unstructuredio/SCORE-Bench · Datasets at Hugging Face

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Growth complementation and methionine production on TF4076BFJ-ΔBC
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15
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glucose used met intermediate (mg/L) GA and HS (g/L)
TF4076BJF-ΔBC OD (g/L) OSH met HS GA
empty vector 2.5 10.0 3867 0.0 0.0 0.4
pCL-metB 20.9 38.1 0.0 0.0 0.6 0.2
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20
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pCL-metB-metC 9.7 40.0 0.0 670 4.36 2.4
pPro-metZ 13.0 40.0 0.0 101 3.1 4.3
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--------------------------------------------------- Unstructured Caption Begin
pCL-metB: metB with its own promoter in pCL1920
pCL-metB-metC: metB and metC with their own promoters in pCL1920
pPro-Z: metZ from Pseudomonas aeruginosa in pProLar vector (ClonTech)
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25
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B. Construction of a Microorganism Having Both metABC (Transulfuration) and metXY (Direct Sulfhydrylation)
This example shows simultaneous methionine production
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from two pathways in E. coli. One pathway is the endogenous metABC pathway and the second pathway allows for direct sulfhydrylation via the expression of metY and metX from various organisms.
As shown in FIG. 1 E. coli produces methionine endog-
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35
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enously using the transsulfuration pathway genes metA, metB and metC and goes through OSHS. Genetic engineering was used to add an additional pathway to E. coil by cloning and expressing the genes metX and metY into E. coli, which resulted in a host organism that makes methio-
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40
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nine through both transsulfuration and direct sulfhydrylation simultaneously.
The metY and metX genes used to construct the heterologous pathway were cloned from Leptospira meyeri, Deinococcus radiodurans, Chloroflexus aurantiacus,Brevi-
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45
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bacterium linens, Nostoc punctiforme and Pseudomonas aeruginosa DNA as described below, and several different strains were constructed to analyze the impact of the addition of these genes on methionine production. The homo-
--------------------------------------------------- Unstructured Line Number Begin
50
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cysteine synthase from Corynebacterium glutamicum and Saccharomyces cerevisiae were also cloned and tested. Both pathways were demonstrated to work simultaneously and methionine production was improved with this addition.
To evaluate whether the L. meyeri metX and metY
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55
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enzymes could complement the growth of an E. coli methionine auxotroph, the L. meyeri metYX gene cluster was amplified from plasmid metXY-pCR2.0-TOPO and cloned into the pPRO-Nde-del vector. The transcription of the metYX genes in this plasmid was initiated by a lac/ara
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60
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promoter located on the vector.
Four E. coli strains including W3110 ΔmetA (stopping production of OSHS), TF4076BJF (increased homoserine production), TF4076BJF ΔmetA (stopping production of OSHS), and TF4076BJF ΔmetAmetB (stopping production
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65
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of OSHS and cystathionine from OAHS or OSHS) were evaluated. Strain TF4076BJF is a threonine auxotroph, deregulated for methionine production with an increase
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53. Gier, B., et al. Chronic GLP-1 receptor activation by exendin-4 induces expansion of pancreatic duct glands in rats and accelerates formation of dysplastic lesions and chronic pancreatitis in the Kras(G12D) mouse model. Diabetes 61, 1250-1262 (2012).
54. Goggins, M. GLP-1 receptor agonist effects on normal and neoplastic pancreata. Diabetes 61, 989-990 (2012).
55. Nauck, M.A. & Friedrich, N. Do GLP-1-Based Therapies Increase Cancer Risk? Diabetes care 36 Suppl 2, S245-252 (2013).
56. Metformin hydrochloride in treating patients with pancreatic cancer that can be removed by surgery. ClinicalTrials.gov Identifier: NCT01954732.
57. Haab, B.B., et al. Glycosylation variants of mucins and CEACAMs as candidate biomarkers for the diagnosis of pancreatic cystic neoplasms. Annals of surgery 251, 937-945 (2010).
58. Mann, B.F., Goetz, J.A., House, M.G., Schmidt, C.M. & Novotny, M.V. Glycomic and proteomic profiling of pancreatic cyst fluids identifies hyperfucosylated lactosamines on the N-linked glycans of overexpressed glycoproteins. Molecular & cellular proteomics : MCP 11, M111 015792 (2012).
59. Gheonea, D.I. & Saftoiu, A. Beyond conventional endoscopic ultrasound: elastography, contrast enhancement and hybrid techniques. Current opinion in gastroenterology 27, 423-429 (2011).
60. Yue, T., et al. Enhanced discrimination of malignant from benign pancreatic disease by measuring the CA 19-9 antigen on specific protein carriers. PloS one 6, e29180 (2011).
61. Bausch, D., et al. Plectin-1 as a novel biomarker for pancreatic cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 17, 302-309 (2011).
62. Konkalmatt, P.R., et al. Plectin-1 Targeted AAV Vector for the Molecular Imaging of Pancreatic Cancer. Frontiers in oncology 3, 84 (2013).
63. Neesse, A., et al. Claudin-4-targeted optical imaging detects pancreatic cancer and its precursor lesions. Gut 62, 1034-1043 (2013).
64. Garbe, A.I., et al. Genetically induced pancreatic adenocarcinoma is highly immunogenic and causes spontaneous tumor-specific immune responses. Cancer research 66, 508-516 (2006).
65. Laheru, D. & Jaffee, E.M. Immunotherapy for pancreatic cancer - science driving clinical progress. Nature reviews. Cancer 5, 459-467 (2005).
66. Laheru, D.A., Pardoll, D.M. & Jaffee, E.M. Genes to vaccines for immunotherapy: how the molecular biology revolution has influenced cancer immunology. Molecular cancer therapeutics 4, 1645-1652 (2005).
67. Lutz, E., et al. A lethally irradiated allogeneic granulocyte-macrophage colony stimulating factor-secreting tumor vaccine for pancreatic adenocarcinoma. A Phase II trial of safety, efficacy, and immune activation. Annals of surgery 253, 328-335 (2011).
68. Le, D.T., et al. Evaluation of Ipilimumab in Combination With Allogeneic Pancreatic Tumor Cells Transfected With a GM-CSF Gene in Previously Treated Pancreatic Cancer. Journal of immunotherapy 36, 382-389 (2013).
69. Le, D.T. & Jaffee, E.M. Next-generation cancer vaccine approaches: integrating lessons learned from current successes with promising biotechnologic advances. Journal of the National Comprehensive Cancer Network : JNCCN 11, 766-772 (2013).
70. Bigelow, E., et al. Immunohistochemical staining of B7-H1 (PD-L1) on paraffin-embedded slides of pancreatic adenocarcinoma tissue. Journal of visualized experiments : JoVE (2013).
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Addenda
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Growth complementation and methionine production on TF4076BFJ-ΔBC

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15

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glucose used met intermediate (mg/L) GA and HS (g/L)

TF4076BJF-ΔBC OD (g/L) OSH met HS GA

empty vector 2.5 10.0 3867 0.0 0.0 0.4

pCL-metB 20.9 38.1 0.0 0.0 0.6 0.2

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20

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pCL-metB-metC 9.7 40.0 0.0 670 4.36 2.4

pPro-metZ 13.0 40.0 0.0 101 3.1 4.3

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pCL-metB: metB with its own promoter in pCL1920

pCL-metB-metC: metB and metC with their own promoters in pCL1920

pPro-Z: metZ from Pseudomonas aeruginosa in pProLar vector (ClonTech)

--------------------------------------------------- Unstructured Caption End

--------------------------------------------------- Unstructured Line Number Begin

25

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B. Construction of a Microorganism Having Both metABC (Transulfuration) and metXY (Direct Sulfhydrylation)

This example shows simultaneous methionine production

--------------------------------------------------- Unstructured Line Number Begin

30

--------------------------------------------------- Unstructured Line Number End

from two pathways in E. coli. One pathway is the endogenous metABC pathway and the second pathway allows for direct sulfhydrylation via the expression of metY and metX from various organisms.

As shown in FIG. 1 E. coli produces methionine endog-

--------------------------------------------------- Unstructured Line Number Begin

35

--------------------------------------------------- Unstructured Line Number End

enously using the transsulfuration pathway genes metA, metB and metC and goes through OSHS. Genetic engineering was used to add an additional pathway to E. coil by cloning and expressing the genes metX and metY into E. coli, which resulted in a host organism that makes methio-

--------------------------------------------------- Unstructured Line Number Begin

40

--------------------------------------------------- Unstructured Line Number End

nine through both transsulfuration and direct sulfhydrylation simultaneously.

The metY and metX genes used to construct the heterologous pathway were cloned from Leptospira meyeri, Deinococcus radiodurans, Chloroflexus aurantiacus,Brevi-

--------------------------------------------------- Unstructured Line Number Begin

45

--------------------------------------------------- Unstructured Line Number End

bacterium linens, Nostoc punctiforme and Pseudomonas aeruginosa DNA as described below, and several different strains were constructed to analyze the impact of the addition of these genes on methionine production. The homo-

--------------------------------------------------- Unstructured Line Number Begin

50

--------------------------------------------------- Unstructured Line Number End

cysteine synthase from Corynebacterium glutamicum and Saccharomyces cerevisiae were also cloned and tested. Both pathways were demonstrated to work simultaneously and methionine production was improved with this addition.

To evaluate whether the L. meyeri metX and metY

--------------------------------------------------- Unstructured Line Number Begin

55

--------------------------------------------------- Unstructured Line Number End

enzymes could complement the growth of an E. coli methionine auxotroph, the L. meyeri metYX gene cluster was amplified from plasmid metXY-pCR2.0-TOPO and cloned into the pPRO-Nde-del vector. The transcription of the metYX genes in this plasmid was initiated by a lac/ara

--------------------------------------------------- Unstructured Line Number Begin

60

--------------------------------------------------- Unstructured Line Number End

promoter located on the vector.

Four E. coli strains including W3110 ΔmetA (stopping production of OSHS), TF4076BJF (increased homoserine production), TF4076BJF ΔmetA (stopping production of OSHS), and TF4076BJF ΔmetAmetB (stopping production

--------------------------------------------------- Unstructured Line Number Begin

65

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of OSHS and cystathionine from OAHS or OSHS) were evaluated. Strain TF4076BJF is a threonine auxotroph, deregulated for methionine production with an increase

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53. Gier, B., et al. Chronic GLP-1 receptor activation by exendin-4 induces expansion of pancreatic duct glands in rats and accelerates formation of dysplastic lesions and chronic pancreatitis in the Kras(G12D) mouse model. Diabetes 61, 1250-1262 (2012).

54. Goggins, M. GLP-1 receptor agonist effects on normal and neoplastic pancreata. Diabetes 61, 989-990 (2012).

55. Nauck, M.A. & Friedrich, N. Do GLP-1-Based Therapies Increase Cancer Risk? Diabetes care 36 Suppl 2, S245-252 (2013).

56. Metformin hydrochloride in treating patients with pancreatic cancer that can be removed by surgery. ClinicalTrials.gov Identifier: NCT01954732.

57. Haab, B.B., et al. Glycosylation variants of mucins and CEACAMs as candidate biomarkers for the diagnosis of pancreatic cystic neoplasms. Annals of surgery 251, 937-945 (2010).

58. Mann, B.F., Goetz, J.A., House, M.G., Schmidt, C.M. & Novotny, M.V. Glycomic and proteomic profiling of pancreatic cyst fluids identifies hyperfucosylated lactosamines on the N-linked glycans of overexpressed glycoproteins. Molecular & cellular proteomics : MCP 11, M111 015792 (2012).

59. Gheonea, D.I. & Saftoiu, A. Beyond conventional endoscopic ultrasound: elastography, contrast enhancement and hybrid techniques. Current opinion in gastroenterology 27, 423-429 (2011).

60. Yue, T., et al. Enhanced discrimination of malignant from benign pancreatic disease by measuring the CA 19-9 antigen on specific protein carriers. PloS one 6, e29180 (2011).

61. Bausch, D., et al. Plectin-1 as a novel biomarker for pancreatic cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 17, 302-309 (2011).

62. Konkalmatt, P.R., et al. Plectin-1 Targeted AAV Vector for the Molecular Imaging of Pancreatic Cancer. Frontiers in oncology 3, 84 (2013).

63. Neesse, A., et al. Claudin-4-targeted optical imaging detects pancreatic cancer and its precursor lesions. Gut 62, 1034-1043 (2013).

64. Garbe, A.I., et al. Genetically induced pancreatic adenocarcinoma is highly immunogenic and causes spontaneous tumor-specific immune responses. Cancer research 66, 508-516 (2006).

65. Laheru, D. & Jaffee, E.M. Immunotherapy for pancreatic cancer - science driving clinical progress. Nature reviews. Cancer 5, 459-467 (2005).

66. Laheru, D.A., Pardoll, D.M. & Jaffee, E.M. Genes to vaccines for immunotherapy: how the molecular biology revolution has influenced cancer immunology. Molecular cancer therapeutics 4, 1645-1652 (2005).

67. Lutz, E., et al. A lethally irradiated allogeneic granulocyte-macrophage colony stimulating factor-secreting tumor vaccine for pancreatic adenocarcinoma. A Phase II trial of safety, efficacy, and immune activation. Annals of surgery 253, 328-335 (2011).

68. Le, D.T., et al. Evaluation of Ipilimumab in Combination With Allogeneic Pancreatic Tumor Cells Transfected With a GM-CSF Gene in Previously Treated Pancreatic Cancer. Journal of immunotherapy 36, 382-389 (2013).

69. Le, D.T. & Jaffee, E.M. Next-generation cancer vaccine approaches: integrating lessons learned from current successes with promising biotechnologic advances. Journal of the National Comprehensive Cancer Network : JNCCN 11, 766-772 (2013).

70. Bigelow, E., et al. Immunohistochemical staining of B7-H1 (PD-L1) on paraffin-embedded slides of pancreatic adenocarcinoma tissue. Journal of visualized experiments : JoVE (2013).

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23

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--------------------------------------------------- Unstructured Title Begin

Addenda

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