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  1. Article ; Online: Robust performance of a live bacterial therapeutic chassis lacking the colibactin gene cluster.

    Aida Kalantari / Michael J James / Lauren A Renaud / Mylene Perreault / Catherine E Monahan / Mary N McDonald / David L Hava / Vincent M Isabella

    PLoS ONE, Vol 18, Iss 2, p e

    2023  Volume 0280499

    Abstract: E. coli Nissle (EcN) is a non-pathogenic probiotic bacterium of the Enterobacteriaceae family that has been used for over a century to promote general gut health. Despite the history of safe usage of EcN, concerns have been raised regarding the presence ... ...

    Abstract E. coli Nissle (EcN) is a non-pathogenic probiotic bacterium of the Enterobacteriaceae family that has been used for over a century to promote general gut health. Despite the history of safe usage of EcN, concerns have been raised regarding the presence of the pks gene cluster, encoding the genotoxin colibactin, due to its association with colorectal cancer. Here, we sought to determine the effect of pks island removal on the in vitro and in vivo robustness and activity of EcN and EcN-derived strains. A deletion of the pks island (Δpks) was constructed in wild type and engineered strains of EcN using lambda red recombineering. Mass spectrometric measurement of N-myristoyl-D-asparagine, released during colibactin maturation, confirmed that the pks deletion abrogated colibactin production. Growth curves were comparable between Δpks strains and their isogenic parents, and wild type EcN displayed no competitive advantage to the Δpks strain in mixed culture. Deletion of pks also had no effect on the activity of strains engineered to degrade phenylalanine (SYNB1618 and SYNB1934) or oxalate (SYNB8802). Furthermore, 1:1 mixed dosing of wild type and Δpks EcN in preclinical mouse and nonhuman primate models demonstrated no competitive disadvantage for the Δpks strain with regards to transit time or colonization. Importantly, there was no significant difference on in vivo strain performance between the clinical-stage strain SYNB1934 and its isogenic Δpks variant with regards to recovery of the quantitative strain-specific biomarkers d5- trans-cinnamic acid, and d5-hippuric acid. Taken together, these data support that the pks island is dispensable for Synthetic Biotic fitness and activity in vivo and that its removal from engineered strains of EcN will not have a deleterious effect on strain efficacy.
    Keywords Medicine ; R ; Science ; Q
    Subject code 500
    Language English
    Publishing date 2023-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: An engineered bacterial therapeutic lowers urinary oxalate in preclinical models and in silico simulations of enteric hyperoxaluria

    David Lubkowicz / Nicholas G Horvath / Michael J James / Pasquale Cantarella / Lauren Renaud / Christopher G Bergeron / Ron B Shmueli / Cami Anderson / Jian‐Rong Gao / Caroline B Kurtz / Mylene Perreault / Mark R Charbonneau / Vincent M Isabella / David L Hava

    Molecular Systems Biology, Vol 18, Iss 3, Pp n/a-n/a (2022)

    2022  

    Abstract: Abstract Enteric hyperoxaluria (EH) is a metabolic disease caused by excessive absorption of dietary oxalate leading to the formation of chronic kidney stones and kidney failure. There are no approved pharmaceutical treatments for EH. SYNB8802 is an ... ...

    Abstract Abstract Enteric hyperoxaluria (EH) is a metabolic disease caused by excessive absorption of dietary oxalate leading to the formation of chronic kidney stones and kidney failure. There are no approved pharmaceutical treatments for EH. SYNB8802 is an engineered bacterial therapeutic designed to consume oxalate in the gut and lower urinary oxalate as a potential treatment for EH. Oral administration of SYNB8802 leads to significantly decreased urinary oxalate excretion in healthy mice and non‐human primates, demonstrating the strain's ability to consume oxalate in vivo. A mathematical modeling framework was constructed that combines in vitro and in vivo preclinical data to predict the effects of SYNB8802 administration on urinary oxalate excretion in humans. Simulations of SYNB8802 administration predict a clinically meaningful lowering of urinary oxalate excretion in healthy volunteers and EH patients. Together, these findings suggest that SYNB8802 is a promising treatment for EH.
    Keywords engineered bacteria ; enteric hyperoxaluria ; in silico modeling ; oxalate ; synthetic biology ; Biology (General) ; QH301-705.5 ; Medicine (General) ; R5-920
    Subject code 610
    Language English
    Publishing date 2022-03-01T00:00:00Z
    Publisher Wiley
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article: Rainbow trout (Oncorhynchus mykiss) Elovl5 and Elovl2 differ in selectivity for elongation of omega-3 docosapentaenoic acid

    Gregory, Melissa K / Michael J. James

    BBA - Molecular and Cell Biology of Lipids. 2014 Dec., v. 1841

    2014  

    Abstract: The synthesis of the omega-3 long-chain polyunsaturated fatty acids (LCPUFA) eicosapentaenoic acid (EPA; 20:5n−3) and docosahexaenoic acid (DHA; 22:6n−3) from dietary α-linolenic acid (ALA; 18:3n−3) requires three desaturation and three elongation ...

    Abstract The synthesis of the omega-3 long-chain polyunsaturated fatty acids (LCPUFA) eicosapentaenoic acid (EPA; 20:5n−3) and docosahexaenoic acid (DHA; 22:6n−3) from dietary α-linolenic acid (ALA; 18:3n−3) requires three desaturation and three elongation steps in vertebrates. The elongation of EPA to docosapentaenoic acid (DPA; 22:5n−3) can be catalysed by the elongase enzymes Elovl5 or Elovl2, but further elongation of DPA to 24:5n−3, the penultimate precursor of DHA, is limited to Elovl2, at least in mammals. Elovl5 enzymes have been characterised from seventeen fish species but Elovl2 enzymes have only been characterised in two of these fish. The essentiality of Elovl2 for DHA synthesis is unknown in fish. This study is the first to identify an Elovl2 in rainbow trout (Oncorhynchus mykiss) and functionally characterise the Elovl5 and Elovl2 using a yeast expression system. Elovl5 was active with C18–20 PUFA substrates and not C22 PUFA. In contrast, Elovl2 was active with C20–22 PUFA substrates and not C18 PUFA. Thus, rainbow trout is dependent on Elovl2 for DPA to 24:5n−3 synthesis and ultimately DHA synthesis. The expression of elovl5 was significantly higher than elovl2 in liver. Elucidating this dependence on Elovl2 to elongate DPA and the low elovl2 gene expression compared with elovl5 are critical findings in understanding the potential for rainbow trout to synthesize DHA.
    Keywords alpha-linolenic acid ; docosahexaenoic acid ; docosapentaenoic acid ; eicosapentaenoic acid ; enzymes ; fish ; gene expression ; liver ; mammals ; omega-3 fatty acids ; Oncorhynchus mykiss ; yeasts
    Language English
    Dates of publication 2014-12
    Size p. 1656-1660.
    Publishing place Elsevier B.V.
    Document type Article
    ISSN 1388-1981
    DOI 10.1016/j.bbalip.2014.10.001
    Database NAL-Catalogue (AGRICOLA)

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  4. Article: Ag(I)-Catalyzed Synthesis of Azabicyclic Alkaloid Frameworks from Ketimine-Tethered Ynones: Total Synthesis of Indolizidine 209D

    Ho, Hon Eong / Michael J. James / Peter O’Brien / Richard J. K. Taylor / William P. Unsworth

    Organic letters. 2018 Mar. 02, v. 20, no. 5

    2018  

    Abstract: An efficient Ag(I)-catalyzed π-acid activation method for the cyclization of cyclic ketimine-tethered ynones is reported. Various nitrogen-containing scaffolds commonly found in bioactive alkaloids can be prepared in high yields, and the utility of the ... ...

    Abstract An efficient Ag(I)-catalyzed π-acid activation method for the cyclization of cyclic ketimine-tethered ynones is reported. Various nitrogen-containing scaffolds commonly found in bioactive alkaloids can be prepared in high yields, and the utility of the method is demonstrated by a formal synthesis of (±)-lasubine II and in a short total synthesis of (±)-indolizidine 209D.
    Keywords alkaloids ; chemical reactions ; chemical structure ; indolizidines ; silver
    Language English
    Dates of publication 2018-0302
    Size p. 1439-1443.
    Publishing place American Chemical Society
    Document type Article
    ISSN 1523-7052
    DOI 10.1021/acs.orglett.8b00225
    Database NAL-Catalogue (AGRICOLA)

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  5. Article ; Online: Immunotherapy with engineered bacteria by targeting the STING pathway for anti-tumor immunity

    Daniel S. Leventhal / Anna Sokolovska / Ning Li / Christopher Plescia / Starsha A. Kolodziej / Carey W. Gallant / Rudy Christmas / Jian-Rong Gao / Michael J. James / Andres Abin-Fuentes / Munira Momin / Christopher Bergeron / Adam Fisher / Paul F. Miller / Kip A. West / Jose M. Lora

    Nature Communications, Vol 11, Iss 1, Pp 1-

    2020  Volume 15

    Abstract: Synthetic biology can be used to create rationally designed living therapeutics. Here the authors engineer E. coli Nissle to target STING activation in antigen presenting cells for the treatment of solid tumors and demonstrate preclinical activity in ... ...

    Abstract Synthetic biology can be used to create rationally designed living therapeutics. Here the authors engineer E. coli Nissle to target STING activation in antigen presenting cells for the treatment of solid tumors and demonstrate preclinical activity in murine models.
    Keywords Science ; Q
    Language English
    Publishing date 2020-06-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Immunotherapy with engineered bacteria by targeting the STING pathway for anti-tumor immunity

    Daniel S. Leventhal / Anna Sokolovska / Ning Li / Christopher Plescia / Starsha A. Kolodziej / Carey W. Gallant / Rudy Christmas / Jian-Rong Gao / Michael J. James / Andres Abin-Fuentes / Munira Momin / Christopher Bergeron / Adam Fisher / Paul F. Miller / Kip A. West / Jose M. Lora

    Nature Communications, Vol 11, Iss 1, Pp 1-

    2020  Volume 15

    Abstract: Synthetic biology can be used to create rationally designed living therapeutics. Here the authors engineer E. coli Nissle to target STING activation in antigen presenting cells for the treatment of solid tumors and demonstrate preclinical activity in ... ...

    Abstract Synthetic biology can be used to create rationally designed living therapeutics. Here the authors engineer E. coli Nissle to target STING activation in antigen presenting cells for the treatment of solid tumors and demonstrate preclinical activity in murine models.
    Keywords Science ; Q
    Language English
    Publishing date 2020-06-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Elongase reactions as control points in long-chain polyunsaturated fatty acid synthesis.

    Melissa K Gregory / Robert A Gibson / Rebecca J Cook-Johnson / Leslie G Cleland / Michael J James

    PLoS ONE, Vol 6, Iss 12, p e

    2011  Volume 29662

    Abstract: BACKGROUND: Δ6-Desaturase (Fads2) is widely regarded as rate-limiting in the conversion of dietary α-linolenic acid (18:3n-3; ALA) to the long-chain omega-3 polyunsaturated fatty acid docosahexaenoic acid (22:6n-3; DHA). However, increasing dietary ALA ... ...

    Abstract BACKGROUND: Δ6-Desaturase (Fads2) is widely regarded as rate-limiting in the conversion of dietary α-linolenic acid (18:3n-3; ALA) to the long-chain omega-3 polyunsaturated fatty acid docosahexaenoic acid (22:6n-3; DHA). However, increasing dietary ALA or the direct Fads2 product, stearidonic acid (18:4n-3; SDA), increases tissue levels of eicosapentaenoic acid (20:5n-3; EPA) and docosapentaenoic acid (22:5n-3; DPA), but not DHA. These observations suggest that one or more control points must exist beyond ALA metabolism by Fads2. One possible control point is a second reaction involving Fads2 itself, since this enzyme catalyses desaturation of 24:5n-3 to 24:6n-3, as well as ALA to SDA. However, metabolism of EPA and DPA both require elongation reactions. This study examined the activities of two elongase enzymes as well as the second reaction of Fads2 in order to concentrate on the metabolism of EPA to DHA. METHODOLOGY/PRINCIPAL FINDINGS: The substrate selectivities, competitive substrate interactions and dose response curves of the rat elongases, Elovl2 and Elovl5 were determined after expression of the enzymes in yeast. The competitive substrate interactions for rat Fads2 were also examined. Rat Elovl2 was active with C(20) and C(22) polyunsaturated fatty acids and this single enzyme catalysed the sequential elongation reactions of EPA→DPA→24:5n-3. The second reaction DPA→24:5n-3 appeared to be saturated at substrate concentrations not saturating for the first reaction EPA→DPA. ALA dose-dependently inhibited Fads2 conversion of 24:5n-3 to 24:6n-3. CONCLUSIONS: The competition between ALA and 24:5n-3 for Fads2 may explain the decrease in DHA levels observed after certain intakes of dietary ALA have been exceeded. In addition, the apparent saturation of the second Elovl2 reaction, DPA→24:5n-3, provides further explanations for the accumulation of DPA when ALA, SDA or EPA is provided in the diet. This study suggests that Elovl2 will be critical in understanding if DHA synthesis can be increased by dietary means.
    Keywords Medicine ; R ; Science ; Q
    Subject code 540 ; 660
    Language English
    Publishing date 2011-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article: ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models

    Cramer, Paige E / Adriana E. Zinn / Brad T. Casali / C. Y. Daniel Lee / Daniel W. Wesson / Donald A. Wilson / Gary E. Landreth / J. Colleen Karlo / Jessica L. Restivo / John R. Cirrito / Kurt R. Brunden / Michael J. James / Whitney D. Goebel

    Science. 2012 Mar. 23, v. 335, no. 6075

    2012  

    Abstract: Alzheimer’s disease (AD) is associated with impaired clearance of β-amyloid (Aβ) from the brain, a process normally facilitated by apolipoprotein E (apoE). ApoE expression is transcriptionally induced through the action of the nuclear receptors ... ...

    Abstract Alzheimer’s disease (AD) is associated with impaired clearance of β-amyloid (Aβ) from the brain, a process normally facilitated by apolipoprotein E (apoE). ApoE expression is transcriptionally induced through the action of the nuclear receptors peroxisome proliferator–activated receptor gamma and liver X receptors in coordination with retinoid X receptors (RXRs). Oral administration of the RXR agonist bexarotene to a mouse model of AD resulted in enhanced clearance of soluble Aβ within hours in an apoE-dependent manner. Aβ plaque area was reduced more than 50% within just 72 hours. Furthermore, bexarotene stimulated the rapid reversal of cognitive, social, and olfactory deficits and improved neural circuit function. Thus, RXR activation stimulates physiological Aβ clearance mechanisms, resulting in the rapid reversal of a broad range of Aβ-induced deficits.
    Keywords agonists ; Alzheimer disease ; animal models ; apolipoprotein E ; brain ; cognition ; liver ; oral administration ; peroxisome proliferator-activated receptors ; therapeutics ; transcription (genetics)
    Language English
    Dates of publication 2012-0323
    Size p. 1503-1506.
    Publishing place American Association for the Advancement of Science
    Document type Article
    ZDB-ID 128410-1
    ISSN 1095-9203 ; 0036-8075
    ISSN (online) 1095-9203
    ISSN 0036-8075
    DOI 10.1126/science.1217697
    Database NAL-Catalogue (AGRICOLA)

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