, through the presentation of a clinical case, to accomplish a literature review concerning general characteristics, etiology, physiopathology and treatment of progressive hemifacial atrophy. PMID:23878573

  10. Final Report

    SciTech Connect

    Normanly, J.

    1999-11-29

    The primary goal was the characterization of tryptophan (Trp)-independent biosynthesis of the auxin indole-3-acetic acid (IAA). Our work and that of others indicates that indole is a precursor to IAA in a Trp-independent pathway and the objectives of this grant have been the isolation of indole-metabolizing genes from Arabidopsis.

  11. Transcriptome atlas of aromatic amino acid family metabolism-related genes in eight liver cell types uncovers the corresponding metabolic pathways in rat liver regeneration.

    PubMed

    Chang, Cuifang; Xu, CunShuan

    2010-10-01

    To explore gene expression of aromatic amino acid family metabolism and their metabolic pathways of eight liver cell types in rat liver regeneration, eight kinds of rat regenerating liver cells were isolated by using the combination of percoll density gradient centrifugation and immunomagnetic bead methods. Rat Genome 230 2.0 Array was used to detect the expression changes of genes associated with aromatic amino acid family metabolism. The transcriptome atlas showed that the metabolic pathway of phenylalanine was mainly catalyzed into tyrosine in hepatic stellate cells in the initiation stage, tyrosine was oxidized into dopa and norepinephrine in biliary epithelia cells and dendritic cells, and norepinephrine was finally catalyzed into adrenaline in biliary epithelia cells and pit cells in the progress stage. Thyroid hormone of tyrosine catabolites was synthesized from tyrosine in almost all cells in different stage of LR, among which genes of T3 biosynthesis were increased in HCs, BECs, SECs and DCs in the progress stage. Tryptophan was decarboxylated to 5-hydroxytryptamine in dendritic cells in the progress stage. Based on the results as above, we concluded that phenylalanine is the major source of tyrosine, proliferation of biliary epithelia cells and dendritic cells maybe promote by tyrosine catabolites-dopa and norepinephrine, biliary epithelia cells and pit cells maybe promote by adrenaline. T3 maybe play a major role on proliferation of HCs, BECs, SECs and DCs in the progress stage. The proliferation of dendritic cells maybe promote by tryptophan catabolites-5-hydroxytryptamine. Copyright 2010. Published by Elsevier Ltd.

  12. The gut microbiota modulates host amino acid and glutathione metabolism in mice

    PubMed Central

    Mardinoglu, Adil; Shoaie, Saeed; Bergentall, Mattias; Ghaffari, Pouyan; Zhang, Cheng; Larsson, Erik; Bäckhed, Fredrik; Nielsen, Jens

    2015-01-01

    The gut microbiota has been proposed as an environmental factor that promotes the progression of metabolic diseases. Here, we investigated how the gut microbiota modulates the global metabolic differences in duodenum, jejunum, ileum, colon, liver, and two white adipose tissue depots obtained from conventionally raised (CONV-R) and germ-free (GF) mice using gene expression data and tissue-specific genome-scale metabolic models (GEMs). We created a generic mouse metabolic reaction (MMR) GEM, reconstructed 28 tissue-specific GEMs based on proteomics data, and manually curated GEMs for small intestine, colon, liver, and adipose tissues. We used these functional models to determine the global metabolic differences between CONV-R and GF mice. Based on gene expression data, we found that the gut microbiota affects the host amino acid (AA) metabolism, which leads to modifications in glutathione metabolism. To validate our predictions, we measured the level of AAs and N-acetylated AAs in the hepatic portal vein of CONV-R and GF mice. Finally, we simulated the metabolic differences between the small intestine of the CONV-R and GF mice accounting for the content of the diet and relative gene expression differences. Our analyses revealed that the gut microbiota influences host amino acid and glutathione metabolism in mice. PMID:26475342

  13. Final Report

    SciTech Connect

    Gurney, Kevin R.

    2015-01-12

    This document constitutes the final report under DOE grant DE-FG-08ER64649. The organization of this document is as follows: first, I will review the original scope of the proposed research. Second, I will present the current draft of a paper nearing submission to Nature Climate Change on the initial results of this funded effort. Finally, I will present the last phase of the research under this grant which has supported a Ph.D. student. To that end, I will present the graduate student’s proposed research, a portion of which is completed and reflected in the paper nearing submission. This final work phase will be completed in the next 12 months. This final workphase will likely result in 1-2 additional publications and we consider the results (as exemplified by the current paper) high quality. The continuing results will acknowledge the funding provided by DOE grant DE-FG-08ER64649.

  14. Final Report

    SciTech Connect

    DeTar, Carleton

    2012-12-10

    This document constitutes the Final Report for award DE-FC02-06ER41446 as required by the Office of Science. It summarizes accomplishments and provides copies of scientific publications with significant contribution from this award.

  15. Dysregulated metabolism contributes to oncogenesis

    PubMed Central

    Hirschey, Matthew D.; DeBerardinis, Ralph J.; Diehl, Anna Mae E.; Drew, Janice E.; Frezza, Christian; Green, Michelle F.; Jones, Lee W.; Ko, Young H.; Le, Anne; Lea, Michael A.; Locasale, Jason W.; Longo, Valter D.; Lyssiotis, Costas A.; McDonnell, Eoin; Mehrmohamadi, Mahya; Michelotti, Gregory; Muralidhar, Vinayak; Murphy, Michael P.; Pedersen, Peter L.; Poore, Brad; Raffaghello, Lizzia; Rathmell, Jeffrey C.; Sivanand, Sharanya; Vander Heiden, Matthew G.; Wellen, Kathryn E.

    2015-01-01

    Cancer is a disease characterized by unrestrained cellular proliferation. In order to sustain growth, cancer cells undergo a complex metabolic rearrangement characterized by changes in metabolic pathways involved in energy production and biosynthetic processes. The relevance of the metabolic transformation of cancer cells has been recently included in the updated version of the review “Hallmarks of Cancer”, where the dysregulation of cellular metabolism was included as an emerging hallmark. While several lines of evidence suggest that metabolic rewiring is orchestrated by the concerted action of oncogenes and tumor suppressor genes, in some circumstances altered metabolism can play a primary role in oncogenesis. Recently, mutations of cytosolic and mitochondrial enzymes involved in key metabolic pathways have been associated with hereditary and sporadic forms of cancer. Together, these results suggest that aberrant metabolism, once seen just as an epiphenomenon of oncogenic reprogramming, plays a key role in oncogenesis with the power to control both genetic and epigenetic events in cells. In this review, we discuss the relationship between metabolism and cancer, as part of a larger effort to identify a broad-spectrum of therapeutic approaches. We focus on major alterations in nutrient metabolism and the emerging link between metabolism and epigenetics. Finally, we discuss potential strategies to manipulate metabolism in cancer and tradeoffs that should be considered. More research on the suite of metabolic alterations in cancer holds the potential to discover novel approaches to treat it. PMID:26454069

  16. Dysregulated metabolism contributes to oncogenesis.

    PubMed

    Hirschey, Matthew D; DeBerardinis, Ralph J; Diehl, Anna Mae E; Drew, Janice E; Frezza, Christian; Green, Michelle F; Jones, Lee W; Ko, Young H; Le, Anne; Lea, Michael A; Locasale, Jason W; Longo, Valter D; Lyssiotis, Costas A; McDonnell, Eoin; Mehrmohamadi, Mahya; Michelotti, Gregory; Muralidhar, Vinayak; Murphy, Michael P; Pedersen, Peter L; Poore, Brad; Raffaghello, Lizzia; Rathmell, Jeffrey C; Sivanand, Sharanya; Vander Heiden, Matthew G; Wellen, Kathryn E

    2015-12-01

    Cancer is a disease characterized by unrestrained cellular proliferation. In order to sustain growth, cancer cells undergo a complex metabolic rearrangement characterized by changes in metabolic pathways involved in energy production and biosynthetic processes. The relevance of the metabolic transformation of cancer cells has been recently included in the updated version of the review "Hallmarks of Cancer", where dysregulation of cellular metabolism was included as an emerging hallmark. While several lines of evidence suggest that metabolic rewiring is orchestrated by the concerted action of oncogenes and tumor suppressor genes, in some circumstances altered metabolism can play a primary role in oncogenesis. Recently, mutations of cytosolic and mitochondrial enzymes involved in key metabolic pathways have been associated with hereditary and sporadic forms of cancer. Together, these results demonstrate that aberrant metabolism, once seen just as an epiphenomenon of oncogenic reprogramming, plays a key role in oncogenesis with the power to control both genetic and epigenetic events in cells. In this review, we discuss the relationship between metabolism and cancer, as part of a larger effort to identify a broad-spectrum of therapeutic approaches. We focus on major alterations in nutrient metabolism and the emerging link between metabolism and epigenetics. Finally, we discuss potential strategies to manipulate metabolism in cancer and tradeoffs that should be considered. More research on the suite of metabolic alterations in cancer holds the potential to discover novel approaches to treat it.

  17. (Regulation of terpene metabolism. ) Progress report

    SciTech Connect

    Croteau, R.

    1984-01-01

    This research program represents a very broad-based approach to understanding the biochemistry of the monoterpene and sesquiterpene constituents of the essential oils. This program includes basic research on the pathways, enzymes and mechanisms of terpene biosynthesis and catabolism, on the physiology of essential oil production, and on the morphology and development of oil glands, as well as practical approaches to manipulating essential oil composition and yield. As a natural extension of research on monoterpene biosynthesis and catabolism in sage and peppermint we have explored some aspects of possible regulatory mechanisms. Tentative evidence has been obtained for developmental regulation of the levels of biosynthetic and catabolic enzymes. 10 refs., 8 figs.

  18. Metabolic Constraints on the Eukaryotic Transition

    NASA Astrophysics Data System (ADS)

    Wallace, Rodrick

    2009-04-01

    Mutualism, obligate mutualism, symbiosis, and the eukaryotic ‘fusion’ of Serial Endosymbiosis Theory represent progressively more rapid and less distorted real-time communication between biological structures instantiating information sources. Such progression in accurate information transmission requires, in turn, progressively greater channel capacity that, through the homology between information source uncertainty and free energy density, requires ever more energetic metabolism. The eukaryotic transition, according to this model, may have been entrained by an ecosystem resilience shift from anaerobic to aerobic metabolism.

  19. Hepatitic inherited metabolic disorders.

    PubMed

    Arroyo, May; Crawford, James M

    2006-01-01

    Primary metabolic disorders are a disparate group of diseases that may or may not be accompanied by hepatic manifestations. Those with liver involvement may show a range of histopathologic changes. Proper histologic diagnosis requires correlation with clinical and laboratory data, including evaluation for mutations either via serum protein electrophoresis or through formal genetic analysis. This article is a review of the three most common inherited metabolic disorders which may present with a hepatitic pattern. In alpha1-antitrypsin disorder, there is a broad range of clinical presentations, age at presentation, and histological features ranging from "neonatal hepatitis" to a chronic progressive hepatitis in later childhood and adulthood. Hence, this disorder must be in the differential diagnosis of liver disease of the very young, and in older children and adults, with or without coexistent overt pulmonary symptoms. In Wilson disease, presentation tends to be in older childhood or the adult, with a progressive chronic hepatitis. Cystic fibrosis may feature a characteristic obstructive biliary syndrome, coexisting with the many extrahepatic manifestations of this debilitating disease. Lastly, the progressive familial intrahepatic cholestasis (PFIC) syndromes are given as examples of inherited metabolic conditions in which relentlessly progressive cholestatic liver disease eventuates over years in end-stage cholestatic liver disease with cirrhosis. Distinguishing features include absence of elevated serum gamma-glutamyl transpeptidase (GGT) in PFIC-1 and PFIC-2, and elevated GGT in PFIC-3. However, molecular studies are required for a confident diagnosis of the rare PFIC syndromes.

  20. Metabolic syndrome as a peculiar target for management of prostate cancer patients.

    PubMed

    Conteduca, Vincenza; Di Lorenzo, Giuseppe; Bozza, Giovanni; Ardito, Raffaele; Aieta, Michele

    2013-09-01

    An interesting and reciprocal association between the metabolic syndrome and prostate cancer has been identified. Metabolic alterations, such as hyperinsulinemia, increased levels of insulin growth factor-1, and insulin resistance could be on the basis of development and progression of many tumors, including prostate cancer, and changes in body composition, in turn, can represent some side effects of androgen deprivation therapy and novel drugs, such as mammalian target of rapamycin inhibitors. This review evaluates this interrelation between metabolic syndrome and prostate tumor scanning in many clinical and preclinical epidemiological studies and describes possible pathogenetic biological mechanisms. Finally, this article discusses feasible clinical implications for the management, prevention, diagnosis, prognosis, and treatment of patients affected by metabolic syndrome and prostate cancer, with particular attention to the metformin action. Copyright © 2013 Elsevier Inc. All rights reserved.

  1. Progress in physiological optics.

    PubMed

    Boynton, R M

    1967-08-01

    A survey is made of the current state of physiological optics, broadly defined as equated with visual science. After a survey of some historical and definitional matters, recent progress in a number of areas is critically reviewed. Finally, seven examples of important recent discoveries in physiological optics are given.

  2. Discovery of Metabolite Biomarkers for Acute Ischemic Stroke Progression.

    PubMed

    Liu, Peifang; Li, Ruiting; Antonov, Anton A; Wang, Lihua; Li, Wei; Hua, Yunfei; Guo, Huimin; Wang, Lijuan; Liu, Peijia; Chen, Lixia; Tian, Yuan; Xu, Fengguo; Zhang, Zunjian; Zhu, Yulan; Huang, Yin

    2017-02-03

    Stroke remains a major public health problem worldwide; it causes severe disability and is associated with high mortality rates. However, early diagnosis of stroke is difficult, and no reliable biomarkers are currently established. In this study, mass-spectrometry-based metabolomics was utilized to characterize the metabolic features of the serum of patients with acute ischemic stroke (AIS) to identify novel sensitive biomarkers for diagnosis and progression. First, global metabolic profiling was performed on a training set of 80 human serum samples (40 cases and 40 controls). The metabolic profiling identified significant alterations in a series of 26 metabolites with related metabolic pathways involving amino acid, fatty acid, phospholipid, and choline metabolism. Subsequently, multiple algorithms were run on a test set consisting of 49 serum samples (26 cases and 23 controls) to develop different classifiers for verifying and evaluating potential biomarkers. Finally, a panel of five differential metabolites, including serine, isoleucine, betaine, PC(5:0/5:0), and LysoPE(18:2), exhibited potential to differentiate AIS samples from healthy control samples, with area under the receiver operating characteristic curve values of 0.988 and 0.971 in the training and test sets, respectively. These findings provided insights for the development of new diagnostic tests and therapeutic approaches for AIS.

  3. Metabolic control of signalling pathways and metabolic auto-regulation.

    PubMed

    Lorendeau, Doriane; Christen, Stefan; Rinaldi, Gianmarco; Fendt, Sarah-Maria

    2015-08-01

    Metabolic alterations have emerged as an important hallmark in the development of various diseases. Thus, understanding the complex interplay of metabolism with other cellular processes such as cell signalling is critical to rationally control and modulate cellular physiology. Here, we review in the context of mammalian target of rapamycin, AMP-activated protein kinase and p53, the orchestrated interplay between metabolism and cellular signalling as well as transcriptional regulation. Moreover, we discuss recent discoveries in auto-regulation of metabolism (i.e. how metabolic parameters such as metabolite levels activate or inhibit enzymes and thus metabolic pathways). Finally, we review functional consequences of post-translational modification on metabolic enzyme abundance and/or activities.

  4. Effective date of requirement for premarket approval for transilluminator for breast evaluation and sorbent hemoperfusion system (SHS) devices for the treatment of hepatic coma and metabolic disturbances; reclassification of SHS and devices for the treatment of poisoning and drug overdose. Final order.

    PubMed

    2014-01-17

    The Food and Drug Administration (FDA) is issuing a final order to require the filing of a premarket approval application (PMA) for the transilluminator for breast evaluation and sorbent hemoperfusion system (SHS) devices for the treatment of hepatic coma and metabolic disturbances and to reclassify SHS devices for the treatment of poisoning and drug overdose, a preamendments class III device, into class II (special controls).

  5. [Abscisic acid metabolism].

    PubMed

    Frankowski, Kamil; Wilmowicz, Emilia; Kućko, Agata; Sidłowska, Magdalena; Kesy, Jacek; Kopcewicz, Jan

    2013-01-01

    Abscisic acid is one of the plant hormones that determines normal growth and development, i.e. seeds ripening and germination, stomata opening and closure, flowering and stress responses. An appropriate level of endogenous ABA plays a key role in the regulation of most of these processes. Its content in a particular tissue is a balance between the rate of its biosynthesis, oxidative degradation and formation of inactive derivatives (mainly ester). The progress on ABA metabolism was relatively slow in the past. Application of modern molecular biology methods let the most of genes encoding enzymes involved in the regulation of ABA metabolism be identified and contributed to the understanding of its action.

  6. Final Report

    SciTech Connect

    Baron, Edward

    2014-04-28

    The progress over the course of the grant period was excellent. We went from 3-D test codes to full 3-D production codes. We studied several SNe Ia. Most of the support has gone for the 3 years of support of OU graduate student Brian Friesen, who is now mature in his fourth year of research. It is unfortunate that there will be no further DOE support to see him through to the completion of his PhD.

  7. Mitochondria and metabolic homeostasis.

    PubMed

    Cheng, Zhiyong; Ristow, Michael

    2013-07-20

    Mitochondrial function is fundamental to metabolic homeostasis. In addition to converting the nutrient flux into the energy molecule ATP, the mitochondria generate intermediates for biosynthesis and reactive oxygen species (ROS) that serve as a secondary messenger to mediate signal transduction and metabolism. Alterations of mitochondrial function, dynamics, and biogenesis have been observed in various metabolic disorders, including aging, cancer, diabetes, and obesity. However, the mechanisms responsible for mitochondrial changes and the pathways leading to metabolic disorders remain to be defined. In the last few years, tremendous efforts have been devoted to addressing these complex questions and led to a significant progress. In a timely manner, the Forum on Mitochondria and Metabolic Homeostasis intends to document the latest findings in both the original research article and review articles, with the focus on addressing three major complex issues: (1) mitochondria and mitochondrial oxidants in aging-the oxidant theory (including mitochondrial ROS) being revisited by a hyperfunction hypothesis and a novel role of SMRT in mitochondrion-mediated aging process being discussed; (2) impaired mitochondrial capacity (e.g., fatty acid oxidation and oxidative phosphorylation [OXPHOS] for ATP synthesis) and plasticity (e.g., the response to endocrine and metabolic challenges, and to calorie restriction) in diabetes and obesity; (3) mitochondrial energy adaption in cancer progression-a new view being provided for H(+)-ATP synthase in regulating cell cycle and proliferation by mediating mitochondrial OXPHOS, oxidant production, and cell death signaling. It is anticipated that this timely Forum will advance our understanding of mitochondrial dysfunction in metabolic disorders.

  8. Final Report

    NASA Technical Reports Server (NTRS)

    Bozzolo, Guillermo

    1997-01-01

    As an ongoing project, the original proposal of implementing BFS (Bozzolo-Ferrante-Smith methods) to the process of alloy design was satisfied beyond the original expectations, as the project evolved from the original goal of backing the experimental results with theoretical and computational evidence, to the point where theoretical predictions lead the way for further experimental studies. For the first time, computer simulations were used to predict the phase stability of many component systems (four and five elements), which are currently being developed and analyzed experimentally. Similar progress was made in the area of surface structure analysis via computer simulations.

  9. Final Report

    SciTech Connect

    Stinis, Panos

    2016-08-07

    This is the final report for the work conducted at the University of Minnesota (during the period 12/01/12-09/18/14) by PI Panos Stinis as part of the "Collaboratory on Mathematics for Mesoscopic Modeling of Materials" (CM4). CM4 is a multi-institution DOE-funded project whose aim is to conduct basic and applied research in the emerging field of mesoscopic modeling of materials.

  10. Final Report

    SciTech Connect

    Marchant, Gary E.

    2013-04-23

    This is the final report of a two year project entitled "Governing Nanotechnology Risks and Benefits in the Transition to Regulation: Innovative Public and Private Approaches." This project examined the role of new governance or "soft law" mechanisms such as codes of conduct, voluntary programs and partnership agreements to manage the risks of emerging technologies such as nanotechnology. A series of published or in publication papers and book chapters are attached.

  11. Final Report

    SciTech Connect

    R. Paul Drake

    2001-11-30

    This final report describes work involving 22 investigators from 11 institutions to explore the dynamics present in supernova explosions by means of experiments on the Omega laser. The specific experiments emphasized involved the unstable expansion of a spherical capsule and the coupling of perturbations at a first interface to a second interface by means of a strong shock. Both effects are present in supernovae. The experiments were performed at Omega and the computer simulations were undertaken at several institutions. B139

  12. A link between lipid metabolism and epithelial-mesenchymal transition provides a target for colon cancer therapy.

    PubMed

    Sánchez-Martínez, Ruth; Cruz-Gil, Silvia; Gómez de Cedrón, Marta; Álvarez-Fernández, Mónica; Vargas, Teodoro; Molina, Susana; García, Belén; Herranz, Jesús; Moreno-Rubio, Juan; Reglero, Guillermo; Pérez-Moreno, Mirna; Feliu, Jaime; Malumbres, Marcos; Ramírez de Molina, Ana

    2015-11-17

    The alterations in carbohydrate metabolism that fuel tumor growth have been extensively studied. However, other metabolic pathways involved in malignant progression, demand further understanding. Here we describe a metabolic acyl-CoA synthetase/stearoyl-CoA desaturase ACSL/SCD network causing an epithelial-mesenchymal transition (EMT) program that promotes migration and invasion of colon cancer cells. The mesenchymal phenotype produced upon overexpression of these enzymes is reverted through reactivation of AMPK signaling. Furthermore, this network expression correlates with poorer clinical outcome of stage-II colon cancer patients. Finally, combined treatment with chemical inhibitors of ACSL/SCD selectively decreases cancer cell viability without reducing normal cells viability. Thus, ACSL/SCD network stimulates colon cancer progression through conferring increased energetic capacity and invasive and migratory properties to cancer cells, and might represent a new therapeutic opportunity for colon cancer treatment.

  13. Metabolic mechanisms in heart failure.

    PubMed

    Ashrafian, Houman; Frenneaux, Michael P; Opie, Lionel H

    2007-07-24

    Although neurohumoral antagonism has successfully reduced heart failure morbidity and mortality, the residual disability and death rate remains unacceptably high. Though abnormalities of myocardial metabolism are associated with heart failure, recent data suggest that heart failure may itself promote metabolic changes such as insulin resistance, in part through neurohumoral activation. A detrimental self-perpetuating cycle (heart failure --> altered metabolism --> heart failure) that promotes the progression of heart failure may thus be postulated. Accordingly, we review the cellular mechanisms and pathophysiology of altered metabolism and insulin resistance in heart failure. It is hypothesized that the ensuing detrimental myocardial energetic perturbations result from neurohumoral activation, increased adverse free fatty acid metabolism, decreased protective glucose metabolism, and in some cases insulin resistance. The result is depletion of myocardial ATP, phosphocreatine, and creatine kinase with decreased efficiency of mechanical work. On the basis of the mechanisms outlined, appropriate therapies to mitigate aberrant metabolism include intense neurohumoral antagonism, limitation of diuretics, correction of hypokalemia, exercise, and diet. We also discuss more novel mechanistic-based therapies to ameliorate metabolism and insulin resistance in heart failure. For example, metabolic modulators may optimize myocardial substrate utilization to improve cardiac function and exercise performance beyond standard care. The ultimate success of metabolic-based therapy will be manifest by its capacity further to lessen the residual mortality in heart failure.

  14. Drug metabolism and ageing

    PubMed Central

    Kinirons, M T; O'Mahony, M S

    2004-01-01

    Important changes in drug metabolism occur with ageing. Age-associated reductions in function of some but not all cytochrome P450 enzymes (CYPs) have been described. Induction and inhibition of CYPs needs to be revisited in light of recent advances. The function and pharmacology of transporters have not yet been examined for an age-related effect. Finally, the concept of frailty is being underpinned by studies documenting a decline in drug metabolism and changes in disposition in frail older people compared with either healthy elderly or the young. PMID:15089805

  15. Final Report

    SciTech Connect

    R Paul Drake

    2004-01-12

    OAK-B135 This is the final report from the project Hydrodynamics by High-Energy-Density Plasma Flow and Hydrodynamics and Radiation Hydrodynamics with Astrophysical Applications. This project supported a group at the University of Michigan in the invention, design, performance, and analysis of experiments using high-energy-density research facilities. The experiments explored compressible nonlinear hydrodynamics, in particular at decelerating interfaces, and the radiation hydrodynamics of strong shock waves. It has application to supernovae, astrophysical jets, shock-cloud interactions, and radiative shock waves.

  16. Final Report

    SciTech Connect

    Yelton, John Martin; Mitselmakher, Guenakh; Korytov, Andrey; Avery, Paul; Furic, Ivan; Acosta, Darin; Konigsberg, Jacobo; Field, Richard; Matchev, Konstantin; Ramond, Pierre; Thorn, Richard; Sikivie, Pierre; Ray, Heather; Tanner, David

    2013-10-10

    We report on progress in a series of different directions within high energy physics research. 1. Neutrino research in hardware and software on the Minerva and MiniBooNE experiments 2. Experimental particle physics at the hadron colliders, with emphasis on research and development and data analysis on the CMS experiment operating at the CERN LHC. This includes research on the discovery and properties on the Higgs Boson. 3. Educational outreach through the Quarknet program, taking physics research into High School classrooms. 4. Theoretical and Phenomenological High Energy research, covering a broad range of activities ranging from fundamental theoretical issues to areas of immediate phenomenological importance. 5. Experiment searches for the Axion, as part of the ADMX experiment.

  17. Disposition and Metabolism of Investigational New Drugs.

    DTIC Science & Technology

    1982-09-01

    UNCLASSIFIED N EL MDISPOSITION AND METABOLISM OF INVESTIGATIONAL NEW DRUGS rN4 MRI PROJECT NO. 4266-B FINAL REPORT By Thomas E. Shellenberger September 1982...documents. Ii I DISPOSITION AND METABOLISM OF INVESTIGATIONAL NEW DRUGS [RI PROJECT NO. 4266-B [FINAL REPORT BY Thomas E. Shellenberger September 1982...the Army, Contract No. DAMD-17-76-C-6059, MRI Project No. 4266-B, "Disposition and Metabolism of Investigational New Drugs ." The work was supported by

  18. Tumor cell metabolism

    PubMed Central

    Romero-Garcia, Susana; Lopez-Gonzalez, Jose Sullivan; B´ez-Viveros, José Luis; Aguilar-Cazares, Dolores

    2011-01-01

    Cancer is a genetic disease that is caused by mutations in oncogenes, tumor suppressor genes and stability genes. The fact that the metabolism of tumor cells is altered has been known for many years. However, the mechanisms and consequences of metabolic reprogramming have just begun to be understood. In this review, an integral view of tumor cell metabolism is presented, showing how metabolic pathways are reprogrammed to satisfy tumor cell proliferation and survival requirements. In tumor cells, glycolysis is strongly enhanced to fulfill the high ATP demands of these cells; glucose carbons are the main building blocks in fatty acid and nucleotide biosynthesis. Glutaminolysis is also increased to satisfy NADPH regeneration, whereas glutamine carbons replenish the Krebs cycle, which produces metabolites that are constantly used for macromolecular biosynthesis. A characteristic feature of the tumor microenvironment is acidosis, which results from the local increase in lactic acid production by tumor cells. This phenomenon is attributed to the carbons from glutamine and glucose, which are also used for lactic acid production. Lactic acidosis also directs the metabolic reprogramming of tumor cells and serves as an additional selective pressure. Finally, we also discuss the role of mitochondria in supporting tumor cell metabolism. PMID:22057267

  19. Scaling metabolic rate fluctuations

    PubMed Central

    Labra, Fabio A.; Marquet, Pablo A.; Bozinovic, Francisco

    2007-01-01

    Complex ecological and economic systems show fluctuations in macroscopic quantities such as exchange rates, size of companies or populations that follow non-Gaussian tent-shaped probability distributions of growth rates with power-law decay, which suggests that fluctuations in complex systems may be governed by universal mechanisms, independent of particular details and idiosyncrasies. We propose here that metabolic rate within individual organisms may be considered as an example of an emergent property of a complex system and test the hypothesis that the probability distribution of fluctuations in the metabolic rate of individuals has a “universal” form regardless of body size or taxonomic affiliation. We examined data from 71 individuals belonging to 25 vertebrate species (birds, mammals, and lizards). We report three main results. First, for all these individuals and species, the distribution of metabolic rate fluctuations follows a tent-shaped distribution with power-law decay. Second, the standard deviation of metabolic rate fluctuations decays as a power-law function of both average metabolic rate and body mass, with exponents −0.352 and −1/4 respectively. Finally, we find that the distributions of metabolic rate fluctuations for different organisms can all be rescaled to a single parent distribution, supporting the existence of general principles underlying the structure and functioning of individual organisms. PMID:17578913

  20. Metabolic myopathies

    NASA Technical Reports Server (NTRS)

    Martin, A.; Haller, R. G.; Barohn, R.; Blomqvist, C. G. (Principal Investigator)

    1994-01-01

    Metabolic myopathies are disorders of muscle energy production that result in skeletal muscle dysfunction. Cardiac and systemic metabolic dysfunction may coexist. Symptoms are often intermittent and provoked by exercise or changes in supply of lipid and carbohydrate fuels. Specific disorders of lipid and carbohydrate metabolism in muscle are reviewed. Evaluation often requires provocative exercise testing. These tests may include ischemic forearm exercise, aerobic cycle exercise, and 31P magnetic resonance spectroscopy with exercise.

  1. Metabolic myopathies

    NASA Technical Reports Server (NTRS)

    Martin, A.; Haller, R. G.; Barohn, R.; Blomqvist, C. G. (Principal Investigator)

    1994-01-01

    Metabolic myopathies are disorders of muscle energy production that result in skeletal muscle dysfunction. Cardiac and systemic metabolic dysfunction may coexist. Symptoms are often intermittent and provoked by exercise or changes in supply of lipid and carbohydrate fuels. Specific disorders of lipid and carbohydrate metabolism in muscle are reviewed. Evaluation often requires provocative exercise testing. These tests may include ischemic forearm exercise, aerobic cycle exercise, and 31P magnetic resonance spectroscopy with exercise.

  2. Metabolic myopathies.

    PubMed

    Martin, A; Haller, R G; Barohn, R

    1994-11-01

    Metabolic myopathies are disorders of muscle energy production that result in skeletal muscle dysfunction. Cardiac and systemic metabolic dysfunction may coexist. Symptoms are often intermittent and provoked by exercise or changes in supply of lipid and carbohydrate fuels. Specific disorders of lipid and carbohydrate metabolism in muscle are reviewed. Evaluation often requires provocative exercise testing. These tests may include ischemic forearm exercise, aerobic cycle exercise, and 31P magnetic resonance spectroscopy with exercise.

  3. Opioid metabolism.

    PubMed

    Smith, Howard S

    2009-07-01

    Clinicians understand that individual patients differ in their response to specific opioid analgesics and that patients may require trials of several opioids before finding an agent that provides effective analgesia with acceptable tolerability. Reasons for this variability include factors that are not clearly understood, such as allelic variants that dictate the complement of opioid receptors and subtle differences in the receptor-binding profiles of opioids. However, altered opioid metabolism may also influence response in terms of efficacy and tolerability, and several factors contributing to this metabolic variability have been identified. For example, the risk of drug interactions with an opioid is determined largely by which enzyme systems metabolize the opioid. The rate and pathways of opioid metabolism may also be influenced by genetic factors, race, and medical conditions (most notably liver or kidney disease). This review describes the basics of opioid metabolism as well as the factors influencing it and provides recommendations for addressing metabolic issues that may compromise effective pain management. Articles cited in this review were identified via a search of MEDLINE, EMBASE, and PubMed. Articles selected for inclusion discussed general physiologic aspects of opioid metabolism, metabolic characteristics of specific opioids, patient-specific factors influencing drug metabolism, drug interactions, and adverse events.

  4. Opioid Metabolism

    PubMed Central

    Smith, Howard S.

    2009-01-01

    Clinicians understand that individual patients differ in their response to specific opioid analgesics and that patients may require trials of several opioids before finding an agent that provides effective analgesia with acceptable tolerability. Reasons for this variability include factors that are not clearly understood, such as allelic variants that dictate the complement of opioid receptors and subtle differences in the receptor-binding profiles of opioids. However, altered opioid metabolism may also influence response in terms of efficacy and tolerability, and several factors contributing to this metabolic variability have been identified. For example, the risk of drug interactions with an opioid is determined largely by which enzyme systems metabolize the opioid. The rate and pathways of opioid metabolism may also be influenced by genetic factors, race, and medical conditions (most notably liver or kidney disease). This review describes the basics of opioid metabolism as well as the factors influencing it and provides recommendations for addressing metabolic issues that may compromise effective pain management. Articles cited in this review were identified via a search of MEDLINE, EMBASE, and PubMed. Articles selected for inclusion discussed general physiologic aspects of opioid metabolism, metabolic characteristics of specific opioids, patient-specific factors influencing drug metabolism, drug interactions, and adverse events. PMID:19567715

  5. The Implications of Relationships between Human Diseases and Metabolic Subpathways

    PubMed Central

    Li, Jing; Han, Junwei; Miao, Yingbo; Wang, Yan; Wang, Qianghu; Li, Wei; Wu, Chao; Zhang, Yunpeng; Li, Xiang; Yao, Qianlan

    2011-01-01

    One of the challenging problems in the etiology of diseases is to explore the relationships between initiation and progression of diseases and abnormalities in local regions of metabolic pathways. To gain insight into such relationships, we applied the “k-clique” subpathway identification method to all disease-related gene sets. For each disease, the disease risk regions of metabolic pathways were then identified and considered as subpathways associated with the disease. We finally built a disease-metabolic subpathway network (DMSPN). Through analyses based on network biology, we found that a few subpathways, such as that of cytochrome P450, were highly connected with many diseases, and most belonged to fundamental metabolisms, suggesting that abnormalities of fundamental metabolic processes tend to cause more types of diseases. According to the categories of diseases and subpathways, we tested the clustering phenomenon of diseases and metabolic subpathways in the DMSPN. The results showed that both disease nodes and subpathway nodes displayed slight clustering phenomenon. We also tested correlations between network topology and genes within disease-related metabolic subpathways, and found that within a disease-related subpathway in the DMSPN, the ratio of disease genes and the ratio of tissue-specific genes significantly increased as the number of diseases caused by the subpathway increased. Surprisingly, the ratio of essential genes significantly decreased and the ratio of housekeeping genes remained relatively unchanged. Furthermore, the coexpression levels between disease genes and other types of genes were calculated for each subpathway in the DMSPN. The results indicated that those genes intensely influenced by disease genes, including essential genes and tissue-specific genes, might be significantly associated with the disease diversity of subpathways, suggesting that different kinds of genes within a disease-related subpathway may play significantly

  6. Mutant Kras copy number defines metabolic reprogramming and therapeutic susceptibilities.

    PubMed

    Kerr, Emma M; Gaude, Edoardo; Turrell, Frances K; Frezza, Christian; Martins, Carla P

    2016-03-03

    The RAS/MAPK (mitogen-activated protein kinase) signalling pathway is frequently deregulated in non-small-cell lung cancer, often through KRAS activating mutations. A single endogenous mutant Kras allele is sufficient to promote lung tumour formation in mice but malignant progression requires additional genetic alterations. We recently showed that advanced lung tumours from Kras(G12D/+);p53-null mice frequently exhibit Kras(G12D) allelic enrichment (Kras(G12D)/Kras(wild-type) > 1) (ref. 7), implying that mutant Kras copy gains are positively selected during progression. Here we show, through a comprehensive analysis of mutant Kras homozygous and heterozygous mouse embryonic fibroblasts and lung cancer cells, that these genotypes are phenotypically distinct. In particular, Kras(G12D/G12D) cells exhibit a glycolytic switch coupled to increased channelling of glucose-derived metabolites into the tricarboxylic acid cycle and glutathione biosynthesis, resulting in enhanced glutathione-mediated detoxification. This metabolic rewiring is recapitulated in mutant KRAS homozygous non-small-cell lung cancer cells and in vivo, in spontaneous advanced murine lung tumours (which display a high frequency of Kras(G12D) copy gain), but not in the corresponding early tumours (Kras(G12D) heterozygous). Finally, we demonstrate that mutant Kras copy gain creates unique metabolic dependences that can be exploited to selectively target these aggressive mutant Kras tumours. Our data demonstrate that mutant Kras lung tumours are not a single disease but rather a heterogeneous group comprising two classes of tumours with distinct metabolic profiles, prognosis and therapeutic susceptibility, which can be discriminated on the basis of their relative mutant allelic content. We also provide the first, to our knowledge, in vivo evidence of metabolic rewiring during lung cancer malignant progression.

  7. Russian Cargo Craft Final Undocking

    NASA Image and Video Library

    The ISS Progress 47 resupply vehicle, loaded with trash, undocked from the International Space Station’s Pirs docking compartment for the final time July 30 at 5:19 p.m. EDT. The cargo ship undo...

  8. Final Report

    SciTech Connect

    J. Toulouse

    2012-04-05

    The purpose of this project was to better understand the 'Multiscale Dynamics of Relaxor Ferroelectrics'. The output of the project is summarized in the narrative. The results of the work were presented at a number of different conferences and four papers were written, the references to which are also indicated in the report and which have also been uploaded on e-link. The multiscale dynamics of relaxors was clearly identified in the three characteristic temperatures that were identified. In particular, we were the first group to identify an intermediate temperature, T*, at which the correlations between off-center ions in relaxor cross-over from being dynamic to being static and giving rise to the characteristic relaxor behavior in the dielectric constant. Other groups have now confirmed the existence of such an intermediate temperature. We also made and reported two other observations: (1) a coherent interference phenomena (EIT-like effect) near the transition of several relaxors, which provides information on the nature and mechanism of the transition; and (2) in a similar way, inelastic neutron scattering results were interpreted as resonant scattering of acoustic phonons by localized modes in polar nanodomains. In parallel with the neutron scattering work, we also developed a theory of the scattering of phonons by the above localized modes. The theoretical development is very formal at this point and did not allow an easy comparison with the experimental results. This work is in progress.

  9. Interrogating Metabolism in Brain Cancer.

    PubMed

    Salzillo, Travis C; Hu, Jingzhe; Nguyen, Linda; Whiting, Nicholas; Lee, Jaehyuk; Weygand, Joseph; Dutta, Prasanta; Pudakalakatti, Shivanand; Millward, Niki Zacharias; Gammon, Seth T; Lang, Frederick F; Heimberger, Amy B; Bhattacharya, Pratip K

    2016-11-01

    This article reviews existing and emerging techniques of interrogating metabolism in brain cancer from well-established proton magnetic resonance spectroscopy to the promising hyperpolarized metabolic imaging and chemical exchange saturation transfer and emerging techniques of imaging inflammation. Some of these techniques are at an early stage of development and clinical trials are in progress in patients to establish the clinical efficacy. It is likely that in vivo metabolomics and metabolic imaging is the next frontier in brain cancer diagnosis and assessing therapeutic efficacy; with the combined knowledge of genomics and proteomics a complete understanding of tumorigenesis in brain might be achieved. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Current progress in pharmacogenetics

    PubMed Central

    Blakey, John D; Hall, Ian P

    2011-01-01

    The study of genetic variation has the potential to aid understanding of the mechanisms underlying the observed inter-individual variation in drug response and by which idiosyncratic adverse effects occur. In this review, we outline current progress in pharmacogenetics using examples to highlight both mechanisms of influence of polymorphisms and research strategies for their detection. In the final sections we discuss contemporary challenges for both researchers and clinicians. PMID:21235621

  11. Metabolic acidosis.

    PubMed

    Lim, Salim

    2007-01-01

    Acute metabolic acidosis is frequently encountered in critically ill patients. Metabolic acidosis can occur as a result of either the accumulation of endogenous acids that consumes bicarbonate (high anion gap metabolic acidosis) or loss of bicarbonate from the gastrointestinal tract or the kidney (hyperchloremic or normal anion gap metabolic acidosis). The cause of high anion gap metabolic acidosis includes lactic acidosis, ketoacidosis, renal failure and intoxication with ethylene glycol, methanol, salicylate and less commonly with pyroglutamic acid (5-oxoproline), propylene glycole or djenkol bean (gjenkolism). The most common causes of hyperchloremic metabolic acidosis are gastrointestinal bicarbonate loss, renal tubular acidosis, drugs-induced hyperkalemia, early renal failure and administration of acids. The appropriate treatment of acute metabolic acidosis, in particular organic form of acidosis such as lactic acidosis, has been very controversial. The only effective treatment for organic acidosis is cessation of acid production via improvement of tissue oxygenation. Treatment of acute organic acidosis with sodium bicarbonate failed to reduce the morbidity and mortality despite improvement in acid-base parameters. Further studies are required to determine the optimal treatment strategies for acute metabolic acidosis.

  12. (Carbon monoxide metabolism by photosynthetic bacteria)

    SciTech Connect

    Not Available

    1989-01-01

    Research continued on the metabolism of carbon monoxide by Rhodospirillum rubrum. This report discusses progress on the activity, induction, inhibition, and spectroscopic analysis of the enzyme Carbon Monoxide Dehydrogenase. (CBS)

  13. Final Report

    SciTech Connect

    Webb, Robert C.; Kamon, Teruki; Toback, David; Safonov, Alexei; Dutta, Bhaskar; Dimitri, Nanopoulos; Pope, Christopher; White, James

    2013-11-18

    Overview The High Energy Physics Group at Texas A&M University is submitting this final report for our grant number DE-FG02-95ER40917. This grant has supported our wide range of research activities for over a decade. The reports contained here summarize the latest work done by our research team. Task A (Collider Physics Program): CMS & CDF Profs. T. Kamon, A. Safonov, and D. Toback co-lead the Texas A&M (TAMU) collider program focusing on CDF and CMS experiments. Task D: Particle Physics Theory Our particle physics theory task is the combined effort of Profs. B. Dutta, D. Nanopoulos, and C. Pope. Task E (Underground Physics): LUX & NEXT Profs. R. Webb and J. White(deceased) lead the Xenon-based underground research program consisting of two main thrusts: the first, participation in the LUX two-phase xenon dark matter search experiment and the second, detector R&D primarily aimed at developing future detectors for underground physics (e.g. NEXT and LZ).

  14. Final report

    SciTech Connect

    Susan S. Golden

    2005-03-31

    The originally funded project was geared to pursue research on regulation of photosystem II (PSII) in the cyanobacterium Synechococcus elongatus PCC 7942. We characterized a locus, psfR, (psbA stimulating factor) that affects expression of the psbAI gene, which encodes the PSII protein D1. Over-expression of psfR, which encodes a protein with receiver and pseudo-receiver domains, acts at the promoter region to elevate expression of psbAI and a subset of other loci. We reoriented the remainder of the funding to make a greater impact through completion of a functional genomics project that had been initiated with funding from another agency. The goal is inactivation of each gene individually in the S. elongatus genome, and completion of the entire genome sequence. At the end of the project we will have screened all loci for involvement in circadian rhythms of gene expression and assembled an archived set of clones that can be used to create the mutations to screen for any other phenotype. During the project period we: (1) prepared a functional genomics website for S. elongatus PCC 7942 that posts sequences prior to GenBank release, and presents the strategy and progress for the genomics project (http://www.bio.tamu.edu/synecho/); (2) determined the sequence of and annotated the S. elongatus 46 kb plasmid, pANL; (3) submitted assembled sequences with annotation of 8 cosmid inserts to GenBank (313 kb), with sites of transposon insertions indicated; (4) mutagenized approximately an additional 600 kb of the genome (16 cosmids) and identified sequences flanking the mutations; (5) recombined mutagenesis substrates into the S. elongatus genome to produce gene inactivations (at the sites of transposon insertions) for approximately 415 kb of mutagenized sequence (85% of these have already been screened for circadian phenotypes) (6) identified the clpPIIclpX locus as important in determining circadian period; and (7) demonstrated effectiveness of antisense RNA for decreasing

  15. FINAL REPORT

    SciTech Connect

    PETER, GARY F.

    2014-07-16

    Excellent progress was made in standardizing three complementary methods: Magnetic resonance imaging, x-ray micro CT, and MALDI imaging linear ion trap mass spectroscopy to image biomass and chemical, anatomical and functional changes that occur during pretreatment and hydrolysis. Magnetic resonance microscopy provides excellent images with as low as 5 uM resolution with hydrated biomass samples. We visualized dramatic changes in signal associated with the hydrolysis of the carbohydrates by strong acids. Quantitative diffusion approaches were used to probe more subtle structural changes in biomass. Diffusion tensor calculations reflect diffusion anisotropy and fractional anisotropy maps clearly show the longer range diffusion within the vessels compared to within the fiber cells. The diffusion is increased along the cell walls of the vessels. Suggesting that further research with NMR imaging should be pursued. X-ray CT provides excellent images at as low as 3.5 uM resolution from dried biomass. Small increases in surface area, and decreases in local density have been quantified in with wood after mild pretreatments; these changes are expected to be underestimates of the hydrated wood, due to the ~12% shrinkage that occurs upon drying untreated wood. MALDI-MS spectra show high ion intensities at most mass to charge ratios in untreated and pretreated woody material. MALDI-MSn is required to improve specificity and reduce background for imaging. MALDI-TOF is not specific enough for carbohydrate identification. Using MALDI-LIT/MSn we can readily identify oligomeric glucans and xylans and their fragmentation patterns as well as those of the glucuronic acid side chains of birch 4-O-methyl glucuronxylan. Imaging of glucan and xylan oligomers show that many contain isobaric ions with different distributions, indicating again that MSn is needed for accurate imaging of lignocellulosic materials. We are now starting to integrate the three imaging methods by using the same set

  16. Final Report

    SciTech Connect

    Gentile, Thomas R.

    2014-03-14

    We propose to extend the technique of polarized neutron scattering into new domains by continued development and application of polarized 3He spin-filters. These devices are particularly relevant to the Spallation Neutron Source, as the polarizing monochromators historically used at reactor sources will usually not be suitable polarizers, and wide-angle polarization analysis will be essential. With prior support from the Office of Science, we have developed neutron spin-filters based on the large spin dependence of the cross section for neutron capture by 3He, and applied these devices to a small angle neutron scattering spectrometer (SANS), polarized neutron reflectometers, a thermal energy single crystal diffractometer (SCD), and a thermal energy triple-axis instrument. Our developments have been adopted for application on the magnetism reflectometer at the SNS and for the NIST Center for Neutron Research (NCNR) 3He user capability. Results from both these programs are emerging. We have made significant progress in the past grant period on wide-angle polarization analysis. We have also performed several studies relevant to continuous optical pumping, including collaboration on experiments that have revealed neutron beam effects on spin filters that are continuously pumped by spin-exchange optical pumping. We contributed to an experiment on a neutron interferometer, in which the successful results obtained are directly related to both 3He cell technology and high accuracy 3He -based neutron polarimetry. Implementation of wide-angle polarization analysis will continue to be key thrust for our work in this new proposal. We will also focus on continuous optical pumping and the fundamental issues that determine the achievable 3He polarization. This project will be carried out by a collaboration involving scientists at NIST, Indiana University, Hamilton College, and the Univ. of Wisconsin who are experts in 3He polarization techniques, and materials scientists from the

  17. Urban metabolism: a review of research methodologies.

    PubMed

    Zhang, Yan

    2013-07-01

    Urban metabolism analysis has become an important tool for the study of urban ecosystems. The problems of large metabolic throughput, low metabolic efficiency, and disordered metabolic processes are a major cause of unhealthy urban systems. In this paper, I summarize the international research on urban metabolism, and describe the progress that has been made in terms of research methodologies. I also review the methods used in accounting for and evaluating material and energy flows in urban metabolic processes, simulation of these flows using a network model, and practical applications of these methods. Based on this review of the literature, I propose directions for future research, and particularly the need to study the urban carbon metabolism because of the modern context of global climate change. Moreover, I recommend more research on the optimal regulation of urban metabolic systems.

  18. Cancer metabolism: current perspectives and future directions

    PubMed Central

    Muñoz-Pinedo, C; El Mjiyad, N; Ricci, J-E

    2012-01-01

    Cellular metabolism influences life and death decisions. An emerging theme in cancer biology is that metabolic regulation is intricately linked to cancer progression. In part, this is due to the fact that proliferation is tightly regulated by availability of nutrients. Mitogenic signals promote nutrient uptake and synthesis of DNA, RNA, proteins and lipids. Therefore, it seems straight-forward that oncogenes, that often promote proliferation, also promote metabolic changes. In this review we summarize our current understanding of how ‘metabolic transformation' is linked to oncogenic transformation, and why inhibition of metabolism may prove a cancer′s ‘Achilles' heel'. On one hand, mutation of metabolic enzymes and metabolic stress sensors confers synthetic lethality with inhibitors of metabolism. On the other hand, hyperactivation of oncogenic pathways makes tumors more susceptible to metabolic inhibition. Conversely, an adequate nutrient supply and active metabolism regulates Bcl-2 family proteins and inhibits susceptibility to apoptosis. Here, we provide an overview of the metabolic pathways that represent anti-cancer targets and the cell death pathways engaged by metabolic inhibitors. Additionally, we will detail the similarities between metabolism of cancer cells and metabolism of proliferating cells. PMID:22237205

  19. Cancer metabolism: current perspectives and future directions.

    PubMed

    Muñoz-Pinedo, C; El Mjiyad, N; Ricci, J-E

    2012-01-12

    Cellular metabolism influences life and death decisions. An emerging theme in cancer biology is that metabolic regulation is intricately linked to cancer progression. In part, this is due to the fact that proliferation is tightly regulated by availability of nutrients. Mitogenic signals promote nutrient uptake and synthesis of DNA, RNA, proteins and lipids. Therefore, it seems straight-forward that oncogenes, that often promote proliferation, also promote metabolic changes. In this review we summarize our current understanding of how 'metabolic transformation' is linked to oncogenic transformation, and why inhibition of metabolism may prove a cancer's 'Achilles' heel'. On one hand, mutation of metabolic enzymes and metabolic stress sensors confers synthetic lethality with inhibitors of metabolism. On the other hand, hyperactivation of oncogenic pathways makes tumors more susceptible to metabolic inhibition. Conversely, an adequate nutrient supply and active metabolism regulates Bcl-2 family proteins and inhibits susceptibility to apoptosis. Here, we provide an overview of the metabolic pathways that represent anti-cancer targets and the cell death pathways engaged by metabolic inhibitors. Additionally, we will detail the similarities between metabolism of cancer cells and metabolism of proliferating cells.

  20. Robustness of metabolic networks

    NASA Astrophysics Data System (ADS)

    Jeong, Hawoong

    2009-03-01

    We investigated the robustness of cellular metabolism by simulating the system-level computational models, and also performed the corresponding experiments to validate our predictions. We address the cellular robustness from the ``metabolite''-framework by using the novel concept of ``flux-sum,'' which is the sum of all incoming or outgoing fluxes (they are the same under the pseudo-steady state assumption). By estimating the changes of the flux-sum under various genetic and environmental perturbations, we were able to clearly decipher the metabolic robustness; the flux-sum around an essential metabolite does not change much under various perturbations. We also identified the list of the metabolites essential to cell survival, and then ``acclimator'' metabolites that can control the cell growth were discovered. Furthermore, this concept of ``metabolite essentiality'' should be useful in developing new metabolic engineering strategies for improved production of various bioproducts and designing new drugs that can fight against multi-antibiotic resistant superbacteria by knocking-down the enzyme activities around an essential metabolite. Finally, we combined a regulatory network with the metabolic network to investigate its effect on dynamic properties of cellular metabolism.

  1. Carbon Source Metabolism and Its Regulation in Cancer Cells

    PubMed Central

    Yin, Chengqian; Qie, Shuo; Sang, Nianli

    2013-01-01

    Cancer cell proliferation and progression require sufficient supplies of nutrients including carbon sources, nitrogen sources, and molecular oxygen. Particularly, carbon sources and molecular oxygen are critical for the generation of ATP and building blocks, and for the maintenance of intracellular redox status. However, solid tumors frequently outgrow the blood supply, resulting in nutrient insufficiency. Accordingly, cancer cell metabolism shows aberrant biochemical features that are consequences of oncogenic signaling and adaptation. Those adaptive metabolism features, including the Warburg effect and addiction to glutamine, may form the biochemical basis for resistance to chemotherapy and radiation. A better understanding of the regulatory mechanisms that link the signaling pathways to adaptive metabolic reprogramming may identify novel biomarkers for drug development. In this review we focus on the regulation of carbon source utilization at a cellular level, emphasizing its relevance to proliferative biosynthesis in cancer cells. We summarize the essential needs of proliferating cells and the metabolic features of glucose, lipids, and glutamine, and we review the roles of transcription regulators (i.e.,HIF-l, c-Myc, and p53) and two major oncogenic signaling pathways (i.e., PI3K-Akt and MAPK) in regulating the utilization of carbon sources. Finally, the effects of glucose on cell proliferation and perspective from both biochemical and cellular angles are discussed. PMID:22339657

  2. Hypothalamic inflammation in the control of metabolic function.

    PubMed

    Valdearcos, Martin; Xu, Allison W; Koliwad, Suneil K

    2015-01-01

    Diet-induced obesity leads to devastating and common chronic diseases, fueling ongoing interest in determining new mechanisms underlying both obesity and its consequences. It is now well known that chronic overnutrition produces a unique form of inflammation in peripheral insulin target tissues, and efforts to limit this inflammation have met with some success in preserving insulin sensitivity in obese individuals. Recently, the activation of inflammatory pathways by dietary excess has also been observed among cells located in the mediobasal hypothalamus, a brain area that exerts central control over peripheral glucose, fat, and energy metabolism. Here we review progress in the field of diet-induced hypothalamic inflammation, drawing key distinctions between metabolic inflammation in the hypothalamus and that occurring in peripheral tissues. We focus on specific stimuli of the inflammatory response, the roles of individual hypothalamic cell types, and the links between hypothalamic inflammation and metabolic function under normal and pathophysiological circumstances. Finally, we explore the concept of controlling hypothalamic inflammation to mitigate metabolic disease.

  3. Ferredoxin-linked chloreplast enzymes. Progress report, August 15, 1990--August 14, 1993

    SciTech Connect

    1996-01-01

    Progress has clearly been made on all of the goals set forth in the original proposal. Although the monoclonal antibodies raised against FNR turned out no to be useful for mapping the FNR/ferredoxin or FNR/NADP+ interaction domains, good progress has been made on mapping the FNR/ferredoxin interaction domains by an alternative technique, differential chemical modification. Furthermore, the techniques developed for differential chemical modifications of these two proteins - taurine modification of aspartate and glutamate residues and biotin modification of lysine residues - should be useful for mapping the interaction domains of many proteins that associate through electrostatic interactions. Finally, progress has also been made with respect to another ferredoxin-dependent enzyme involved in the earliest steps of plant nitrogen metabolism - nitrite reductase. Questions concerning the subunit composition and heme content of the enzyme have been resolved and evidence demonstrating the involvement of lysine and arginine residues in binding ferredoxin has been obtained for the first time.

  4. Final Report

    SciTech Connect

    Wessels, B. W.

    2002-08-02

    Final report for program on the study of structure and properties of epitaxial oxide films. The defect structure of epitaxial oxide thin films was investigated. Both binary and complex oxides were studied. Epitaxial oxides were synthesized by organometallic chemical vapor deposition (OMCVD). This technique has been found to be highly versatile for the synthesis of a wide range of epitaxial oxide including dielectrics, ferroelectrics and high T{sub c} superconductors. Systems investigated include the binary oxides ZnO and TiO{sub 2} and ferroelectric oxides BaTiO{sub 3}, BaSrTiO{sub 3} and KNbO{sub 3}. Techniques used to evaluate the defect structure included deep level transient spectroscopy (DLTS), photocapacitance spectroscopy, and photoluminescence (PL) spectroscopy. High purity, stoichiometric oxide films were deposited and their defect structure evaluated. Epitaxial ZnO was deposited at temperatures as low as 250 C. PL indicated only near band edge ultraviolet emission showing that both extrinsic and intrinsic point defects could be significantly lowered in OMCVD derived thin films compared to that of the bulk. This presumably was a result of low deposition temperatures and high purity starting materials. Ferroelectric oxides epitaxial thin films of BaTiO{sub 3} and the solid solution BaSrTiO{sub 3} were synthesized and the defect structure determined. Photocapacitance spectroscopy was developed to quantify electrically active defects in the oxides. Defects with concentrations as low as 10{sup 14} cm{sup -3} were observed and their properties determined. A new model was developed for the electronic transport properties of intrinsic and extrinsic BaTiO{sub 3}. A transport model was proposed whereby conduction in La doped films occurs via hopping in localized states within a pseudogap formed between a lower Hubbard band and the conduction band edge. The influence of the size effect on the ferroelectric phase transition in the thin films was investigated. The

  5. Gait Dynamics and Locomotor Metabolism

    DTIC Science & Technology

    2013-10-01

    weighted and unweighted walking metabolic rates can be estimated in field settings using simple, inexpensive wearable technologies. Metabolic rates...our walking model and to continue to work toward the final algorithm and publication of a walking test for predicting aerobic fitness . The...number of subjects tested in the last year was limited and targeted toward enrolling highly aerobically fit subjects needed for objective two

  6. Metabolic changes in malnutrition.

    PubMed

    Emery, P W

    2005-10-01

    This paper is concerned with malnutrition caused by inadequate intake of all the major nutrients rather than deficiency diseases relating to a single micronutrient. Three common situations are recognised: young children in third world countries with protein-energy malnutrition; adults in the same countries who are chronically adapted to subsisting on marginally inadequate diets; and patients who become malnourished as a result of chronic diseases. In all these situations infectious diseases are often also present, and this complicates the interpretation of biochemical and physiological observations. The metabolic response to starvation is primarily concerned with maintaining a supply of water-soluble substrates to supply energy to the brain. Thus there is an initial rise in metabolic rate, reflecting gluconeogenic activity. As fasting progresses, gluconeogenesis is suppressed to minimise muscle protein breakdown and ketones become the main fuel for the brain. With chronic underfeeding the basal metabolic rate per cell appears to fall, but the mechanistic basis for this is not clear. The main adaptation to chronic energy deficiency is slow growth and low adult body size, although the reduction in energy requirement achieved by this is partially offset by the preservation of the more metabolically active organs at the expense of muscle, which has a lower metabolic rate. The interaction between malnutrition and the metabolic response to trauma has been studied using an animal model. The rise in energy expenditure and urinary nitrogen excretion following surgery were significantly attenuated in malnourished rats, suggesting that malnutrition impairs the ability of the body to mobilise substrates to support inflammatory and reparative processes. However, the healing process in wounded muscle remained unimpaired in malnutrition, suggesting that this process has a high biological priority.

  7. Final report

    SciTech Connect

    Dobbs, Fred C.

    2003-01-15

    species of flagellates, Spumella sp. and Bodo sp. (identifications are tentative) were isolated from South Oyster sediments by repetitive serial dilution/extinction method. Protistan cells were cultured with Cereal leaf Prescott medium and pelleted by centrifugation. Protistan DNAs were extracted with a DNA extraction kit (Sigma Co.) and the sequencing of their SSrDNA is underway. Finally, to follow up on our collaboration of Dr. Bill Johnson (Univ. of Utah), one of the co-PIs under the same NABIR umbrella, we are pleased to report we have successfully tested antibody-ferrographic capture of protists (See previous year's report for more background). Polyclonal FITC-conjugated antibody specific for a flagellate, Spumella sp., was produced by Rockland Inc., and we now are able to enumerate that species using ferrographic capture. There are, however, some issues of non-specific staining that remain to be resolved.

  8. Metabolic Syndrome

    MedlinePlus

    ... cause of metabolic syndrome. The cause might be insulin resistance. Insulin is a hormone your body produces to help ... into energy for your body. If you are insulin resistant, too much sugar builds up in your ...

  9. Metabolic neuropathies

    MedlinePlus

    ... as porphyria Severe infection throughout the body ( sepsis ) Thyroid disease Vitamin deficiencies (including vitamins B12 , B6 , E , and B1 ) Some metabolic disorders are passed down through families (inherited), while ...

  10. Metabolic Myopathies

    MedlinePlus

    ... muscles. Metabolic refers to chemical reactions that provide energy, nutrients and substances necessary for health and growth. ... occur when muscle cells don’t get enough energy. Without enough energy, the muscle lacks enough fuel ...

  11. Metabolic Disorders

    MedlinePlus

    Metabolism is the process your body uses to get or make energy from the food you eat. Food is made up of proteins, carbohydrates, and fats. Chemicals in your digestive system break the food parts down into sugars and ...

  12. Metabolic Myopathies

    MedlinePlus

    ... muscles. Metabolic refers to chemical reactions that provide energy, nutrients and substances necessary for health and growth. ... occur when muscle cells don’t get enough energy. Without enough energy, the muscle lacks enough fuel ...

  13. Starch metabolism in leaves.

    PubMed

    Orzechowski, Sławomir

    2008-01-01

    Starch is the most abundant storage carbohydrate produced in plants. The initiation of transitory starch synthesis and degradation in plastids depends mainly on diurnal cycle, post-translational regulation of enzyme activity and starch phosphorylation. For the proper structure of starch granule the activities of all starch synthase isoenzymes, branching enzymes and debranching enzymes are needed. The intensity of starch biosynthesis depends mainly on the activity of AGPase (adenosine 5'-diphosphate glucose pyrophosphorylase). The key enzymes in starch degradation are beta-amylase, isoamylase 3 and disproportionating enzyme. However, it should be underlined that there are some crucial differences in starch metabolism between heterotrophic and autotrophic tissues, e.g. is the ability to build multiprotein complexes responsible for biosynthesis and degradation of starch granules in chloroplasts. The observed huge progress in understanding of starch metabolism was possible mainly due to analyses of the complete Arabidopsis and rice genomes and of numerous mutants with altered starch metabolism in leaves. The aim of this paper is to review current knowledge on transient starch metabolism in higher plants.

  14. Productization and Manufacturing Scaling of High-Efficiency Solar Cell and Module Products Based on a Disruptive Low-Cost, Mono-Crystalline Technology: Final Technical Progress Report, April 1, 2009 - December 30, 2010

    SciTech Connect

    Fatemi, H.

    2012-07-01

    Final report for PV incubator subcontract with Solexel, Inc. The purpose of this project was to develop Solexel's Unique IP, productize it, and transfer it to manufacturing. Silicon constitutes a significant fraction of the total solar cell cost, resulting in an industry-wide drive to lower silicon usage. Solexel's disruptive Solar cell structure got around these challenges and promised superior light trapping, efficiency and mechanical strength, despite being significantly thinner than commercially available cells. Solexel's successful participation in this incubator project became evident as the company is now moving into commercial production and position itself to be competitive for the next Technology Pathway Partnerships (TPP) funding opportunity.

  15. Economic feasibility analysis of distributed electric power generation based upon the natural gas fired fuel cell. Draft and final progress report for the period May 1, 1993--July 31, 1993

    SciTech Connect

    Not Available

    1993-09-01

    This report is an account of the work performed from May 1, 1993 to July 30,1993 on the economic feasibility generating electrical power by natural gas-fired fuel cells. The study is comprised of a survey of energy users, the development of numeric models of an energy distribution system and a central plant utilities system that includes a fuel cell. A model of the capital cost of the hardware elements is combined with a series of ownership scenarios and an operations model that provide the necessary input for a model of the cost of ownership of a fuel cell-based power generation system. The primary model development tasks are complete. The remaining study emphasis is to perform an economic analysis of varied ownership scenarios using the model. This report outlines the progress to date.

  16. Targeting Phospholipid Metabolism in Cancer

    PubMed Central

    Cheng, Menglin; Bhujwalla, Zaver M.; Glunde, Kristine

    2016-01-01

    All cancers tested so far display abnormal choline and ethanolamine phospholipid metabolism, which has been detected with numerous magnetic resonance spectroscopy (MRS) approaches in cells, animal models of cancer, as well as the tumors of cancer patients. Since the discovery of this metabolic hallmark of cancer, many studies have been performed to elucidate the molecular origins of deregulated choline metabolism, to identify targets for cancer treatment, and to develop MRS approaches that detect choline and ethanolamine compounds for clinical use in diagnosis and treatment monitoring. Several enzymes in choline, and recently also ethanolamine, phospholipid metabolism have been identified, and their evaluation has shown that they are involved in carcinogenesis and tumor progression. Several already established enzymes as well as a number of emerging enzymes in phospholipid metabolism can be used as treatment targets for anticancer therapy, either alone or in combination with other chemotherapeutic approaches. This review summarizes the current knowledge of established and relatively novel targets in phospholipid metabolism of cancer, covering choline kinase α, phosphatidylcholine-specific phospholipase D1, phosphatidylcholine-specific phospholipase C, sphingomyelinases, choline transporters, glycerophosphodiesterases, phosphatidylethanolamine N-methyltransferase, and ethanolamine kinase. These enzymes are discussed in terms of their roles in oncogenic transformation, tumor progression, and crucial cancer cell properties such as fast proliferation, migration, and invasion. Their potential as treatment targets are evaluated based on the current literature. PMID:28083512

  17. Catabolic metabolism during cancer EMT.

    PubMed

    Cha, Yong Hoon; Yook, Jong In; Kim, Hyun Sil; Kim, Nam Hee

    2015-03-01

    Aerobic glycolysis is widely accepted as the glucose metabolism for production of biomass such as nucleotides, amino acids, and fatty acids which underlie the anabolic process of cancer cell proliferation. The epithelial-mesenchymal transition (EMT) is a complex cellular mechanism for invasion and metastatic progression in cancer cells. While Snail-mediated EMT regulated by major oncogenic signaling has been well-studied over the last decade, metabolic reprogramming during the EMT has not. In this work, we emphasize the importance of catabolic metabolism for cancer cell survival during cancer cell EMT. Because specific catabolic processes such as autophage and fatty acid oxidation have been well explained, we mainly focus on the general aspects of energy metabolism promoting cancer cell survival under metabolic stress. We also revisit the role of mitochondria in catabolism as oxidative phosphorylation in cancer has long been underestimated. Considering the highly inefficient process of metastatic progression and profound metabolic stress following matrix detachment of solid cancer, catabolic reprogramming during the EMT may play an important role in overcoming metastatic inefficiency of cancer cells.

  18. Clinical efficacy, radiographic progression, and safety through 156 weeks of therapy with subcutaneous golimumab in combination with methotrexate in Japanese patients with active rheumatoid arthritis despite prior methotrexate therapy: final results of the randomized GO-FORTH trial

    PubMed Central

    Tanaka, Yoshiya; Harigai, Masayoshi; Takeuchi, Tsutomu; Yamanaka, Hisashi; Ishiguro, Naoki; Yamamoto, Kazuhiko; Miyasaka, Nobuyuki; Koike, Takao; Baker, Daniel; Ishii, Yutaka; Yoshinari, Toru

    2016-01-01

    Abstract Objective: To evaluate the safety and efficacy of golimumab + methotrexate (MTX) in Japanese patients with active rheumatoid arthritis (RA). Methods: Japanese patients with active RA despite MTX were randomized to placebo + MTX (Group 1, n = 88), golimumab 50 mg + MTX (Group 2, n = 86), or golimumab 100 mg + MTX (Group 3, n = 87). Patients with <20% improvement in swollen/tender joint counts entered early escape at week 16. At week 24, all remaining placebo patients crossed over to golimumab 50 mg. Efficacy assessments included ACR20, DAS28-ESR, and HAQ-DI. Radiographic progression was assessed with the van der Heijde-modified Sharp (vdH-S) score. Results: ACR20 response rates in Group 1, Group 2, and Group 3 were 67.9, 86.1, and 82.4%, respectively, at week 52 and were maintained through week 104 (87.1, 94.0, and 88.7%) and week 156 (97.1, 94.1, and 89.5%). Proportions of patients with good/moderate DAS28-ESR response or clinically meaningful improvement in HAQ-DI were also maintained through week 156. The majority of patients did not experience radiographic progression through week 156. Among 257 golimumab-treated patients, 251 (97.7%) had ≥1 AE; 54 (21.0%) had ≥1 serious AE through week 156. Infections were the most common type of AE. Conclusions: Response to golimumab + MTX was maintained over 3 years in Japanese patients with active RA despite MTX. Safety results were consistent with the known safety profile of golimumab. PMID:26474192

  19. Regulation of Terpene Metabolism

    SciTech Connect

    Rodney Croteau

    2004-03-14

    OAK-B135 Research over the last four years has progressed fairly closely along the lines initially proposed, with progress-driven expansion of Objectives 1, 2 and 3. Recent advances have developed from three research thrusts: 1. Random sequencing of an enriched peppermint oil gland cDNA library has given access to a large number of potential pathway and regulatory genes for test of function; 2. The availability of new DNA probes and antibodies has permitted investigation of developmental regulation and organization of terpenoid metabolism; and 3. The development of a transformation system for peppermint by colleagues at Purdue University has allowed direct transgenic testing of gene function and added a biotechnological component to the project. The current status of each of the original research objectives is outlined below.

  20. Tech Prep II: Implementation Final Report.

    ERIC Educational Resources Information Center

    Brown, Jane A.

    This document contains the final progress report on a tech prep implementation project and the Work Force Challenge 2000 Report developed during the project. The final report lists these major accomplishments: approximately 1,500 educators in grades K-12 were provided information concerning future global issues in the work force and the effects in…

  1. Metabolic Adaptations of Azospirillum brasilense to Oxygen Stress by Cell-to-Cell Clumping and Flocculation

    SciTech Connect

    Bible, Amber N.; Khalsa-Moyers, Gurusahai K.; Mukherjee, Tanmoy; Green, Calvin S.; Mishra, Priyanka; Purcell, Alicia; Aksenova, Anastasia; Hurst, Gregory B.; Alexandre, Gladys

    2015-09-25

    The ability of bacteria to monitor their metabolism and adjust their behavior accordingly is critical to maintain competitiveness in the environment. The motile microaerophilic bacteriumAzospirillum brasilensenavigates oxygen gradients by aerotaxis in order to locate low oxygen concentrations that can support metabolism. When cells are exposed to elevated levels of oxygen in their surroundings, motileA. brasilensecells implement an alternative response to aerotaxis and form transient clumps by cell-to-cell interactions. Clumping was suggested to represent a behavior protecting motile cells from transiently elevated levels of aeration. Using the proteomics of wild-type and mutant strains affected in the extent of their clumping abilities, we show that cell-to-cell clumping represents a metabolic scavenging strategy that likely prepares the cells for further metabolic stresses. Analysis of mutants affected in carbon or nitrogen metabolism confirmed this assumption. The metabolic changes experienced as clumping progresses prime cells for flocculation, a morphological and metabolic shift of cells triggered under elevated-aeration conditions and nitrogen limitation. The analysis of various mutants during clumping and flocculation characterized an ordered set of changes in cell envelope properties accompanying the metabolic changes. These data also identify clumping and early flocculation to be behaviors compatible with the expression of nitrogen fixation genes, despite the elevated-aeration conditions. Finally, cell-to-cell clumping may thus license diazotrophy to microaerophilicA. brasilensecells under elevated oxygen conditions and prime them for long-term survival via flocculation if metabolic stress persists.

  2. Metabolic Adaptations of Azospirillum brasilense to Oxygen Stress by Cell-to-Cell Clumping and Flocculation

    DOE PAGES

    Bible, Amber N.; Khalsa-Moyers, Gurusahai K.; Mukherjee, Tanmoy; ...

    2015-09-25

    The ability of bacteria to monitor their metabolism and adjust their behavior accordingly is critical to maintain competitiveness in the environment. The motile microaerophilic bacteriumAzospirillum brasilensenavigates oxygen gradients by aerotaxis in order to locate low oxygen concentrations that can support metabolism. When cells are exposed to elevated levels of oxygen in their surroundings, motileA. brasilensecells implement an alternative response to aerotaxis and form transient clumps by cell-to-cell interactions. Clumping was suggested to represent a behavior protecting motile cells from transiently elevated levels of aeration. Using the proteomics of wild-type and mutant strains affected in the extent of their clumping abilities,more » we show that cell-to-cell clumping represents a metabolic scavenging strategy that likely prepares the cells for further metabolic stresses. Analysis of mutants affected in carbon or nitrogen metabolism confirmed this assumption. The metabolic changes experienced as clumping progresses prime cells for flocculation, a morphological and metabolic shift of cells triggered under elevated-aeration conditions and nitrogen limitation. The analysis of various mutants during clumping and flocculation characterized an ordered set of changes in cell envelope properties accompanying the metabolic changes. These data also identify clumping and early flocculation to be behaviors compatible with the expression of nitrogen fixation genes, despite the elevated-aeration conditions. Finally, cell-to-cell clumping may thus license diazotrophy to microaerophilicA. brasilensecells under elevated oxygen conditions and prime them for long-term survival via flocculation if metabolic stress persists.« less

  3. Current perspectives between metabolic syndrome and cancer.

    PubMed

    Micucci, Carla; Valli, Debora; Matacchione, Giulia; Catalano, Alfonso

    2016-06-21

    Metabolic syndrome is a cluster of risk factors that lead to cardiovascular morbidity and mortality. Recent studies linked metabolic syndrome and several types of cancer. Although metabolic syndrome may not necessarily cause cancer, it is linked to poorer cancer outcomes including increased risk of recurrence and overall mortality. This review tends to discuss the major biological and physiological alterations involved in the increase of incidence and mortality of cancer patients affected by metabolic syndrome. We focus on metabolic syndrome-associated visceral adiposity, hyperinsulinemia, hyperglycemia, insulin-like growth factor (IGF-I) pathway as well as estrogen signaling and inflammation. Several of these factors are also involved in carcinogenesis and cancer progression. A better understanding of the link between metabolic syndrome and cancer may provide new insight about oncogenesis. Moreover, prevention of metabolic syndrome - related alterations may be an important aspect in the management of cancer patients during simultaneous palliative care.

  4. Current perspectives between metabolic syndrome and cancer

    PubMed Central

    Micucci, Carla; Valli, Debora; Matacchione, Giulia; Catalano, Alfonso

    2016-01-01

    Metabolic syndrome is a cluster of risk factors that lead to cardiovascular morbidity and mortality. Recent studies linked metabolic syndrome and several types of cancer. Although metabolic syndrome may not necessarily cause cancer, it is linked to poorer cancer outcomes including increased risk of recurrence and overall mortality. This review tends to discuss the major biological and physiological alterations involved in the increase of incidence and mortality of cancer patients affected by metabolic syndrome. We focus on metabolic syndrome-associated visceral adiposity, hyperinsulinemia, hyperglycemia, insulin-like growth factor (IGF-I) pathway as well as estrogen signaling and inflammation. Several of these factors are also involved in carcinogenesis and cancer progression. A better understanding of the link between metabolic syndrome and cancer may provide new insight about oncogenesis. Moreover, prevention of metabolic syndrome – related alterations may be an important aspect in the management of cancer patients during simultaneous palliative care. PMID:27029038

  5. Interplay between oxidant species and energy metabolism

    PubMed Central

    Quijano, Celia; Trujillo, Madia; Castro, Laura; Trostchansky, Andrés

    2015-01-01

    It has long been recognized that energy metabolism is linked to the production of reactive oxygen species (ROS) and critical enzymes allied to metabolic pathways can be affected by redox reactions. This interplay between energy metabolism and ROS becomes most apparent during the aging process and in the onset and progression of many age-related diseases (i.e. diabetes, metabolic syndrome, atherosclerosis, neurodegenerative diseases). As such, the capacity to identify metabolic pathways involved in ROS formation, as well as specific targets and oxidative modifications is crucial to our understanding of the molecular basis of age-related diseases and for the design of novel therapeutic strategies. Herein we review oxidant formation associated with the cell's energetic metabolism, key antioxidants involved in ROS detoxification, and the principal targets of oxidant species in metabolic routes and discuss their relevance in cell signaling and age-related diseases. PMID:26741399

  6. Metabolic consequences of sleep and circadian disorders

    PubMed Central

    Depner, Christopher M.; Stothard, Ellen R.; Wright, Kenneth P.

    2014-01-01

    Sleep and circadian rhythms modulate or control daily physiological patterns with importance for normal metabolic health. Sleep deficiencies associated with insufficient sleep schedules, insomnia with short-sleep duration, sleep apnea, narcolepsy, circadian misalignment, shift work, night eating syndrome and sleep-related eating disorder may all contribute to metabolic dysregulation. Sleep deficiencies and circadian disruption associated with metabolic dysregulation may contribute to weight gain, obesity, and type 2 diabetes potentially by altering timing and amount of food intake, disrupting energy balance, inflammation, impairing glucose tolerance and insulin sensitivity. Given the rapidly increasing prevalence of metabolic diseases, it is important to recognize the role of sleep and circadian disruption in the development, progression, and morbidity of metabolic disease. Some findings indicate sleep treatments and countermeasures improve metabolic health, but future clinical research investigating prevention and treatment of chronic metabolic disorders through treatment of sleep and circadian disruption is needed. PMID:24816752

  7. Tumor macroenvironment and metabolism.

    PubMed

    Al-Zoughbi, Wael; Al-Zhoughbi, Wael; Huang, Jianfeng; Paramasivan, Ganapathy S; Till, Holger; Pichler, Martin; Guertl-Lackner, Barbara; Hoefler, Gerald

    2014-04-01

    In this review we introduce the concept of the tumor macroenvironment and explore it in the context of metabolism. Tumor cells interact with the tumor microenvironment including immune cells. Blood and lymph vessels are the critical components that deliver nutrients to the tumor and also connect the tumor to the macroenvironment. Several factors are then released from the tumor itself but potentially also from the tumor microenvironment, influencing the metabolism of distant tissues and organs. Amino acids, and distinct lipid and lipoprotein species can be essential for further tumor growth. The role of glucose in tumor metabolism has been studied extensively. Cancer-associated cachexia is the most important tumor-associated systemic syndrome and not only affects the quality of life of patients with various malignancies but is estimated to be the cause of death in 15%-20% of all cancer patients. On the other hand, systemic metabolic diseases such as obesity and diabetes are known to influence tumor development. Furthermore, the clinical implications of the tumor macroenvironment are explored in the context of the patient's outcome with special consideration for pediatric tumors. Finally, ways to target the tumor macroenvironment that will provide new approaches for therapeutic concepts are described.

  8. Complexity of dopamine metabolism

    PubMed Central

    2013-01-01

    Parkinson’s disease (PD) coincides with a dramatic loss of dopaminergic neurons within the substantia nigra. A key player in the loss of dopaminergic neurons is oxidative stress. Dopamine (DA) metabolism itself is strongly linked to oxidative stress as its degradation generates reactive oxygen species (ROS) and DA oxidation can lead to endogenous neurotoxins whereas some DA derivatives show antioxidative effects. Therefore, DA metabolism is of special importance for neuronal redox-homeostasis and viability. In this review we highlight different aspects of dopamine metabolism in the context of PD and neurodegeneration. Since most reviews focus only on single aspects of the DA system, we will give a broader overview by looking at DA biosynthesis, sequestration, degradation and oxidation chemistry at the metabolic level, as well as at the transcriptional, translational and posttranslational regulation of all enzymes involved. This is followed by a short overview of cellular models currently used in PD research. Finally, we will address the topic from a medical point of view which directly aims to encounter PD. PMID:23683503

  9. Sleep and metabolic function

    PubMed Central

    Morselli, Lisa L.; Guyon, Aurore; Spiegel, Karine

    2012-01-01

    Evidence for the role of sleep on metabolic and endocrine function has been reported more than four decades ago. In the past 30 years, the prevalence of obesity and diabetes has greatly increased in industrialized countries, and self-imposed sleep curtailment, now very common, is starting to be recognized as a contributing factor, alongside with increased caloric intake and decreased physical activity. Furthermore, obstructive sleep apnea, a chronic condition characterized by recurrent upper airway obstruction leading to intermittent hypoxemia and sleep fragmentation, has also become highly prevalent as a consequence of the epidemic of obesity and has been shown to contribute, in a vicious circle, to the metabolic disturbances observed in obese patients. In this article, we summarize the current data supporting the role of sleep in the regulation of glucose homeostasis and the hormones involved in the regulation of appetite. We also review the results of the epidemiologic and laboratory studies that investigated the impact of sleep duration and quality on the risk of developing diabetes and obesity, as well as the mechanisms underlying this increased risk. Finally, we discuss how obstructive sleep apnea affects glucose metabolism and the beneficial impact of its treatment, the continuous positive airway pressure. In conclusion, the data available in the literature highlight the importance of getting enough good sleep for metabolic health. PMID:22101912

  10. Nutrigenetics of the lipoprotein metabolism.

    PubMed

    Garcia-Rios, Antonio; Perez-Martinez, Pablo; Delgado-Lista, Javier; Lopez-Miranda, Jose; Perez-Jimenez, Francisco

    2012-01-01

    It is well known that lipid metabolism is a cornerstone in the development of the commonest important chronic diseases worldwide, such as obesity, cardiovascular disease, or metabolic syndrome. In this regard, the area of lipid and lipoprotein metabolism is one of the areas in which the understanding of the development and progression of those metabolic disorders has been studied in greater depth. Thus, growing evidence has demonstrated that while universal recommendations might be appropriate for the general population, in this area there is great variability among individuals, related to a combination of environmental and genetic factors. Moreover, the interaction between genetic and dietary components has helped in understanding this variability. Therefore, with further study into the interaction between the most important genetic markers or single-nucleotide polymorphisms (SNPs) and diet, it may be possible to understand the variability in lipid metabolism, which could lead to an increase in the use of personalized nutrition as the best support to combat metabolic disorders. This review discusses some of the evidence in which candidate SNPs can affect the key players of lipid metabolism and how their phenotypic manifestations can be modified by dietary intake. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Mineral metabolism in heart disease.

    PubMed

    Heine, Gunnar H

    2015-07-01

    Strong experimental and clinical evidence points towards a substantial contribution of mineral metabolism disorders to the initiation and progression of cardiovascular disease. Vice versa, recent work suggests that cardiovascular disease may also cause mineral metabolism alterations. Experimental studies suggest that hyperphosphatemia, elevated plasma levels of phosphaturic hormones--parathyroid hormone and fibroblast growth factor-23 (FGF-23)--and hypovitaminosis D exert detrimental effects on vascular tissue and on the myocardium. Accordingly, in longitudinal clinical cohort studies, individuals with high plasma levels of phosphate, parathyroid hormone and FGF-23, and with low vitamin D levels, face worst cardiovascular prognosis.Notably, recent evidence suggests that cardiovascular disease may not only follow but also induce mineral metabolism disorders: severe derangements in mineral metabolism were observed in patients with acute heart failure, who face a tremendous increase in plasma FGF-23. Unfortunately, few prospective studies have been completed hitherto that specifically target components of the mineral metabolism for cardiovascular disease prevention or treatment. A bidirectional interaction exists between mineral metabolism disorders and cardiovascular disease. However, clinical evidence for a cardiovascular benefit of therapeutic interventions into mineral metabolism is outstanding.

  12. Final Technical Report

    SciTech Connect

    Michael Laub

    2008-12-29

    Our team of investigators from MIT (Michael Laub) and Stanford (Harley McAdams and Lucy Shapiro) conducted a multi-faceted, systematic experimental analysis of the 106 Caulobacter two-component signal transduction system proteins (62 histidine kinases and 44 response regulators) to understand how they coordinate cell cycle progression, metabolism, and response to environmental changes. These two-component signaling proteins were characterized at the genetic, biochemical, and genomic levels. The results generated by our laboratories have provided numerous insights into how Caulobacter cells sense and respond to a myriad of signals. As nearly all bacteria use two-component signaling for cell regulation, the results from this project help to deepen our general understanding of bacterial signal transduction. The tools and approaches developed can be applied to other bacteria. In particular, work from the Laub laboratory now enables the systematic, rational rewiring of two-component signaling proteins, a major advance that stands to impact synthetic biology and the development of biosensors and other designer molecular circuits. Results are summarized from our work. Each section lists publications and publicly-available resources which result from the work described.

  13. Final project report

    SciTech Connect

    Nitin S. Baliga and Leroy Hood

    2008-11-12

    The proposed overarching goal for this project was the following: Data integration, simulation and visualization will facilitate metabolic and regulatory network prediction, exploration, and formulation of hypotheses. We stated three specific aims to achieve the overarching goal of this project: (1) Integration of multiple levels of information such as mRNA and protein levels, predicted protein-protein interactions/associations and gene function will enable construction of models describing environmental response and dynamic behavior. (2) Flexible tools for network inference will accelerate our understanding of biological systems. (3) Flexible exploration and queries of model hypotheses will provide focus and reveal novel dependencies. The underlying philosophy of these proposed aims is that an iterative cycle of experiments, experimental design, and verification will lead to a comprehensive and predictive model that will shed light on systems level mechanisms involved in responses elicited by living systems upon sensing a change in their environment. In the previous years report we demonstrated considerable progress in development of data standards, regulatory network inference and data visualization and exploration. We are pleased to report that several manuscripts describing these procedures have been published in top international peer reviewed journals including Genome Biology, PNAS, and Cell. The abstracts of these manuscripts are given and they summarize our accomplishments in this project.

  14. [Progress in eyeglass optics].

    PubMed

    Köppen, W

    1995-08-01

    In this article product developments for ophthalmic lenses are discussed: new materials, designs and coatings. High-index plastic substrates allow to offer corrections which are simultaneously light and thin and for the first time there are high performant plastic photochromic lenses. Head and eye movements with latest generation's progressives are very similar to natural vision behaviour. Special aspheric designs have been developed for comfortable vision for near and intermediate distances. Finally there are new coatings which protect the high quality surfaces of plastic lenses distinctly longer than before.

  15. Progressive image denoising.

    PubMed

    Knaus, Claude; Zwicker, Matthias

    2014-07-01

    Image denoising continues to be an active research topic. Although state-of-the-art denoising methods are numerically impressive and approch theoretical limits, they suffer from visible artifacts.While they produce acceptable results for natural images, human eyes are less forgiving when viewing synthetic images. At the same time, current methods are becoming more complex, making analysis, and implementation difficult. We propose image denoising as a simple physical process, which progressively reduces noise by deterministic annealing. The results of our implementation are numerically and visually excellent. We further demonstrate that our method is particularly suited for synthetic images. Finally, we offer a new perspective on image denoising using robust estimators.

  16. Plant metabolic modeling: achieving new insight into metabolism and metabolic engineering.

    PubMed

    Baghalian, Kambiz; Hajirezaei, Mohammad-Reza; Schreiber, Falk

    2014-10-01

    Models are used to represent aspects of the real world for specific purposes, and mathematical models have opened up new approaches in studying the behavior and complexity of biological systems. However, modeling is often time-consuming and requires significant computational resources for data development, data analysis, and simulation. Computational modeling has been successfully applied as an aid for metabolic engineering in microorganisms. But such model-based approaches have only recently been extended to plant metabolic engineering, mainly due to greater pathway complexity in plants and their highly compartmentalized cellular structure. Recent progress in plant systems biology and bioinformatics has begun to disentangle this complexity and facilitate the creation of efficient plant metabolic models. This review highlights several aspects of plant metabolic modeling in the context of understanding, predicting and modifying complex plant metabolism. We discuss opportunities for engineering photosynthetic carbon metabolism, sucrose synthesis, and the tricarboxylic acid cycle in leaves and oil synthesis in seeds and the application of metabolic modeling to the study of plant acclimation to the environment. The aim of the review is to offer a current perspective for plant biologists without requiring specialized knowledge of bioinformatics or systems biology. © 2014 American Society of Plant Biologists. All rights reserved.

  17. Plant Metabolic Modeling: Achieving New Insight into Metabolism and Metabolic Engineering

    PubMed Central

    Baghalian, Kambiz; Hajirezaei, Mohammad-Reza; Schreiber, Falk

    2014-01-01

    Models are used to represent aspects of the real world for specific purposes, and mathematical models have opened up new approaches in studying the behavior and complexity of biological systems. However, modeling is often time-consuming and requires significant computational resources for data development, data analysis, and simulation. Computational modeling has been successfully applied as an aid for metabolic engineering in microorganisms. But such model-based approaches have only recently been extended to plant metabolic engineering, mainly due to greater pathway complexity in plants and their highly compartmentalized cellular structure. Recent progress in plant systems biology and bioinformatics has begun to disentangle this complexity and facilitate the creation of efficient plant metabolic models. This review highlights several aspects of plant metabolic modeling in the context of understanding, predicting and modifying complex plant metabolism. We discuss opportunities for engineering photosynthetic carbon metabolism, sucrose synthesis, and the tricarboxylic acid cycle in leaves and oil synthesis in seeds and the application of metabolic modeling to the study of plant acclimation to the environment. The aim of the review is to offer a current perspective for plant biologists without requiring specialized knowledge of bioinformatics or systems biology. PMID:25344492

  18. Metabolic Analysis

    NASA Astrophysics Data System (ADS)

    Tolstikov, Vladimir V.

    Analysis of the metabolome with coverage of all of the possibly detectable components in the sample, rather than analysis of each individual metabolite at a given time, can be accomplished by metabolic analysis. Targeted and/or nontargeted approaches are applied as needed for particular experiments. Monitoring hundreds or more metabolites at a given time requires high-throughput and high-end techniques that enable screening for relative changes in, rather than absolute concentrations of, compounds within a wide dynamic range. Most of the analytical techniques useful for these purposes use GC or HPLC/UPLC separation modules coupled to a fast and accurate mass spectrometer. GC separations require chemical modification (derivatization) before analysis, and work efficiently for the small molecules. HPLC separations are better suited for the analysis of labile and nonvolatile polar and nonpolar compounds in their native form. Direct infusion and NMR-based techniques are mostly used for fingerprinting and snap phenotyping, where applicable. Discovery and validation of metabolic biomarkers are exciting and promising opportunities offered by metabolic analysis applied to biological and biomedical experiments. We have demonstrated that GC-TOF-MS, HPLC/UPLC-RP-MS and HILIC-LC-MS techniques used for metabolic analysis offer sufficient metabolome mapping providing researchers with confident data for subsequent multivariate analysis and data mining.

  19. Metabolic cardiomyopathies

    PubMed Central

    Guertl, Barbara; Noehammer, Christa; Hoefler, Gerald

    2000-01-01

    The energy needed by cardiac muscle to maintain proper function is supplied by adenosine Ariphosphate primarily (ATP) production through breakdown of fatty acids. Metabolic cardiomyopathies can be caused by disturbances in metabolism, for example diabetes mellitus, hypertrophy and heart failure or alcoholic cardiomyopathy. Deficiency in enzymes of the mitochondrial β-oxidation show a varying degree of cardiac manifestation. Aberrations of mitochondrial DNA lead to a wide variety of cardiac disorders, without any obvious correlation between genotype and phenotype. A completely different pathogenetic model comprises cardiac manifestation of systemic metabolic diseases caused by deficiencies of various enzymes in a variety of metabolic pathways. Examples of these disorders are glycogen storage diseases (e.g. glycogenosis type II and III), lysosomal storage diseases (e.g. Niemann-Pick disease, Gaucher disease, I-cell disease, various types of mucopolysaccharidoses, GM1 gangliosidosis, galactosialidosis, carbohydrate–deficient glycoprotein syndromes and Sandhoff's disease). There are some systemic diseases which can also affect the heart, for example triosephosphate isomerase deficiency, hereditary haemochromatosis, CD 36 defect or propionic acidaemia. PMID:11298185

  20. Sphingosylphosphorylcholine in cancer progress

    PubMed Central

    Yue, Hong-Wei; Jing, Qing-Chuan; Liu, Ping-Ping; Liu, Jing; Li, Wen-Jing; Zhao, Jing

    2015-01-01

    Sphingosylphosphorylcholine (SPC) is a naturally occurring bioactive sphingolipid in blood plasma, metabolizing from the hydrolysis of the membrane sphingolipid. It has been shown to exert multifunctional role in cell physiological regulation either as an intracellular second messenger or as an extracellular agent through G protein coupled receptors (GPCRs). Because of elevated levels of SPC in malicious ascites of patients with cancer, the role of SPC in tumor progression has prompted wide interest. The factor was reported to affect the proliferation and/or migration of many cancer cells, including pancreatic cancer cells, epithelial ovarian carcinoma cells, rat C6 glioma cells, neuroblastoma cells, melanoma cells, and human leukemia cells. This review covers current knowledge of the role of SPC in tumor. PMID:26550104

  1. Gene Therapy for Metabolic Diseases

    PubMed Central

    Chandler, Randy J.; Venditti, Charles P.

    2016-01-01

    SUMMARY Gene therapy has recently shown great promise as an effective treatment for a number of metabolic diseases caused by genetic defects in both animal models and human clinical trials. Most of the current success has been achieved using a viral mediated gene addition approach, but gene-editing technology has progressed rapidly and gene modification is being actively pursued in clinical trials. This review focuses on viral mediated gene addition approaches, because most of the current clinical trials utilize this approach to treat metabolic diseases. PMID:27853673

  2. METABOLISM OF IRON STORES

    PubMed Central

    SAITO, HIROSHI

    2014-01-01

    ABSTRACT Remarkable progress was recently achieved in the studies on molecular regulators of iron metabolism. Among the main regulators, storage iron, iron absorption, erythropoiesis and hepcidin interact in keeping iron homeostasis. Diseases with gene-mutations resulting in iron overload, iron deficiency, and local iron deposition have been introduced in relation to the regulators of storage iron metabolism. On the other hand, the research on storage iron metabolism has not advanced since the pioneering research by Shoden in 1953. However, we recently developed a new method for determining ferritin iron and hemosiderin iron by computer-assisted serum ferritin kinetics. Serum ferritin increase or decrease curves were measured in patients with normal storage iron levels (chronic hepatitis C and iron deficiency anemia treated by intravenous iron injection), and iron overload (hereditary hemochromatosis and transfusion dependent anemia). We thereby confirmed the existence of two iron pathways where iron flows followed the numbered order (1) labile iron, (2) ferritin and (3) hemosiderin in iron deposition and mobilization among many previously proposed but mostly unproven routes. We also demonstrated the increasing and decreasing phases of ferritin iron and hemosiderin iron in iron deposition and mobilization. The author first demonstrated here the change in proportion between pre-existing ferritin iron and new ferritin iron synthesized by removing iron from hemosiderin in the course of iron removal. In addition, the author disclosed the cause of underestimation of storage iron turnover rate which had been reported by previous investigators in estimating storage iron turnover rate of normal subjects. PMID:25741033

  3. Metabolic neuropathies and myopathies.

    PubMed

    D'Amico, Adele; Bertini, Enrico

    2013-01-01

    Inborn errors of metabolism may impact on muscle and peripheral nerve. Abnormalities involve mitochondria and other subcellular organelles such as peroxisomes and lysosomes related to the turnover and recycling of cellular compartments. Treatable causes are β-oxidation defects producing progressive neuropathy; pyruvate dehydrogenase deficiency, porphyria, or vitamin B12 deficiency causing recurrent episodes of neuropathy or acute motor deficit mimicking Guillain-Barré syndrome. On the other hand, lysosomal (mucopolysaccharidosis, Gaucher and Fabry diseases), mitochondriopathic (mitochondrial or nuclear mutations or mDNA depletion), peroxisomal (adrenomyeloneuropathy, Refsum disease, sterol carrier protein-2 deficiency, cerebrotendinous xanthomatosis, α-methylacyl racemase deficiency) diseases are multisystemic disorders involving also the heart, liver, brain, retina, and kidney. Pathophysiology of most metabolic myopathies is related to the impairment of energy production or to abnormal production of reactive oxygen species (ROS). Main symptoms are exercise intolerance with myalgias, cramps and recurrent myoglobinuria or limb weakness associated with elevation of serum creatine kinase. Carnitine palmitoyl transferase deficiency, followed by acid maltase deficiency, and lipin deficiency, are the most common cause of isolated rhabdomyolysis. Metabolic myopathies are frequently associated to extra-neuromuscular disorders particularly involving the heart, liver, brain, retina, skin, and kidney.

  4. Final Scientific/Technical Report, DE-FG02-06ER64171, Integrated Nucleic Acid System for In-Field Monitoring of Microbial Community Dynamics and Metabolic Activity – Subproject to Co-PI Eric E. Roden

    SciTech Connect

    Eric E. Roden

    2009-07-08

    This report summarizes research conducted in conjunction with a project entitled “Integrated Nucleic Acid System for In-Field Monitoring of Microbial Community Dynamics and Metabolic Activity”, which was funded through the Integrative Studies Element of the former NABIR Program (now the Environmental Remediation Sciences Program) within the Office of Biological and Environmental Research. Dr. Darrell Chandler (originally at Argonne National Laboratory, now with Akonni Biosystems) was the overall PI/PD for the project. The overall project goals were to (1) apply a model iron-reducer and sulfate-reducer microarray and instrumentation systems to sediment and groundwater samples from the Scheibe et al. FRC Area 2 field site, UMTRA sediments, and other DOE contaminated sites; (2) continue development and expansion of a 16S rRNA/rDNA¬-targeted probe suite for microbial community dynamics as new sequences are obtained from DOE-relevant sites; and (3) address the fundamental molecular biology and analytical chemistry associated with the extraction, purification and analysis of functional genes and mRNA in environmental samples. Work on the UW subproject focused on conducting detailed batch and semicontinuous culture reactor experiments with uranium-contaminated FRC Area 2 sediment. The reactor experiments were designed to provide coherent geochemical and microbiological data in support of microarray analyses of microbial communities in Area 2 sediments undergoing biostimulation with ethanol. A total of four major experiments were conducted (one batch and three semicontinuous culture), three of which (the batch and two semicontinuous culture) provided samples for DNA microarray analysis. A variety of other molecular analyses (clone libraries, 16S PhyloChip, RT-PCR, and T-RFLP) were conducted on parallel samples from the various experiments in order to provide independent information on microbial community response to biostimulation.

  5. Genome-scale modeling for metabolic engineering

    SciTech Connect

    Simeonidis, E; Price, ND

    2015-01-13

    We focus on the application of constraint-based methodologies and, more specifically, flux balance analysis in the field of metabolic engineering, and enumerate recent developments and successes of the field. We also review computational frameworks that have been developed with the express purpose of automatically selecting optimal gene deletions for achieving improved production of a chemical of interest. The application of flux balance analysis methods in rational metabolic engineering requires a metabolic network reconstruction and a corresponding in silico metabolic model for the microorganism in question. For this reason, we additionally present a brief overview of automated reconstruction techniques. Finally, we emphasize the importance of integrating metabolic networks with regulatory information-an area which we expect will become increasingly important for metabolic engineering-and present recent developments in the field of metabolic and regulatory integration.

  6. Genome-scale modeling for metabolic engineering

    PubMed Central

    Simeonidis, Evangelos

    2015-01-01

    We focus on the application of constraint-based methodologies and, more specifically, flux balance analysis in the field of metabolic engineering, and enumerate recent developments and successes of the field. We also review computational frameworks that have been developed with the express purpose of automatically selecting optimal gene deletions for achieving improved production of a chemical of interest. The application of flux balance analysis methods in rational metabolic engineering requires a metabolic network reconstruction and a corresponding in silico metabolic model for the microorganism in question. For this reason, we additionally present a brief overview of automated reconstruction techniques. Finally, we emphasize the importance of integrating metabolic networks with regulatory information—an area which we expect will become increasingly important for metabolic engineering—and present recent developments in the field of metabolic and regulatory integration. PMID:25578304

  7. Genome-scale modeling for metabolic engineering.

    PubMed

    Simeonidis, Evangelos; Price, Nathan D

    2015-03-01

    We focus on the application of constraint-based methodologies and, more specifically, flux balance analysis in the field of metabolic engineering, and enumerate recent developments and successes of the field. We also review computational frameworks that have been developed with the express purpose of automatically selecting optimal gene deletions for achieving improved production of a chemical of interest. The application of flux balance analysis methods in rational metabolic engineering requires a metabolic network reconstruction and a corresponding in silico metabolic model for the microorganism in question. For this reason, we additionally present a brief overview of automated reconstruction techniques. Finally, we emphasize the importance of integrating metabolic networks with regulatory information-an area which we expect will become increasingly important for metabolic engineering-and present recent developments in the field of metabolic and regulatory integration.

  8. Visualizing patterns of neurological disease progression with PET

    NASA Astrophysics Data System (ADS)

    Spetsieris, Phoebe G.; Dhawan, Vijay; Moeller, James R.; Eidelberg, David

    1994-05-01

    By applying non-conventional statistical analysis and visualization techniques to PET data obtained from a combined group of patients and normals, we are able to illustrate topographic covariance profiles unique to the disease at various stages of progression. Each profile represents a neuroanatomical regional network that is not discernible in the unprocessed data sets using standard analytical methods. The magnitude of a profile's manifestation in a given subject is expressed as a subject score which can correlate with independent clinical disease severity measures such as quantitative rigidity and bradykinesia ratings in Parkinson's disease. To create representations of these profiles a semi-automated routine is used which first generates a 2D pseudocolor map of the network where each region is weighted in accordance with its relative contribution to the overall profile. This representation is then transformed to a 3D isometric form so that the metabolic topography becomes more visually apparent. To fully perceive the evolving topographical pattern from initial to final stages of the disease, intermediate stages of disease progression are derived by interpolation to create a smooth progression of images that are displayed in an animated sequence.

  9. Vitamin E slows down the progression of osteoarthritis

    PubMed Central

    LI, XI; DONG, ZHONGLI; ZHANG, FUHOU; DONG, JUNJIE; ZHANG, YUAN

    2016-01-01

    Osteoarthritis is a chronic degenerative joint disorder with the characteristics of articular cartilage destruction, subchondral bone alterations and synovitis. Clinical signs and symptoms of osteoarthritis include pain, stiffness, restricted motion and crepitus. It is the major cause of joint dysfunction in developed nations and has enormous social and economic consequences. Current treatments focus on symptomatic relief, however, they lack efficacy in controlling the progression of this disease, which is a leading cause of disability. Vitamin E is safe to use and may delay the progression of osteoarthritis by acting on several aspects of the disease. In this review, how vitamin E may promote the maintenance of skeletal muscle and the regulation of nucleic acid metabolism to delay osteoarthritis progression is explored. In addition, how vitamin E may maintain the function of sex organs and the stability of mast cells, thus conferring a greater resistance to the underlying disease process is also discussed. Finally, the protective effect of vitamin E on the subchondral vascular system, which decreases the reactive remodeling in osteoarthritis, is reviewed. PMID:27347011

  10. Liver fibrogenesis and metabolic factors.

    PubMed

    Anty, Rodolphe; Lemoine, Maud

    2011-06-01

    Mechanisms of liver fibrosis are complex and varied. Among them, metabolic factors are particularly important in the development of fibrosis associated with nonalcoholic steatohepatitis (NASH). These factors are some of the "multiple parallel hits" responsible for liver damage during NASH. Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. Major profibrogenic protagonists, such as hepatic stellate cells and Kupffer cells, are activated by insulin resistance, apoptosis and local inflammation. Relations between steatosis, insulin resistance and fibrosis are complex. Initially, simple steatosis may be a way to store deleterious free fatty acid in neutral triglycerides. If the lipid storage threshold is exceeded, steatosis may become associated with lipotoxicity. Similarly, interindividual variations of adipose tissue expandability might explain various phenotypes, ranging from "metabolically obese patients with normal weight" to "metabolically normal morbidly obese patients". The metabolic abnormalities in subcutaneous and visceral adipose tissue are insulin resistance and low-grade inflammation, which are associated with increased release of free fatty acid flux and changes in adipocytokines production such as leptin, adiponectin and interleukin 6. The nuclear transcription factor peroxisome proliferator-activated receptor gamma (PPARγ) and the endocannabinoid system might have important roles in liver fibrogenesis and are potential therapeutic targets. Finally, with the development of new molecular tools, gut microbiota has been recently identified for its pleiotropic functions, including metabolism regulation. Better knowledge of these mechanisms should lead to new strategies for the treatment of metabolic factors that play a key role in liver injuries.

  11. Mechanism of Neonicotinoid Toxicity: Impact on Oxidative Stress and Metabolism.

    PubMed

    Wang, Xu; Anadón, Arturo; Qinghua, Wu; Qiao, Fang; Ares, Irma; Martínez-Larrañaga, María-Rosa; Yuan, Zonghui; Martínez, María-Aránzazu

    2017-10-02

    Thousands of tons of neonicotinoids are widely used around the world as broad-spectrum systemic insecticides and veterinary drugs. Researchers originally thought that neonicotinoids exhibited low mammalian toxicity. However, following their widespread use, it became increasingly evident that neonicotinoids could have various toxic effects on vertebrates and invertebrates. The primary focus of this review is to summarize the research progress associated with oxidative stress as a plausible mechanism for neonicotinoid-induced toxicity as well as neonicotinoid metabolism. This review summarizes the research conducted over the past decade into the production of reactive oxygen species, reactive nitrogen species, and oxidative stress as result of neonicotinoid treatments, along with their correlation with the toxicity and metabolism of neonicotinoids. The metabolism of neonicotinoids and protection of various compounds against neonicotinoid-induced toxicity based on their antioxidative effects is also discussed. This review sheds new light on the critical roles of oxidative stress in neonicotinoid-induced toxicity to nontarget species. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 58 is January 6, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

  12. [Homocysteine metabolism].

    PubMed

    Hashimoto, Takao; Shinohara, Yoshihiko; Hasegawa, Hiroshi

    2007-10-01

    Homocysteine, a sulfur amino acid, is an intermediate metabolite of methionine. In 1969, McCully reported autopsy evidence of extensive arterial thrombosis and atherosclerosis in children with elevated plasma homocysteine concentrations and homocystinuria. On the basis of this observation, he proposed that elevated plasma homocysteine (hyperhomocysteinemia) can cause atherosclerotic vascular disease. Hyperhomocysteinemia is now well established as an independent risk factor for atherosclerotic vascular disease. Mild hyperhomocysteinemia is quite prevalent in the general population. It can be caused by genetic defects in the enzymes involved in homocysteine metabolism or nutritional deficiencies in vitamin cofactors, certain medications or renal disease. An increase of 5 micromol per liter in the plasma homocysteine concentration raises the risk of coronary artery disease by as much as an increase of 20 mg per deciliter in the cholesterol concentration. In this article, we review the biochemical, experimental and clinical studies on hyperhomocysteinemia, with emphasis on the metabolism and pharmacokinetics of homocysteine.

  13. Liquid Chromatography-Mass Spectrometry (LC/MS)-based parallel metabolic profiling of human and mouse model serum reveals putative biomarkers associated with the progression of non-alcoholic fatty liver disease

    PubMed Central

    Barr, Jonathan; Alonso, Cristina; Vázquez-Chantada, Mercedes; Cormenzana, Miriam Pérez-; Mayo, Rebeca; Galán, Asier; Caballería, Juan; Martín-Duce, Antonio; Tran, Albert; Wagner, Conrad; Luka, Zigmund; Lu, Shelly C.; Castro, Azucena; Le Marchand-Brustel, Yannick; Martínez-Chantar, M. Luz; Veyrie, Nicolas; Clément, Karine; Tordjman, Joan; Gual, Philippe; Mato, José M.

    2010-01-01

    Non-alcoholic fatty liver disease (NAFLD), is the most common form of chronic liver disease in most western countries. Current NAFLD diagnosis methods (e.g. liver biopsy analysis or imaging techniques) are poorly suited as tests for such a prevalent condition, from both a clinical and financial point of view. The present work aims to demonstrate the potential utility of serum metabolic profiling in defining phenotypic biomarkers that could be useful in NAFLD management. A parallel animal model / human NAFLD exploratory metabolomics approach was employed, using ultra performance liquid chromatography-mass spectrometry (UPLC®-MS) to analyze 42 serum samples collected from non-diabetic, morbidly obese, biopsy-proven NAFLD patients, and 17 animals belonging to the glycine N-methyltransferase knockout (GNMT-KO) NAFLD mouse model. Multivariate statistical analysis of the data revealed a series of common biomarkers that were significantly altered in the NAFLD (GNMT-KO) subjects in comparison to their normal liver counterparts (WT). Many of the compounds observed could be associated with biochemical perturbations associated with liver dysfunction (e.g. reduced Creatine) and inflammation (e.g. eicosanoid signaling). This differential metabolic phenotyping approach may have a future role as a supplement for clinical decision making in NAFLD and in the adaption to more individualized treatment protocols. PMID:20684516

  14. Metabolic model for diversity-generating biosynthesis

    PubMed Central

    Tianero, Ma. Diarey; Pierce, Elizabeth; Raghuraman, Shrinivasan; Sardar, Debosmita; McIntosh, John A.; Heemstra, John R.; Schonrock, Zachary; Covington, Brett C.; Maschek, J. Alan; Cox, James E.; Bachmann, Brian O.; Olivera, Baldomero M.; Ruffner, Duane E.; Schmidt, Eric W.

    2016-01-01

    A conventional metabolic pathway leads to a specific product. In stark contrast, there are diversity-generating metabolic pathways that naturally produce different chemicals, sometimes of great diversity. We demonstrate that for one such pathway, tru, each ensuing metabolic step is slower, in parallel with the increasing potential chemical divergence generated as the pathway proceeds. Intermediates are long lived and accumulate progressively, in contrast with conventional metabolic pathways, in which the first step is rate-limiting and metabolic intermediates are short-lived. Understanding these fundamental differences enables several different practical applications, such as combinatorial biosynthesis, some of which we demonstrate here. We propose that these principles may provide a unifying framework underlying diversity-generating metabolism in many different biosynthetic pathways. PMID:26831074

  15. Metabolic flux rewiring in mammalian cell cultures

    PubMed Central

    Young, Jamey D.

    2013-01-01

    Continuous cell lines (CCLs) engage in “wasteful” glucose and glutamine metabolism that leads to accumulation of inhibitory byproducts, primarily lactate and ammonium. Advances in techniques for mapping intracellular carbon fluxes and profiling global changes in enzyme expression have led to a deeper understanding of the molecular drivers underlying these metabolic alterations. However, recent studies have revealed that CCLs are not necessarily entrenched in a glycolytic or glutaminolytic phenotype, but instead can shift their metabolism toward increased oxidative metabolism as nutrients become depleted and/or growth rate slows. Progress to understand dynamic flux regulation in CCLs has enabled the development of novel strategies to force cultures into desirable metabolic phenotypes, by combining fed-batch feeding strategies with direct metabolic engineering of host cells. PMID:23726154

  16. Metabolic Downregulation

    PubMed Central

    Yenari, Midori; Kitagawa, Kazuo; Lyden, Patrick; Perez-Pinzon, Miguel

    2008-01-01

    Background and Purpose The search for effective neuroprotectants remains frustrating, particularly with regard to specific pharmaceuticals. However, laboratory studies have consistently shown remarkable neuroprotection with 2 nonpharmacological strategies—therapeutic hypothermia and ischemic preconditioning. Recent studies have shown that the mechanism of protection underlying both of these treatments is correlated to downregulation of cellular and tissue metabolism. Thus, understanding the mechanisms underlying such robust protective effects could lead to appropriate translation at the clinical level. In fact, hypothermia is already being used at many centers to improve neurological outcome from cardiac arrest. Methods A systematic review of both topics is presented in terms of underlying pathophysiological mechanisms and application at the clinical level. Results Although the mechanisms of protection for both therapeutic strategies are multifold, both share features of downregulating metabolism. Both therapeutic strategies are robust neuroprotectants, but translating them to the clinical arena is challenging, though not impossible, and clinical studies have shown or suggest benefits of both treatments. Conclusions The strategy of metabolic downregulation should be further explored to identify effective neuroprotectants that can be easily applied clinically. PMID:18658035

  17. What is Metabolic Syndrome?

    MedlinePlus

    ... from the NHLBI on Twitter. What Is Metabolic Syndrome? Metabolic syndrome is the name for a group of ... that may play a role in causing metabolic syndrome. Outlook Metabolic syndrome is becoming more common due to a ...

  18. Resistance to glucose starvation as metabolic trait of platinum-resistant human epithelial ovarian cancer cells

    PubMed Central

    Pastò, Anna; Pagotto, Anna; Pilotto, Giorgia; De Paoli, Angela; De Salvo, Gian Luca; Baldoni, Alessandra; Nicoletto, Maria Ornella; Ricci, Francesca; Damia, Giovanna; Bellio, Chiara

    2017-01-01

    Deregulated glucose metabolism is observed in cancer but whether this metabolic trait influences response to or is modulated by cytotoxic drugs is unknown. We show here that tumor cells from epithelial ovarian cancer (EOC) patients can be categorized, according to their in vitro viability under glucose starvation, into glucose deprivation-sensitive (glucose-addicted, GA) and glucose deprivation-resistant (glucose non-addicted, GNA). When EOC cells were cultured in the absence of glucose, all samples from platinum (PLT)-sensitive patients felt into the GA group; they disclosed higher expression of glucose metabolism enzymes, higher proliferation rates and in vitro sensitivity to PLT. Moreover, GA patients showed reduced multi-drug resistance pump expression and autophagy, compared to GNA samples. The close association between PLT sensitivity and glucose metabolic profile was confirmed in a xenograft model, where a stringent parallelism between PLT sensitivity/resistance and glucose metabolism was identified. Finally, in a cohort of naïve EOC patients categorized as GA or GNA at diagnosis, Kaplan Meier curves showed that the GA phenotype was associated with significantly better progression-free survival, compared to GNA patients. PMID:28031535

  19. Glucose metabolism by adult hepatocytes in primary culture and by cell lines from rat liver.

    PubMed

    Bissell, D M; Levine, G A; Bissell, M J

    1978-03-01

    The metabolic fate of [U-14C]glucose has been examined in detail in adult rat hepatocytes in primary monolayer culture, as well as in two permanent cell lines--Buffalo rat liver (BRL) and transplantable rat hepatoma (HTC) cells-derived from normal rat liver and from rat hepatoma, respectively. Under defined conditions of incubation, at a glucose concentration of 5.5 mM, the three types of cultured liver cells exhibited pronounced differences in glucose metabolism. Primary cultures, like the intact liver, differed from the cell lines in consuming relatively small amounts of glucose and converting approximately 50% of the total metabolized glucose to lactate. By contrast, the permantent cell lines consumed glucose at a 40-fold greater rate than did primary cultures, converting 80--90% of the carbohydrate to lactate. Oxidative metabolism of glucose carbon also differed among the three types of liver culture. Of the total [U-14C]glucose consumed, primary cultures converted approximately 30% to labeled CO2 per hour, whereas the liver cell lines converted 5--10%. Finally, glucose metabolism in primary culture exhibited adaptation as hepatocytes aged in culture, shifting progressively toward the pattern exhibited by the permanent cell lines. This change occurred over a time course similar to that for other kinds of functional change in hepatocytes in primary culture and thus may be relevant to the general problem of phenotypic alteration in liver cell culture.

  20. Glucose Metabolism in T Cells and Monocytes: New Perspectives in HIV Pathogenesis.

    PubMed

    Palmer, Clovis S; Cherry, Catherine L; Sada-Ovalle, Isabel; Singh, Amit; Crowe, Suzanne M

    2016-04-01

    Activation of the immune system occurs in response to the recognition of foreign antigens and receipt of optimal stimulatory signals by immune cells, a process that requires energy. Energy is also needed to support cellular growth, differentiation, proliferation, and effector functions of immune cells. In HIV-infected individuals, persistent viral replication, together with inflammatory stimuli contributes to chronic immune activation and oxidative stress. These conditions remain even in subjects with sustained virologic suppression on antiretroviral therapy. Here we highlight recent studies demonstrating the importance of metabolic pathways, particularly those involving glucose metabolism, in differentiation and maintenance of the activation states of T cells and monocytes. We also discuss how changes in the metabolic status of these cells may contribute to ongoing immune activation and inflammation in HIV- infected persons and how this may contribute to disease progression, establishment and persistence of the HIV reservoir, and the development of co-morbidities. We provide evidence that other viruses such as Epstein-Barr and Flu virus also disrupt the metabolic machinery of their host cells. Finally, we discuss how redox signaling mediated by oxidative stress may regulate metabolic responses in T cells and monocytes during HIV infection.

  1. Integrating gene and protein expression data with genome-scale metabolic networks to infer functional pathways.

    PubMed

    Pey, Jon; Valgepea, Kaspar; Rubio, Angel; Beasley, John E; Planes, Francisco J

    2013-12-08

    The study of cellular metabolism in the context of high-throughput -omics data has allowed us to decipher novel mechanisms of importance in biotechnology and health. To continue with this progress, it is essential to efficiently integrate experimental data into metabolic modeling. We present here an in-silico framework to infer relevant metabolic pathways for a particular phenotype under study based on its gene/protein expression data. This framework is based on the Carbon Flux Path (CFP) approach, a mixed-integer linear program that expands classical path finding techniques by considering additional biophysical constraints. In particular, the objective function of the CFP approach is amended to account for gene/protein expression data and influence obtained paths. This approach is termed integrative Carbon Flux Path (iCFP). We show that gene/protein expression data also influences the stoichiometric balancing of CFPs, which provides a more accurate picture of active metabolic pathways. This is illustrated in both a theoretical and real scenario. Finally, we apply this approach to find novel pathways relevant in the regulation of acetate overflow metabolism in Escherichia coli. As a result, several targets which could be relevant for better understanding of the phenomenon leading to impaired acetate overflow are proposed. A novel mathematical framework that determines functional pathways based on gene/protein expression data is presented and validated. We show that our approach is able to provide new insights into complex biological scenarios such as acetate overflow in Escherichia coli.

  2. Integrating gene and protein expression data with genome-scale metabolic networks to infer functional pathways

    PubMed Central

    2013-01-01

    Background The study of cellular metabolism in the context of high-throughput -omics data has allowed us to decipher novel mechanisms of importance in biotechnology and health. To continue with this progress, it is essential to efficiently integrate experimental data into metabolic modeling. Results We present here an in-silico framework to infer relevant metabolic pathways for a particular phenotype under study based on its gene/protein expression data. This framework is based on the Carbon Flux Path (CFP) approach, a mixed-integer linear program that expands classical path finding techniques by considering additional biophysical constraints. In particular, the objective function of the CFP approach is amended to account for gene/protein expression data and influence obtained paths. This approach is termed integrative Carbon Flux Path (iCFP). We show that gene/protein expression data also influences the stoichiometric balancing of CFPs, which provides a more accurate picture of active metabolic pathways. This is illustrated in both a theoretical and real scenario. Finally, we apply this approach to find novel pathways relevant in the regulation of acetate overflow metabolism in Escherichia coli. As a result, several targets which could be relevant for better understanding of the phenomenon leading to impaired acetate overflow are proposed. Conclusions A novel mathematical framework that determines functional pathways based on gene/protein expression data is presented and validated. We show that our approach is able to provide new insights into complex biological scenarios such as acetate overflow in Escherichia coli. PMID:24314206

  3. Cascading failure and robustness in metabolic networks.

    PubMed

    Smart, Ashley G; Amaral, Luis A N; Ottino, Julio M

    2008-09-09

    We investigate the relationship between structure and robustness in the metabolic networks of Escherichia coli, Methanosarcina barkeri, Staphylococcus aureus, and Saccharomyces cerevisiae, using a cascading failure model based on a topological flux balance criterion. We find that, compared to appropriate null models, the metabolic networks are exceptionally robust. Furthermore, by decomposing each network into rigid clusters and branched metabolites, we demonstrate that the enhanced robustness is related to the organization of branched metabolites, as rigid cluster formations in the metabolic networks appear to be consistent with null model behavior. Finally, we show that cascading in the metabolic networks can be described as a percolation process.

  4. Cascading failure and robustness in metabolic networks

    PubMed Central

    Smart, Ashley G.; Amaral, Luis A. N.; Ottino, Julio M.

    2008-01-01

    We investigate the relationship between structure and robustness in the metabolic networks of Escherichia coli, Methanosarcina barkeri, Staphylococcus aureus, and Saccharomyces cerevisiae, using a cascading failure model based on a topological flux balance criterion. We find that, compared to appropriate null models, the metabolic networks are exceptionally robust. Furthermore, by decomposing each network into rigid clusters and branched metabolites, we demonstrate that the enhanced robustness is related to the organization of branched metabolites, as rigid cluster formations in the metabolic networks appear to be consistent with null model behavior. Finally, we show that cascading in the metabolic networks can be described as a percolation process. PMID:18765805

  5. Biofuel metabolic engineering with biosensors.

    PubMed

    Morgan, Stacy-Anne; Nadler, Dana C; Yokoo, Rayka; Savage, David F

    2016-12-01

    Metabolic engineering offers the potential to renewably produce important classes of chemicals, particularly biofuels, at an industrial scale. DNA synthesis and editing techniques can generate large pathway libraries, yet identifying the best variants is slow and cumbersome. Traditionally, analytical methods like chromatography and mass spectrometry have been used to evaluate pathway variants, but such techniques cannot be performed with high throughput. Biosensors - genetically encoded components that actuate a cellular output in response to a change in metabolite concentration - are therefore a promising tool for rapid and high-throughput evaluation of candidate pathway variants. Applying biosensors can also dynamically tune pathways in response to metabolic changes, improving balance and productivity. Here, we describe the major classes of biosensors and briefly highlight recent progress in applying them to biofuel-related metabolic pathway engineering. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Final technical report.

    SciTech Connect

    Emmanuel J. Candes

    2007-11-06

    In the last two dcades or so, many multiscale algorthms have been proposed to enable large scale computations which were thought as nearly intractable. For example, the fast multipole algorithm and other similar ideas have allowed to considerably speed up fundamental computations in electromagnetism, and many other fields. The thesis underlying this proposal is that traditional multiscale methods have been well-developed and it is clear that we now need new ideas in areas where traditional spatial multiscaling is ill-suited. In this context, the proposal argues that clever phase-space computations is bound to plan a crucial role in advancing algorithms and high-performance scientific computing. Our research past accomplishments have shown the existence of ideas beyond the traditional scale-space viewpoint such as new multiscale geometric representations of phase-space. We have shown that these clever representations lead to enhanced sparsity. We have shown that enhanced sparsity has significant important implications both for analysis, and for numerical applications, where sparsity allows for faster algorithms. We have implemented these ideas and built computational tools to be used as new building blocks of a new generation of wave propagation solvers. Finally, we have deployed these ideas into novel algorithms. In this last year, we assembled all these techniques and made significant progress in solving a variety of computational problems, which we then applied in selected areas of considerable scientific interest.

  7. MicroRNAs in pancreatic cancer metabolism

    PubMed Central

    Singh, Pankaj K.; Brand, Randall E.; Mehla, Kamiya

    2014-01-01

    Advances in understanding the biology of tumour progression and metastasis have clearly highlighted the importance of aberrant tumour metabolism, which supports not only the energy requirements but also the enormous biosynthetic needs of tumour cells. Such metabolic alterations modulate glucose, amino acid and fatty-acid-dependent metabolite bio-synthesis and energy production. Although much progress has been made in understanding the somatic mutations and expression genomics behind these alterations, the regulation of these processes by microRNAs (miRNAs) is only beginning to be appreciated. This Review focuses on the miRNAs that are potential regulators of the expression of genes whose protein products either directly regulate metabolic machinery or serve as master regulators, indirectly modulating the expression of metabolic enzymes. We focus particularly on miRNAs in pancreatic cancer. PMID:22508159

  8. Metabolic regulation via enzyme filamentation

    PubMed Central

    Aughey, Gabriel N.; Liu, Ji-Long

    2016-01-01

    Abstract Determining the mechanisms of enzymatic regulation is central to the study of cellular metabolism. Regulation of enzyme activity via polymerization-mediated strategies has been shown to be widespread, and plays a vital role in mediating cellular homeostasis. In this review, we begin with an overview of the filamentation of CTP synthase, which forms filamentous structures termed cytoophidia. We then highlight other important examples of the phenomenon. Moreover, we discuss recent data relating to the regulation of enzyme activity by compartmentalization into cytoophidia. Finally, we hypothesize potential roles for enzyme filament formation in the regulation of metabolism, development and disease. PMID:27098510

  9. [Metabolic syndrome].

    PubMed

    Takata, Hiroshi; Fujimoto, Shimpei

    2013-02-01

    Metabolic syndrome (Mets) is a combination of disorders including abdominal obesity, impaired glucose tolerance, dyslipidemia and hypertension, which increases risk for cardiovascular disease (CVD) and type 2 diabetes when occurring together. In Japan, diagnosis criteria of Mets consists of an increased waist circumference and 2 or more of CVD risk factors. Annual health checkups and health guidance using Mets criteria were established in 2008 for the prevention of life-style related diseases in Japan. In this issue, history and diagnostic criteria of Mets and concerns for Mets concept were described.

  10. Metabolic Networks

    NASA Astrophysics Data System (ADS)

    Palumbo, Maria Concetta; Farina, Lorenzo; Colosimo, Alfredo; Giuliani, Alessandro

    The use of the term `network' is more and more widespread in all fields of biology. It evokes a systemic approach to biological problems able to overcome the evident limitations of the strict reductionism of the past twenty years. The expectations produced by taking into considerations not only the single elements but even the intermingled `web' of links connecting different parts of biological entities, are huge. Nevertheless, we believe that the lack of consciousness that networks, beside their biological `likelihood', are modeling tools and not real entities, could be detrimental to the exploitation of the full potential of this paradigm. Like any modeling tool the network paradigm has a range of application going from situations in which it is particularly fit to situations in which its application can be largely misleading. In this chapter we deal with an aspect of biological entities that is particularly fit for the network approach: the intermediate metabolism. This fit derives both from the existence of a privileged formalization in which the relative role of nodes (metabolites) and arches (enzymes) is immediately suggested by the system architecture. Here we will discuss some applications of both graph theory based analysis and multidimensional statistics method to metabolic network studies with the emphasis on the derivation of biologically meaningful information.

  11. Metabolic Syndrome.

    PubMed

    Sherling, Dawn Harris; Perumareddi, Parvathi; Hennekens, Charles H

    2017-07-01

    The United States is experiencing its greatest life expectancy ever. Nonetheless, the general health of the US population is far from at an all-time high. An important contributor to the pandemic of cardiovascular disease is that overweight and obesity are also the major determinants of metabolic syndrome, an all too common and all too serious clinical and public health challenge. Clinicians have traditionally evaluated each of the major risk factors contributing to metabolic syndrome on an individual basis. There is evidence, however, that the risk factors are more than additive. The overlap of these factors in each disease state, resulting in increased atherogenic risks, is worth examining as a broader entity rather than separately. While therapeutic lifestyle changes (TLCs) should be strongly recommended, clinicians should not let the perfect be the enemy of the possible. Evidence-based doses of statins, aspirin and angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers should be prescribed as adjuncts, not alternatives, to TLCs. In fact, there is cogent evidence that the benefits of these pharmacologic therapies may also be at least additive.

  12. Carotenoid metabolism in plants.

    PubMed

    Nisar, Nazia; Li, Li; Lu, Shan; Khin, Nay Chi; Pogson, Barry J

    2015-01-01

    Carotenoids are mostly C40 terpenoids, a class of hydrocarbons that participate in various biological processes in plants, such as photosynthesis, photomorphogenesis, photoprotection, and development. Carotenoids also serve as precursors for two plant hormones and a diverse set of apocarotenoids. They are colorants and critical components of the human diet as antioxidants and provitamin A. In this review, we summarize current knowledge of the genes and enzymes involved in carotenoid metabolism and describe recent progress in understanding the regulatory mechanisms underlying carotenoid accumulation. The importance of the specific location of carotenoid enzyme metabolons and plastid types as well as of carotenoid-derived signals is discussed. Copyright © 2015 The Author. Published by Elsevier Inc. All rights reserved.

  13. Metabolism and the UPRmt

    PubMed Central

    Lin, Yi-Fan; Haynes, Cole M.

    2016-01-01

    SUMMARY During mitochondrial dysfunction or the accumulation of unfolded proteins within mitochondria, cells employ a transcriptional response known as the mitochondrial unfolded protein response (UPRmt) to promote cell survival along with the repair and recovery of defective mitochondria. Considerable progress has been made in understanding how cells monitor mitochondrial function and activate the response, as well as in identifying scenarios where the UPRmt plays a protective role such as during bacterial infection, hematopoietic stem cell maintenance or general aging. To date, much of the focus has been on the role of the UPRmt in maintaining or re-establishing protein homeostasis within mitochondria by transcriptionally inducing mitochondrial molecular chaperone and protease genes. In this review, we focus on the metabolic adaptations or rewiring mediated by the UPRmt and how this may contribute to the resolution of mitochondrial unfolded protein stress and cell type-specific physiology. PMID:26942672

  14. Metabolic reprogramming of the tumour microenvironment.

    PubMed

    Xing, Yazhi; Zhao, Shimin; Zhou, Binhua P; Mi, Jun

    2015-10-01

    Tumour cells, stromal cells and the stroma comprise the tumour microenvironment. The metabolism of both tumour cells and several types of tumour stromal cells, such as cancer-associated fibroblasts and tumour-associated macrophages, is reprogrammed. Current studies have found that stromal cells promote tumour progression and metastasis, through not only the paracrine secretion of cytokines or chemokines, but also intermediate metabolites. Here, we summarize the latest insights into the mechanism of metabolic reprogramming in cancer cells, cancer-associated fibroblasts and tumour-associated macrophages, and their potential roles in tumour progression and metastasis. © 2015 FEBS.

  15. Midwest Superconductivity Consortium - Final Progress Report October 2001

    SciTech Connect

    Bement, Arden L.

    2001-10-23

    The basic mission of the Consortium was to advance the science and understanding of high-T{sub c} superconductivity and to promote the development of new materials and improved processing technology. Focused group efforts were the key element of the research program. One program area is the understanding of the layered structures involved in candidate materials and the factors that control their formation, stability and relationship superconductor properties. The other program area had a focus upon factors that limit or control the transport properties such as weak links, flux lattice behavior, and interfaces. Interactions among Consortium d with industrial armiates were an integral part of the program.

  16. Establishment of Northwest Building Testbeds: Final Progress Report

    SciTech Connect

    Stiles, Dennis L.

    2012-08-01

    This document provides a short summary of a project jointly funded by the DOE Building Technologies Program and the Northwest Energy Efficiency Alliance. The report the outcomes achieved in the jointly-funded project, describes major project activities, discusses future plans for the homes and data, and provides details on project costs and schedule performance.

  17. Final Progress Report for Grant Number DE-SC0007229

    SciTech Connect

    Blake, Robert

    2016-08-18

    We exploited a novel spectrophotometer where the cuvette is a reflecting cavity completely filled with an absorbing suspension of live, intact bacteria to monitor the in situ absorbance changes in bacteria as they respired aerobically on soluble ferrous ions. Our prior observations suggested the following hypothesis: acidophilic bacteria that belong to different phyla express different types of electron transfer proteins to respire on extracellular iron. We tested this hypothesis using six different organisms that represented each of the six phyla of microorganisms that respire aerobically on iron. Each of these six organisms expressed spectrally different biomolecules that were redox-active during aerobic respiration on iron. In all six cases, compelling kinetic evidence was collected to indicate that the biomolecules in question were obligatory intermediates in their respective respiratory chains. Additional experiments with intact Acidithiobacillus ferrooxidans revealed that the crowded electron transport proteins in this organism’s periplasm constituted a semi-conducting medium where the network of protein interactions functioned in a concerted fashion as a single ensemble. Thus the molecular oxygen-dependent oxidation of the multi-center respiratory chain occurred with a single macroscopic rate constant, regardless of the proteins’ individual redox potentials or their putative positions in the aerobic iron respiratory chain.

  18. [Numerical methods for multi-fluid flows]. Final progress report

    SciTech Connect

    Pozrikidis, C.

    1998-07-21

    The central objective of this research has been to develop efficient numerical methods for computing multi-fluid flows with large interfacial deformations, and apply these methods to study the rheology of suspensions of deformable particles with viscous and non-Newtonian interfacial behavior. The mathematical formulation employs boundary-integral, immersed-boundary, and related numerical methods. Particles of interest include liquid drops with constant surface tension and capsules whose interfaces exhibit viscoelastic and incompressible characteristics. In one family of problems, the author has considered the shear-driven and pressure-driven flow of a suspension of two-dimensional liquid drops with ordered and random structure. In a second series of investigations, the author carried out dynamic simulations of two-dimensional, unbounded, doubly-periodic shear flows with random structure. Another family of problems addresses the deformation of three-dimensional capsules whose interfaces exhibit isotropic surface tension, viscous, elastic, or incompressible behavior, in simple shear flow. The numerical results extend previous asymptotic theories for small deformations and illuminate the mechanism of membrane rupture.

  19. Rankine cycle generators using geothermal fluids. Final progress report

    SciTech Connect

    Not Available

    1981-01-01

    The Rankine Cycle generator was delivered and installed at Gila Hot Springs. Trial runs were made at that time, using Freon 12 as the expansion fluid. These tests showed that the boiler capacity was inadequate. It could not extract enough heat to generate sufficient volumes of Freon gas at the heat and pressure necessary to operate the system at an acceptable level. Increasing and decreasing the flow of hot water had a direct influence on efficiency, but it was not a linear relationship. Added amounts of hot water increased the power very little, but raised the water temperature at the discharge point. This implied that the heat exchange capacity of the boiler was saturated. The reverse was found in the condenser system. There was little increase in pressure of the condenser when we switched from static to run mode. Efficiency was maintained even when the cold water flow was reduced as much as 40%. The tests using Freon 12 resulted in the conclusion that the boiler volume needs to be increased and/or the configuration changed to radically increase its efficiency.

  20. A Center for Excellence in Mathematical Sciences Final Progress Report

    DTIC Science & Technology

    2013-01-31

    conditions, one can show [9] that particular solutions of (4) are asymptotically stable in the sense of Lyapunov . In (5), A is a scaling parameter... equivalent in a specific sense (as we will show - Sagent Corp. 13 Notice that the state function, computed by the lower level automaton, could be...given as a linear combination of the states in S. We chose to model it as a Chattering Combination, which turns out to be equivalent in a specific sense

  1. MRS feasibility assessment grant technical progress report. Final report

    SciTech Connect

    Not Available

    1993-02-01

    On January 13, 1993, Governor of the State of Utah, Mike Leavitt officially announced that he was opposing a MRS Facility in the State of Utah and informed San Juan County of his decision which will preclude the County from applying for a Phase IIa feasibility grant. A copy of the policy statement made by Governor Leavitt is included in this report. Additionally, a bill in the State House of Representative has been filed opposing the facility. A copy of the bill is also included. The work accomplished under Phase I, indicated that there was about an equal amount of residents in San Juan County opposed and in favor of the facility. There were many concerns and issues presented during the Phase I grant period that would have been continued to Phase IIa, if allowed, including the citizen committee.

  2. Final Progress Report - Heavy Ion Accelerator Theory and Simulation

    SciTech Connect

    Haber, Irving

    2009-10-31

    The use of a beam of heavy ions to heat a target for the study of warm dense matter physics, high energy density physics, and ultimately to ignite an inertial fusion pellet, requires the achievement of beam intensities somewhat greater than have traditionally been obtained using conventional accelerator technology. The research program described here has substantially contributed to understanding the basic nonlinear intense-beam physics that is central to the attainment of the requisite intensities. Since it is very difficult to reverse intensity dilution, avoiding excessive dilution over the entire beam lifetime is necessary for achieving the required beam intensities on target. The central emphasis in this research has therefore been on understanding the nonlinear mechanisms that are responsible for intensity dilution and which generally occur when intense space-charge-dominated beams are not in detailed equilibrium with the external forces used to confine them. This is an important area of study because such lack of detailed equilibrium can be an unavoidable consequence of the beam manipulations such as acceleration, bunching, and focusing necessary to attain sufficient intensity on target. The primary tool employed in this effort has been the use of simulation, particularly the WARP code, in concert with experiment, to identify the nonlinear dynamical characteristics that are important in practical high intensity accelerators. This research has gradually made a transition from the study of idealized systems and comparisons with theory, to study the fundamental scaling of intensity dilution in intense beams, and more recently to explicit identification of the mechanisms relevant to actual experiments. This work consists of two categories; work in direct support beam physics directly applicable to NDCX and a larger effort to further the general understanding of space-charge-dominated beam physics.

  3. Final progress report for award ER61159-1003722-000086

    SciTech Connect

    David L. Balkwill

    1999-06-04

    This project focuses on phylogenetic characterization of selected groups of microorganisms that have been isolated from deep terrestrial subsurface environments. Phylogenetic characterization is accomplished by analysis of 16S ribosomal RNA gene (rDNA) nucleotide base sequences and (in some cases) by restriction endonuclease analysis. This work addresses the primary objectives of the GEMHEX project in the Transitional Phase of the program and several priority research questions in the Origins Research Implementation Plan for the Deep Microbiology Subprogram.

  4. Modification of Children's Racial Attitudes. Final Progress Report.

    ERIC Educational Resources Information Center

    Katz, Phyllis

    This study investigated some of the attitudinal and behavioral components of racial prejudice in elementary school children. It also assessed the effectiveness of various modification procedures upon children's racial attitudes and inter-group behavior at different age levels. A four-stage research design was used. The pre-test stage involved…

  5. IFESS 2005 Special Session 5 Artifical Vision. Final progress report

    SciTech Connect

    Weiland, James D.

    2005-07-05

    A special session on visual prostheses was held during the Annual Meeting of the International Functional Electrical Stimulation Society (IFESS), in Montreal, Canada, July 5-9, 2005. IFESS is a meeting that typically attracts researchers in implantable nerve stimulators, functional electrical stimulation, and rehabilitation. All of these areas have significant overlap with the retinal prosthesis, but these areas have decades of research behind them. The special session provided a forum for researchers with vast experience in nerve stimulation to interact with leading research in retinal and cortical visual prostheses. The grant paid for the travel and conference costs of the presenters in the session. The session was chaired by James Weiland (the PI on this grant). The session co-chair was Phil Troyk, Ph.D., from the Illinois Institute of Technology. The Department of Energy was acknowledged at the start of the session as the sponsor. The following talks were delivered: Clinical Trial of a Prototype Retinal Prosthesis James Weiland, Ph.D. Doheny Eye Institute, Los Angeles, California The U.S. Department of Energy's Artificial Sight Program Elias Greenbaum, Ph.D. Oak Ridge National Laboratory, Oak Ridge, Tennessee A 16-Channel stimulator ASIC for use in an intracortical visual prosthesis Phillip R. Troyk, Ph.D. Illinois Institute of Technology, Chicago, Illinois Two approaches to the Optic Nerve Visual Prosthesis Jean Delbeke, M.D. University Cath de Louvain, Louvain, Belgium Design and Implementation of High Power Efficiency Modules for a Cortical Visual Stimulator Mohammad Sawan, Ph.D. Ecole Polytechnique de Montreal, Montreal, Canada Remaining funds from the grant were used to support Dr. Weiland's travel to the Association for Research in Vision and Ophthalmology in May 2006, with DOE approval, where several projects, supported by the DOE artificial retina program, were presented.

  6. Gene transcription and electromagnetic fields. Final progress report

    SciTech Connect

    Henderson, A.S.

    1992-12-31

    Our overall aim is to obtain sufficient information to allow us to ultimately determine whether ELF EM field exposure is an initiating factor in neoplastic transformation and/or if exposure can mimic characteristics of the second-step counterpart in neoplastic disease. This aim is based on our previous findings that levels of some transcripts are increased in cells exposed to EM fields. While the research is basic in nature, the ramifications have bearing on the general safety of exposure to EM fields in industrial and everyday life. A large array of diverse biological effects are reported to occur as the result of exposure to elf EM fields, suggesting that the cell response to EM fields is at a basic level, presumably initiated by molecular and/or biophysical events at the cell membrane. The hypothesized route is a signal transduction pathway involving membrane calcium fluxes. Information flow resulting from signal transduction can mediate the induction of regulatory factors in the cell, and directly affect how transcription is regulated.

  7. Final progress report for DOE grant [Protein dynamics and biocatalysis

    SciTech Connect

    Karplus, Martin

    2001-09-03

    The purpose of this project was to develop and apply large-scale computer simulation methods to enzyme reactions and protein dynamics. New approaches based on the QM/MM methodology were formulated. New insights on the reaction mechanisms of triosephosphate isomerase and chorismate mutase were obtained.

  8. Final Progress Report for the activity called AMO2010 committee

    SciTech Connect

    Donald Shapero; Michael Moloney

    2006-12-31

    The committee was charged to produce a comprehensive report on the status of AMO Science. The committee was charged to produce a report that: 1. Reviewed the field of AMO science, emphasize recent accomplishments, and identify new opportunities and compelling scientific questions; 2. Identified the impact of AMO science on other scientific fields, emerging technologies, and national needs; 3. Identified future workforce, societal and educational needs for AMO science; and 4. Made recommendations on how the US research enterprise might realize the full potential of AMO science. The committee also produced an intermediate report addressing key research issues and themes facing the research community.

  9. HARNESS: Heterogeneous Adaptable Reconfigurable Networked Systems. Final Progress Report

    SciTech Connect

    Fagg, G. E.

    2004-01-20

    HARNESS was proposed as a system that combined the best of emerging technologies found in current distributed computing research and commercial products into a very flexible, dynamically adaptable framework that could be used by applications to allow them to evolve and better handle their execution environment. The HARNESS system was designed using the considerable experience from previous projects such as PVM, MPI, IceT and Cumulvs. As such, the system was designed to avoid any of the common problems found with using these current systems, such as no single point of failure, ability to survive machine, node and software failures. Additional features included improved intercomponent connectivity, with full support for dynamic down loading of addition components at run-time thus reducing the stress on application developers to build in all the libraries they need in advance.

  10. Rooftop PV system. Final technical progress report, Phase II

    SciTech Connect

    1995-08-01

    Under this four-year PV:BONUS Program, ECD and United Solar are developing and demonstrating two new lightweight flexible building integrated Photovoltaic (BIPV) modules specifically designed as exact replacements for conventional asphalt shingles and standing seam metal roofing. These modules can be economically and aesthetically integrated into new residential and commercial buildings, and address the even larger roofing replacement market. The modules are designed to be installed by roofing contractors without special training which minimizes the installation and balance of system costs. The modules will be fabricated from high-efficiency, multiple-junction a-Si alloy solar cells developed by ECD and United Solar. Under the Phase I Program, which ended in March 1994, we developed two different concept designs for rooftop PV modules: (1) the United Solar overlapping (asphalt shingle replacement) shingle-type modules and (2) the ECD metal roof-type modules. We also developed a plan for fabricating, testing and demonstrating these modules. Candidate demonstration sites for our rooftop PV modules were identified and preliminary engineering designs for these demonstrations were developed; a marketing study plan was also developed. The major objectives of the Phase II Program, which started in June 1994 was (1) to develop, test, and qualify these new rooftop modules; (2) to develop mechanical and electrical engineering specifications for the demonstration projects; and (3) to develop a marketing/commercialization plan.

  11. Improving the Efficient of Ernie Turner Center. Final Progress Report

    SciTech Connect

    Fredeen, Amy

    2011-03-21

    The objective of this project was to complete the specifications and drawings for a variable speed kitchen exhaust system and the boiler heating system which when implemented will improve the heating efficiency of the building. The design work was focused in two key areas: kitchen ventilation and heating for the Ernie Turner Center building (ETC). RSA completed design work and issued a set of 100% drawings. RSA also worked with a cost estimator to put together a detailed cost estimate for the project. The design components are summarized.

  12. Fourth international workshop on human chromosome 5. Final progress report

    SciTech Connect

    McPherson, J.D.

    1996-12-31

    The Fourth International Workshop on Human Chromosome 5 was held in Manchester, UK on November 9--10, 1996 and was hosted by the University of Manchester. The major goals of the workshop were: (1) to collate the various genetic, cytogenetic and physical maps of human chromosome 5; (2) to integrate these maps and identify/correct discrepancies between them wherever possible; (3) to catalogue the sequence-ready contigs of the chromosome; (4) to co-ordinate the various sequencing efforts to avoid future duplication; (5) to establish the first (to the author`s knowledge) web site for the human chromosome 5 community which contains the above information in a readily accessible form.

  13. Converting baker's waste into alcohol. Revised final progress report

    SciTech Connect

    Halsey, R.; Wilson, P.B.

    1982-01-01

    All types of baker's waste (including waste from candy manufacturers) can be converted into alcohol to be used as a fuel. All types of waste at any stage in process can be converted, such as: basic ingredients (including floor sweepings); dry mixes (including floor sweepings); dough at any stage; partially or fully cooked products; and day old returned products. The basic steps are the same, only the initial preparation will vary slightly. The variation will be: amount of water to be added and amount and type of nutrients (if any) to be added. The basic steps are: slurrying, liquefying to put starch into liquid state, saccharifying to convert starch into fermentable sugars, fermentation to convert sugars into alcohol, and distillation to separate the alcohol from the mash. Each step is discussed in detail along with problems that may arise. Directions are given and materials (enzymes, yeast, etc.) and equipment are descibed briefly.

  14. Heat conduction in partial vacuum. Final technical progress report

    SciTech Connect

    Thomas, J R

    1980-09-01

    Methods developed for computing conduction heat losses from evacuated solar collectors are reported. Results of such calculations are given, including the minimum vacuum necessary to effectively eliminate conduction. Experiments performed at Owens-Illinois, Inc. to assess helium penetration rates into evacuated collectors are analyzed, and estimates are given as to the likely penetration rate of atmospheric helium. Conclusions are drawn as to the probable effect of helium penetration on the lifetimes of evacuated solar collectors.

  15. Electric and magnetic fields and tumor progression. Final report

    SciTech Connect

    Keng, P.C.; Grota, L.J.; Michaelson, S.; Lu, S.T.

    1994-12-01

    This laboratory study has rigorously investigated two previously reported biological effects of 60-Hz electric and magnetic fields. The first effect involves nighttime suppression of melatonin synthesis in the pineal glands of rats exposed to high electric fields. The second concerns the increase in colony forming ability of human colon cancer cells exposed to 1.4-G magnetic fields. Neither effect was detected in the present study. A series of published laboratory studies on rats reported that 60-Hz electric fields at various field levels up to 130 kV/m suppress the nighttime synthesis of melatonin, a hormone produced by the pineal gland. Since melatonin is known to modulate the immune system and may inhibit cancer cell activity, changes in physiological levels of melatonin may have significant health consequences. In the repeat experiments, field exposure did not alter nighttime levels of melatonin or enzyme activities in the pineal gland. A small but statistically significant reduction of about 20% in serum melatonin was seen in exposed animals. Pineal melatonin was also unaffected by the presence of red light as a cofactor with field exposure or by time-shifting the daily field exposure period. Another study reported that 60-Hz magnetic fields can affect the colony forming ability of human cancer cells after exposure in a culture medium. In the repeat experiments, field exposure did not alter the colony forming ability of human Colo 205 cells in two different cell concentrations at plating or in two different incubation conditions. Field exposure also did not affect cell cycling in any of the four cell lines tested.

  16. Uranium from seawater research. Final progress report, FY 1982

    SciTech Connect

    Borzekowski, J.; Driscoll, M.J.; Best, F.R.

    1982-09-01

    During the FY 1982 campaign 14 new ion exchange resin formulations, prepared by the Rohm and Haas Company, were tested by MIT at the Woods Hole Oceanographic Institution. The best of these chelating resins was again of the acrylic amidoxime type; it picked up approximately 100 ppM uranium in seven days' exposure to seawater, which represents a factor of better than two improvement over the seven-day results for the best FY 1981 candidate (which saturated at roughly 100 ppM U after 30 days' exposure). Saturation was not reached and, within experimental accuracy, uranium accumulated at a constant rate over the seven-day period; it is speculated that a useful capacity of over 300 ppM U would be achieved. All resins of the styrenic amidoxime type were found to be an order of magnitude lower in their effective capacity for uranium in seawater than the best of the acrylic forms. Particle size effects, which were found to be less than expected from theoretical computations of both fluid and solid side mass transfer resistance, can not account for this difference. Scanning electron microscope examination by R and H scientists of ion exchange resin beads from beds subjected to seawater flow for 30 days in MIT's WHOI columns showed that the internal pores of the macro-reticular-type resins become filled with debris (of undetermined nature and effect) during exposure.

  17. Inventors Center of Michigan Technical Assessment Program. Final progress report

    SciTech Connect

    Not Available

    1992-12-31

    The Technical Assessment Program at the Inventors Center of Michigan is designed to provide independent inventors with a reliable assessment of the technical merits of their proposed inventions. Using faculty from within Ferris State University`s College of Technology an assessment process examines the inventor`s assumptions, documentation, and prototypes, as well as, reviewing patent search results and technical literature to provide the inventor with a written report on the technical aspects of the proposed invention. The forms for applying for a technical assessment of an invention are included.

  18. Final Progress Report: Internship at Los Alamos National Laboratory

    SciTech Connect

    Dunham, Ryan Q.

    2012-08-10

    Originally I was tasked fluidized bed modeling, however, I changed projects. While still working with ANSYS Fluent, I performed a study of particle tracks in glove boxes. This is useful from a Health-Physics perspective, dealing respirable particles that can be hazardous to the human body. I iteratively tested different amounts of turbulent particles in a steady-state flow. The goal of this testing was to discover how Fluent handles built-in Rosin-Rammler distributions for particle injections. I worked on the health physics flow problems and distribution analysis under the direction of two mentors, Bruce Letellier and Dave Decroix. I set up and ran particle injection calculations using Fluent. I tried different combinations of input parameters to produce sets of 500,000, 1 million, and 1.5 million particles to determine what a good test case would be for future experiments. I performed a variety of tasks in my work as an Undergraduate Student Intern at LANL this summer, and learned how to use a powerful CFD application in addition to expanding my skills in MATLAB. I enjoyed my work at LANL and hope to be able to use the experience here to further my career in the future working in a security-conscious environment. My mentors provided guidance and help with all of my projects and I am grateful for the opportunity to work at Los Alamos National Laboratory.

  19. Liver glucose metabolism in humans

    PubMed Central

    Adeva-Andany, María M.; Pérez-Felpete, Noemi; Fernández-Fernández, Carlos; Donapetry-García, Cristóbal; Pazos-García, Cristina

    2016-01-01

    Information about normal hepatic glucose metabolism may help to understand pathogenic mechanisms underlying obesity and diabetes mellitus. In addition, liver glucose metabolism is involved in glycosylation reactions and connected with fatty acid metabolism. The liver receives dietary carbohydrates directly from the intestine via the portal vein. Glucokinase phosphorylates glucose to glucose 6-phosphate inside the hepatocyte, ensuring that an adequate flow of glucose enters the cell to be metabolized. Glucose 6-phosphate may proceed to several metabolic pathways. During the post-prandial period, most glucose 6-phosphate is used to synthesize glycogen via the formation of glucose 1-phosphate and UDP–glucose. Minor amounts of UDP–glucose are used to form UDP–glucuronate and UDP–galactose, which are donors of monosaccharide units used in glycosylation. A second pathway of glucose 6-phosphate metabolism is the formation of fructose 6-phosphate, which may either start the hexosamine pathway to produce UDP-N-acetylglucosamine or follow the glycolytic pathway to generate pyruvate and then acetyl-CoA. Acetyl-CoA may enter the tricarboxylic acid (TCA) cycle to be oxidized or may be exported to the cytosol to synthesize fatty acids, when excess glucose is present within the hepatocyte. Finally, glucose 6-phosphate may produce NADPH and ribose 5-phosphate through the pentose phosphate pathway. Glucose metabolism supplies intermediates for glycosylation, a post-translational modification of proteins and lipids that modulates their activity. Congenital deficiency of phosphoglucomutase (PGM)-1 and PGM-3 is associated with impaired glycosylation. In addition to metabolize carbohydrates, the liver produces glucose to be used by other tissues, from glycogen breakdown or from de novo synthesis using primarily lactate and alanine (gluconeogenesis). PMID:27707936

  20. Diet-induced metabolic acidosis.

    PubMed

    Adeva, María M; Souto, Gema

    2011-08-01

    The modern Western-type diet is deficient in fruits and vegetables and contains excessive animal products, generating the accumulation of non-metabolizable anions and a lifespan state of overlooked metabolic acidosis, whose magnitude increases progressively with aging due to the physiological decline in kidney function. In response to this state of diet-derived metabolic acidosis, the kidney implements compensating mechanisms aimed to restore the acid-base balance, such as the removal of the non-metabolizable anions, the conservation of citrate, and the enhancement of kidney ammoniagenesis and urinary excretion of ammonium ions. These adaptive processes lower the urine pH and induce an extensive change in urine composition, including hypocitraturia, hypercalciuria, and nitrogen and phosphate wasting. Low urine pH predisposes to uric acid stone formation. Hypocitraturia and hypercalciuria are risk factors for calcium stone disease. Even a very mild degree of metabolic acidosis induces skeletal muscle resistance to the insulin action and dietary acid load may be an important variable in predicting the metabolic abnormalities and the cardiovascular risk of the general population, the overweight and obese persons, and other patient populations including diabetes and chronic kidney failure. High dietary acid load is more likely to result in diabetes and systemic hypertension and may increase the cardiovascular risk. Results of recent observational studies confirm an association between insulin resistance and metabolic acidosis markers, including low serum bicarbonate, high serum anion gap, hypocitraturia, and low urine pH.