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Pettersson, Curt
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Publications (10 of 48) Show all publications
Barclay, V. K. H., Tyrefors, N. L., Johansson, I. M. & Pettersson, C. E. (2019). Acidic transformation of nordiazepam can affect recovery estimate during trace analysis of diazepam and nordiazepam in environmental water samples by liquid chromatography-tandem mass spectrometry. Analytical and Bioanalytical Chemistry, 411(17), 3919-3928
Open this publication in new window or tab >>Acidic transformation of nordiazepam can affect recovery estimate during trace analysis of diazepam and nordiazepam in environmental water samples by liquid chromatography-tandem mass spectrometry
2019 (English)In: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 411, no 17, p. 3919-3928Article in journal (Refereed) Published
Abstract [en]

In this study, a special interest was focused on the stability of diazepam and nordiazepam in aqueous samples at acidic and neutral pH. The aim of the study was to isolate and illustrate one of the many possible sources of error that can be encountered when developing and validating analytical methods. This can be of particular importance when developing multi-analyte methods where there is limited time to scrutinize the behavior of each analyte. A method was developed for the analysis of the benzodiazepines diazepam and nordiazepam in treated wastewater. The samples were extracted by solid phase extraction, using SPEC C18AR cartridges, and analyzed by the use of liquid chromatography, with a C18 stationary phase, coupled to tandem mass spectrometry. Environmental water samples are often acidified during storage to reduce the microbial degradation of the target compounds and to preserve the sample. In some cases, the samples are acidified before extraction. In this study, it was found that a chemical equilibrium between nordiazepam and a transformation product could cause inaccurately high extraction recovery values when the samples were stored at low sample pH. The stability of nordiazepam was shown to be low at pH3. Within 12days, 20% of the initial concentration of nordiazepam was transformed. Interestingly, the transformed nordiazepam was shown to be regenerated and reformed to nordiazepam during sample handling. At a sample pH of 7, diazepam and nordiazepam were stable for 12days. It was concluded that great care must be taken when acidifying water samples containing nordiazepam during storage or extraction. The storage and the extraction should be conducted at neutral pH if no internal standard is used to compensate for degradation and conversion of nordiazepam. The developed method was validated in treated wastewater and applied for the quantification of diazepam and nordiazepam in treated wastewater samples.

Place, publisher, year, edition, pages
SPRINGER HEIDELBERG, 2019
Keywords
N-desmethyldiazepam, Nordazepam, Wastewater, Hydrolysis, Stability, LC-MS, MS
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-390803 (URN)10.1007/s00216-019-01870-7 (DOI)000472999900024 ()31104085 (PubMedID)
Available from: 2019-08-20 Created: 2019-08-20 Last updated: 2019-08-20Bibliographically approved
Erngren, I., Haglöf, J., Engskog, M. K., Nestor, M., Hedeland, M., Arvidsson, T. & Pettersson, C. (2019). Adduct formation in electrospray ionisation-mass spectrometry with hydrophilic interaction liquid chromatography is strongly affected by the inorganic ion concentration of the samples. Journal of Chromatography A, 1600, 174-182
Open this publication in new window or tab >>Adduct formation in electrospray ionisation-mass spectrometry with hydrophilic interaction liquid chromatography is strongly affected by the inorganic ion concentration of the samples
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2019 (English)In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1600, p. 174-182Article in journal (Refereed) Published
Abstract [en]

Hydrophilic interaction liquid chromatography (HILIC)/electrospray ionisation-mass spectrometry (ESI-MS) has gained interest for the analysis of polar analytes in bioanalytical applications in recent years. However, ESI-MS is prone to adduct formation of analytes. In contrast to reversed phase chromatography, small inorganic ions have retention in HILIC, i.e. analytes and inorganic ions may co-elute, which could influence the adduct formation. In the present paper, it was demonstrated that the co-elution of sodium ions or potassium ions and analytes in HILIC/ESI-MS affect the adduct formation and that different concentrations of sodium ions and potassium ions in biological samples could have an impact on the quantitative response of the respective adducts as well as the quantitative response of the protonated adduct. The co-elution also lead to cluster formation of analytes and sodium formate or potassium formate, causing extremely complicated spectra. In analytical applications using HILIC/ESI-MS where internal standards are rarely used or not properly matched, great care needs to be taken to ensure minimal variation of inorganic ion concentration between samples. Moreover, the use of alkali metal ion adducts as quantitative target ions in relative quantitative applications should be made with caution if proper internal standards are not used.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV, 2019
Keywords
Adduct formation, Hydrophilic interaction liquid chromatography, Mass spectrometry, Screening, Metabolomics, Cluster formation
National Category
Analytical Chemistry
Identifiers
urn:nbn:se:uu:diva-390383 (URN)10.1016/j.chroma.2019.04.049 (DOI)000472687800021 ()31047661 (PubMedID)
Available from: 2019-08-12 Created: 2019-08-12 Last updated: 2019-08-12Bibliographically approved
Balgoma, D., Pettersson, C. & Hedeland, M. (2019). Common Fatty Markers in Diseases with Dysregulated Lipogenesis. Trends in endocrinology and metabolism, 30(5), 283-285
Open this publication in new window or tab >>Common Fatty Markers in Diseases with Dysregulated Lipogenesis
2019 (English)In: Trends in endocrinology and metabolism, ISSN 1043-2760, E-ISSN 1879-3061, Vol. 30, no 5, p. 283-285Article in journal, Editorial material (Other academic) Published
Abstract [en]

Recent studies have reported the upregulation of a subgroup of triacylglycerides as markers of different diseases with dysregulated lipogenesis, which means that these markers are not selective. This observation has a deep impact on their use as diagnostic tools in clinical practice (e.g., markers of risk of type 2 diabetes).

Place, publisher, year, edition, pages
ELSEVIER SCIENCE LONDON, 2019
National Category
Endocrinology and Diabetes Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-383044 (URN)10.1016/j.tem.2019.02.008 (DOI)000465043400001 ()30926249 (PubMedID)
Available from: 2019-05-13 Created: 2019-05-13 Last updated: 2019-05-13Bibliographically approved
Haglind, A., Hedeland, M., Arvidsson, T. & Pettersson, C. E. (2018). Major signal suppression from metal ion clusters in SFC/ESI-MS: Cause and Effects. Journal of chromatography. B, 1084, 96-105
Open this publication in new window or tab >>Major signal suppression from metal ion clusters in SFC/ESI-MS: Cause and Effects
2018 (English)In: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 1084, p. 96-105Article in journal (Refereed) Published
Abstract [en]

The widening application area of SFC-MS with polar analytes and water-containing samples facilitates the use of quick and simple sample preparation techniques such as “dilute and shoot” and protein precipitation. This has also introduced new polar interfering components such as alkali metal ions naturally abundant in e.g. blood plasma and urine, which have shown to be retained using screening conditions in SFC/ESI-TOF-MS and causing areas of major ion suppression. Analytes co-eluting with these clusters will have a decreased signal intensity, which might have a major effect on both quantification and identification. When investigating the composition of the alkali metal clusters using accurate mass and isotopic pattern, it could be concluded that they were previously not described in the literature. Using NaCl and KCl standards and different chromatographic conditions, varying e.g. column and modifier, the clusters proved to be formed from the alkali metal ions in combination with the alcohol modifier and make-up solvent. Their compositions were [(XOCH3)n+X]+, [(XOH)n+X]+, [(X2CO3)n+X]+ and [(XOOCOCH3)n+X]+ for X= Na+ or K+ in ESI+. In ESI-, the clusters depended more on modifier, with [(XCl)n+Cl]- and [(XOCH3)n+OCH3]- mainly formed in pure methanol and [(XOOCH)n+OOCH]- when 20 mM NH4Fa was added.

To prevent the formation of the clusters by avoiding methanol as modifier might be difficult, as this is a widely used modifier providing good solubility when analyzing polar compounds in SFC. A sample preparation with e.g. LLE would remove the alkali ions, however also introducing a time consuming and discriminating step into the method. Since the alkali metal ions were retained and affected by chromatographic adjustments as e.g. mobile phase modifications, a way to avoid them could therefore be chromatographic tuning, when analyzing samples containing them.

Keywords
SFC-MS, matrix effect, alkali metal, ion cluster, Supercritical fluid chromatography, ESI
National Category
Analytical Chemistry
Research subject
Analytical Pharmaceutical Chemistry
Identifiers
urn:nbn:se:uu:diva-345978 (URN)10.1016/j.jchromb.2018.03.024 (DOI)000430524400012 ()29579734 (PubMedID)
Available from: 2018-03-13 Created: 2018-03-13 Last updated: 2018-06-26Bibliographically approved
Elmsjö, A., Haglöf, J., Engskog, M. K., Erngren, I., Nestor, M., Arvidsson, T. & Pettersson, C. (2018). Method selectivity evaluation using the co-feature ratio in LC/MS metabolomics: Comparison of HILIC stationary phase performance for the analysis of plasma, urine and cell extracts.. Journal of Chromatography A, 1568, 49-56
Open this publication in new window or tab >>Method selectivity evaluation using the co-feature ratio in LC/MS metabolomics: Comparison of HILIC stationary phase performance for the analysis of plasma, urine and cell extracts.
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2018 (English)In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1568, p. 49-56Article in journal (Refereed) Published
Abstract [en]

Evaluation of the chromatographic separation in metabolomics studies has primarily been done using preselected sets of standards or by counting the number of detected features. An alternative approach is to calculate each feature's co-feature ratio, which is a combined selectivity measurement for the separation (i.e. extent of co-elution) and the MS-signal (i.e. adduct formation and in-source fragmentation). The aim of this study was to demonstrate how the selectivity of different HILIC stationary phases can be evaluated using the co-feature ratio approach. The study was based on three sample types; plasma, urine and cell extracts. Samples were analyzed on an UHPLC-ESI-Q-ToF system using an amide, a bare silica and a sulfobetaine stationary phase. For each feature, a co-feature ratio was calculated and used for multivariate analysis of the selectivity differences between the three stationary phases. Unsupervised PCA models indicated that the co-feature ratios were highly dependent on type of stationary phase. For several metabolites a 15-30 fold difference in the co-feature ratio were observed between the stationary phases. Observed selectivity differences related primarily to the retention patterns of unwanted matrix components such as inorganic salts (detected as salt clusters), glycerophospholipids, and polyethylene glycols. These matrix components affected the signal intensity of co-eluting metabolites by interfering with the ionization efficiency and/or their adduct formation. Furthermore, the retention pattern of these matrix components had huge influence on the number of detected features. The co-feature ratio approach has successfully been applied for evaluation of the selectivity performance of three HILIC stationary phases. The co-feature ratio could therefore be used in metabolomics for developing selective methods fit for their purpose, thereby avoiding generic analytical approaches, which are often biased, as type and amount of interfering matrix components are metabolome dependent.

Keywords
Co-feature ratio (CFR), Hydrophilic interaction chromatography, Mass spectrometry, Metabolomics, Salt clusters
National Category
Analytical Chemistry Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-364208 (URN)10.1016/j.chroma.2018.05.007 (DOI)000443669600006 ()29789170 (PubMedID)
Available from: 2018-10-24 Created: 2018-10-24 Last updated: 2018-10-29Bibliographically approved
Svan, A., Hedeland, M., Arvidsson, T. & Pettersson, C. (2018). The differences in matrix effect between supercritical fluid chromatography and reversed phase liquid chromatography coupled to ESI/MS. Analytica Chimica Acta, 1000, 163-171
Open this publication in new window or tab >>The differences in matrix effect between supercritical fluid chromatography and reversed phase liquid chromatography coupled to ESI/MS
2018 (English)In: Analytica Chimica Acta, ISSN 0003-2670, E-ISSN 1873-4324, Vol. 1000, p. 163-171Article in journal (Refereed) Published
Abstract [en]

For many sample matrices, matrix effects are a troublesome phenomenon using the electrospray ionization source. The increasing use of supercritical fluid chromatography with CO2 in combination with the electrospray ionization source for MS detection is therefore raising questions: is the matrix effect behaving differently using SFC in comparison with reversed phase LC? This was investigated using urine, plasma, influent-and effluent-wastewater as sample matrices. The matrix effect was evaluated using the post-extraction addition method and through post-column infusions. Matrix effect profiles generated from the post-column infusions in combination with time of flight-MS detection provided the most valuable information for the study. The combination of both qualitative and semi-quantitative information with the ability to use HRMS-data for identifying interfering compounds from the same experiment was very useful, and has to the authors' knowledge not been used this way before. The results showed that both LC and SFC are affected by matrix effects, however differently depending on sample matrix. Generally, both suppressions and enhancements were seen, with a higher amount of enhancements for LC, where 65% of all compounds and all sample matrices were enhanced, compared to only 7% for SFC. Several interferences were tentatively identified, with phospholipids, creatinine, and metal ion clusters as examples of important interferences, with different impact depending on chromatographic technique. SFC needs a different strategy for limiting matrix interferences, owing to its almost reverse retention order compared to RPLC.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV, 2018
Keywords
Matrix effects, Supercritical fluid chromatography, Electrospray ionization, Liquid chromatography, Ion enhancement, Ion suppression
National Category
Analytical Chemistry
Identifiers
urn:nbn:se:uu:diva-338947 (URN)10.1016/j.aca.2017.10.014 (DOI)000418832900015 ()29289305 (PubMedID)
Available from: 2018-01-25 Created: 2018-01-25 Last updated: 2018-03-15Bibliographically approved
Pierre, P. V., Haglöf, J., Linder, B., Engskog, M. K., Arvidsson, T., Pettersson, C., . . . Laurell, G. (2017). Cisplatin-induced metabolome changes in serum: an experimental approach to identify markers for ototoxicity. Acta Oto-Laryngologica, 137(10), 1024-1030
Open this publication in new window or tab >>Cisplatin-induced metabolome changes in serum: an experimental approach to identify markers for ototoxicity
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2017 (English)In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 137, no 10, p. 1024-1030Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Ototoxicity from treatment with the anticancer drug cisplatin remains a clinical problem. A wide range of intracellular targets of cisplatin has been found in vivo.

AIM: To investigate cisplatin-induced change of the serum metabolite profile and its association with ototoxicity.

MATERIAL AND METHODS: Guinea pigs (n = 14) were treated with cisplatin (8 mg/kg b.w., i.v.) 30 min after administration of the otoprotector candidate sodium thiosulfate (group STS; n = 7) or sodium chloride (group NaCl; n = 7). Ototoxicity was evaluated by ABR (3-30 kHz) before and 4 d after drug treatment, and by assessment of hair cell loss. A blood sample was drawn before and 4 d after drug treatment and the polar metabolome in serum was analyzed using LC-MS.

RESULTS: Cisplatin-treatment caused significant threshold elevations and outer hair cell (OHC) loss in both groups. The ototoxicity was generally lower in group STS, but a significant difference was reached only at 30 kHz (p = .007). Cisplatin treatment altered the metabolite profile significantly and similarly in both groups. A significant inverse correlation was found between L-acetylcarnitine, N-acetylneuraminic acid, ceramide, and cysteinylserine and high frequency hearing loss in group NaCl. The implication of these correlations should be explored in targeted studies.

Keywords
ABR, cisplatin, hair cell, metabolite profiling, ototoxicity, sodium thiosulfate
National Category
Basic Medicine Analytical Chemistry Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-328151 (URN)10.1080/00016489.2017.1325006 (DOI)000407072000002 ()28537102 (PubMedID)
Funder
AFA Insurance
Available from: 2017-08-18 Created: 2017-08-18 Last updated: 2018-09-07Bibliographically approved
Häggblad Sahlberg, S., Mortensen, A. C., Haglöf, J., Engskog, M. K. R., Arvidsson, T., Pettersson, C., . . . Nestor, M. (2017). Different functions of AKT1 and AKT2 in molecular pathways, cell migration and metabolism in colon cancer cells. International Journal of Oncology, 50(1), 5-14
Open this publication in new window or tab >>Different functions of AKT1 and AKT2 in molecular pathways, cell migration and metabolism in colon cancer cells
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2017 (English)In: International Journal of Oncology, ISSN 1019-6439, Vol. 50, no 1, p. 5-14Article in journal (Refereed) Published
Abstract [en]

AKT is a central protein in many cellular pathways such as cell survival, proliferation, glucose uptake, metabolism, angiogenesis, as well as radiation and drug response. The three isoforms of AKT (AKT1, AKT2 and AKT3) are proposed to have different physiological functions, properties and expression patterns in a cell type-dependent manner. As of yet, not much is known about the influence of the different AKT isoforms in the genome and their effects in the metabolism of colorectal cancer cells. In the present study, DLD-1 isogenic AKT1, AKT2 and AKT'/2 knockout colon cancer cell lines were used as a model system in conjunction with the parental cell line in order to further elucidate the differences between the AKT isoforms and how they are involved in various cellular pathways. This was done using genome wide expression analyses, metabolic profiling and cell migration assays. In conclusion, downregulation of genes in the cell adhesion, extracellular matrix and Notch-pathways and upregulation of apoptosis and metastasis inhibitory genes in the p53-pathway, confirm that the knockout of both AKT1 and AKT2 will attenuate metastasis and tumor cell growth. This was verified with a reduction in migration rate in the AKT1 KO and AKT2 KO and most explicitly in the AKT1/2 KO. Furthermore, the knockout of AKT1, AKT2 or both, resulted in a reduction in lactate and alanine, suggesting that the metabolism of carbohydrates and glutathione was impaired. This was further verified in gene expression analyses, showing downregulation of genes involved in glucose metabolism. Additionally, both AKT1 KO and AKT2 KO demonstrated an impaired fatty acid metabolism. However, genes were upregulated in the Wnt and cell proliferation pathways, which could oppose this effect. AKT inhibition should therefore be combined with other effectors to attain the best effect.

Keywords
Microarray, metabolism, cell migration AKT1, AKT2, AKT, PKB, gene expression, colon-cancer, DLD-1, metabolomics, CD44, CD133
National Category
Biochemistry and Molecular Biology
Research subject
Biomedical Radiation Science; Biology with specialization in Molecular Cell Biology; Biology with specialization in Molecular Biology
Identifiers
urn:nbn:se:uu:diva-222834 (URN)10.3892/ijo.2016.3771 (DOI)000391419200001 ()
Available from: 2014-04-14 Created: 2014-04-14 Last updated: 2017-12-05Bibliographically approved
Fransson, A. E., Kisiel, M., Pirttilä, K., Pettersson, C., Videhult Pierre, P. & Laurell, G. (2017). Hydrogen Inhalation Protects against Ototoxicity Induced by Intravenous Cisplatin in the Guinea Pig. Frontiers in Cellular Neuroscience, 11, Article ID 280.
Open this publication in new window or tab >>Hydrogen Inhalation Protects against Ototoxicity Induced by Intravenous Cisplatin in the Guinea Pig
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2017 (English)In: Frontiers in Cellular Neuroscience, ISSN 1662-5102, E-ISSN 1662-5102, Vol. 11, article id 280Article in journal (Refereed) Published
Abstract [en]

Introduction: Permanent hearing loss and tinnitus as side-effects from treatment with the anticancer drug cisplatin is a clinical problem. Ototoxicity may be reduced by co-administration of an otoprotective agent, but the results in humans have so far been modest.

Aim: The present preclinical in vivo study aimed to explore the protective efficacy of hydrogen (H2) inhalation on ototoxicity induced by intravenous cisplatin.

Materials and Methods: Albino guinea pigs were divided into four groups. The Cispt (n = 11) and Cispt+H2 (n = 11) groups were given intravenous cisplatin (8 mg/kg b.w., injection rate 0.2 ml/min). Immediately after, the Cispt+H2 group also received gaseous H2 (2% in air, 60 min). The H2 group (n = 5) received only H2 and the Control group (n = 7) received neither cisplatin nor H2. Ototoxicity was assessed by measuring frequency specific ABR thresholds before and 96 h after treatment, loss of inner (IHCs) and outer (OHCs) hair cells, and by performing densitometry-based immunohistochemistry analysis of cochlear synaptophysin, organic transporter 2 (OCT2), and copper transporter 1 (CTR1) at 12 and 7 mm from the round window. By utilizing metabolomics analysis of perilymph the change of metabolites in the perilymph was assessed.

Results: Cisplatin induced electrophysiological threshold shifts, hair cell loss, and reduced synaptophysin immunoreactivity in the synapse area around the IHCs and OHCs. H2 inhalation mitigated all these effects. Cisplatin also reduced the OCT2 intensity in the inner and outer pillar cells and in the stria vascularis as well as the CTR1 intensity in the synapse area around the IHCs, the Deiters' cells, and the stria vascularis. H2 prevented the majority of these effects.

Conclusion: H2 inhalation can reduce cisplatin-induced ototoxicity on functional, cellular, and subcellular levels. It is proposed that synaptopathy may serve as a marker for cisplatin ototoxicity. The effect of H2 on the antineoplastic activity of cisplatin needs to be further explored.

Keywords
ABR, inner hair cells, outer hair cells, synaptophysin, organic cation transporter 2, copper transporter 1, perilymph metabolomics, in vivo
National Category
Otorhinolaryngology Analytical Chemistry Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-330897 (URN)10.3389/fncel.2017.00280 (DOI)000410583900001 ()28955207 (PubMedID)
Available from: 2017-10-06 Created: 2017-10-06 Last updated: 2018-01-13Bibliographically approved
Niklison-Chirou, M. V., Erngren, I., Engskog, M. K., Haglöf, J., Picard, D., Remke, M., . . . Marino, S. (2017). TAp73 is a marker of glutamine addiction in medulloblastoma. Genes & Development, 31(17), 1738-1753
Open this publication in new window or tab >>TAp73 is a marker of glutamine addiction in medulloblastoma
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2017 (English)In: Genes & Development, ISSN 0890-9369, E-ISSN 1549-5477, Vol. 31, no 17, p. 1738-1753Article in journal (Refereed) Published
Abstract [en]

Medulloblastoma is the most common solid primary brain tumor in children. Remarkable advancements in the understanding of the genetic and epigenetic basis of these tumors have informed their recent molecular classification. However, the genotype/phenotype correlation of the subgroups remains largely uncharacterized. In particular, the metabolic phenotype is of great interest because of its druggability, which could lead to the development of novel and more tailored therapies for a subset of medulloblastoma. p73 plays a critical role in a range of cellular metabolic processes. We show overexpression of p73 in a proportion of non-WNT medulloblastoma. In these tumors, p73 sustains cell growth and proliferation via regulation of glutamine metabolism. We validated our results in a xenograft model in which we observed an increase in survival time in mice on a glutamine restriction diet. Notably, glutamine starvation has a synergistic effect with cisplatin, a component of the current medulloblastoma chemotherapy. These findings raise the possibility that glutamine depletion can be used as an adjuvant treatment for p73-expressing medulloblastoma.

Place, publisher, year, edition, pages
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT, 2017
Keywords
medulloblastoma, p73, glutamine, metabolomics
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-336829 (URN)10.1101/gad.302349.117 (DOI)000412275500004 ()28971956 (PubMedID)
Available from: 2017-12-20 Created: 2017-12-20 Last updated: 2017-12-20Bibliographically approved
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