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Hofer, Anders
Publications (10 of 52) Show all publications
Hulpia, F., Mabille, D., Campagnaro, G. D., Schumann, G., Maes, L., Roditi, I., . . . Van Calenbergh, S. (2019). Combining tubercidin and cordycepin scaffolds results in highly active candidates to treat late-stage sleeping sickness. Nature Communications, 10, Article ID 5564.
Open this publication in new window or tab >>Combining tubercidin and cordycepin scaffolds results in highly active candidates to treat late-stage sleeping sickness
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2019 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 5564Article in journal (Refereed) Published
Abstract [en]

African trypanosomiasis is a disease caused by Trypanosoma brucei parasites with limited treatment options. Trypanosoma is unable to synthesize purines de novo and relies solely on their uptake and interconversion from the host, constituting purine nucleoside analogues a potential source of antitrypanosomal agents. Here we combine structural elements from known trypanocidal nucleoside analogues to develop a series of 3'-deoxy-7-deazaadenosine nucleosides, and investigate their effects against African trypanosomes. 3'-Deoxytubercidin is a highly potent trypanocide in vitro and displays curative activity in animal models of acute and CNS-stage disease, even at low doses and oral administration. Whole-genome RNAi screening reveals that the P2 nucleoside transporter and adenosine kinase are involved in the uptake and activation, respectively, of this analogue. This is confirmed by P1 and P2 transporter assays and nucleotide pool analysis. 3'-Deoxytubercidin is a promising lead to treat late-stage sleeping sickness.

Place, publisher, year, edition, pages
Nature Publishing Group, 2019
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-167057 (URN)10.1038/s41467-019-13522-6 (DOI)000502059600001 ()31804484 (PubMedID)
Available from: 2020-01-09 Created: 2020-01-09 Last updated: 2020-01-09Bibliographically approved
Rozman Grinberg, I., Lundin, D., Sahlin, M., Crona, M., Berggren, G., Hofer, A. & Sjöberg, B.-M. (2018). A glutaredoxin domain fused to the radical-generating subunit of ribonucleotide reductase (RNR) functions as an efficient RNR reductant. Journal of Biological Chemistry, 293(41), 15889-15900
Open this publication in new window or tab >>A glutaredoxin domain fused to the radical-generating subunit of ribonucleotide reductase (RNR) functions as an efficient RNR reductant
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2018 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 293, no 41, p. 15889-15900Article in journal (Refereed) Published
Abstract [en]

Class I ribonucleotide reductase (RNR) consists of a catalytic subunit (NrdA) and a radical-generating subunit (NrdB) that together catalyze reduction of ribonucleotides to their corresponding deoxyribonucleotides. NrdB from the firmicute Facklamia ignava is a unique fusion protein with N-terminal add-ons of a glutaredoxin (Grx) domain followed by an ATP-binding domain, the ATP cone. Grx, usually encoded separately from the RNR operon, is a known RNR reductant. We show that the fused Grx domain functions as an efficient reductant of the F. ignava class I RNR via the common dithiol mechanism and, interestingly, also via a monothiol mechanism, although less efficiently. To our knowledge, a Grx that uses both of these two reaction mechanisms has not previously been observed with a native substrate. The ATP cone is in most RNRs an N-terminal domain of the catalytic subunit. It is an allosteric on/off switch promoting ribonucleotide reduction in the presence of ATP and inhibiting RNR activity in the presence of dATP. We found that dATP bound to the ATP cone of F. ignava NrdB promotes formation of tetramers that cannot form active complexes with NrdA. The ATP cone bound two dATP molecules but only one ATP molecule. F. ignava NrdB contains the recently identified radical-generating cofactor MnIII/MnIV. We show that NrdA from F. ignava can form a catalytically competent RNR with the MnIII/MnIV-containing NrdB from the flavobacterium Leeuwenhoekiella blandensis. In conclusion, F. ignava NrdB is fused with a Grx functioning as an RNR reductant and an ATP cone serving as an on/off switch.

Place, publisher, year, edition, pages
American Society for Biochemistry and Molecular Biology, 2018
Keywords
ribonucleotide reductase, allosteric regulation, oxidation-reduction (redox), radical, manganese, ATP-cone, dATP inhibition, dithiol-monothiol, glutaredoxin, tetramers
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-153125 (URN)10.1074/jbc.RA118.004991 (DOI)000447256000013 ()30166338 (PubMedID)
Available from: 2018-11-12 Created: 2018-11-12 Last updated: 2018-11-12Bibliographically approved
Gupta, A. A., Reinartz, I., Karunanithy, G., Spilotros, A., Jonna, V. R., Hofer, A., . . . Wolf-Watz, M. (2018). Formation of a Secretion-Competent Protein Complex by a Dynamic Wrap-around Binding Mechanism. Journal of Molecular Biology, 430(18, Part B), 3157-3169
Open this publication in new window or tab >>Formation of a Secretion-Competent Protein Complex by a Dynamic Wrap-around Binding Mechanism
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2018 (English)In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 430, no 18, Part B, p. 3157-3169Article in journal (Refereed) Published
Abstract [en]

Bacterial virulence is typically initiated by translocation of effector or toxic proteins across host cell membranes. A class of gram-negative pathogenic bacteria including Yersinia pseudotuberculosis and Yersinia pestis accomplishes this objective with a protein assembly called the type III secretion system. Yersinia effector proteins (Yop) are presented to the translocation apparatus through formation of specific complexes with their cognate chaperones (Syc). In the complexes where the structure is available, the Yops are extended and wrap around their cognate chaperone. This structural architecture enables secretion of the Yop from the bacterium in early stages of translocation. It has been shown previously that the chaperone-binding domain of YopE is disordered in its isolation but becomes substantially more ordered in its wrap-around complex with its chaperone SycE. Here, by means of NMR spectroscopy, small-angle X-ray scattering and molecular modeling, we demonstrate that while the free chaperone-binding domain of YopH (YopHCBD) adopts a fully ordered and globular fold, it populates an elongated, wrap-around conformation when it engages in a specific complex with its chaperone SycH2. Hence, in contrast to YopE that is unstructured in its free state, YopH transits from a globular free state to an elongated chaperone-bound state. We demonstrate that a sparsely populated YopHCBD state has an elevated affinity for SycH2 and represents an intermediate in the formation of the protein complex. Our results suggest that Yersinia has evolved a binding mechanism where SycH2 passively stimulates an elongated YopH conformation that is presented to the type III secretion system in a secretion-competent conformation.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
NMR spectroscopy, protein complex, binding mechanism
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-151495 (URN)10.1016/j.jmb.2018.07.014 (DOI)000444668100010 ()
Funder
Swedish Research Council, 2013-5954Knut and Alice Wallenberg FoundationCarl Tryggers foundation , CTS 15:210The Kempe Foundations
Available from: 2018-09-05 Created: 2018-09-05 Last updated: 2018-10-04Bibliographically approved
Kamte, S. L. N., Ranjbarian, F., Cianfaglione, K., Sut, S., Dall'Acqua, S., Bruno, M., . . . Petrelli, R. (2018). Identification of highly effective antitrypanosomal compounds in essential oils from the Apiaceae family. Ecotoxicology and Environmental Safety, 156, 154-165
Open this publication in new window or tab >>Identification of highly effective antitrypanosomal compounds in essential oils from the Apiaceae family
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2018 (English)In: Ecotoxicology and Environmental Safety, ISSN 0147-6513, E-ISSN 1090-2414, Vol. 156, p. 154-165Article in journal (Refereed) Published
Abstract [en]

The Apiaceae family encompasses aromatic plants of economic importance employed in foodstuffs, beverages, perfumery, pharmaceuticals and cosmetics. Apiaceae are rich sources of essential oils because of the wealth of secretory structures (ducts and vittae) they are endowed with. The Apiaceae essential oils are available on an industrial level because of the wide cultivation and disposability of the bulky material from which they are extracted as well as their relatively cheap price. In the fight against protozoal infections, essential oils may represent new therapeutic options. In the present work, we focused on a panel of nine Apiaceae species (Siler montamon, Sison amomum, Echinophora spinosa, Kundmannia sicula, Crithmum maritimum, Helosciadium nodiforum, Pimpinella anisum, Heracleum sphondylium and Trachyspermum cunmi) and their essential oils as a model for the identification of trypanocidal compounds to be used as alternative/integrative therapies in the treatment of Human African trypanosomiasis (HAT) and as starting material for drug design. The evaluation of inhibitory effects of the Apiaceae essential oils against Trypanosoma brucei showed that some of them (E. spinosa, S. amomum, C. maritimwn and H. nodifloruin) were active, with EC50 in the range 2.7-10.7 mu g/mL. Most of these oils were selective against T. brucei, except the one from C. maritimum that was highly selective against the BALB/3T3 mammalian cells. Testing nine characteristic individual components (a-pinene, sabinene, alpha-phellandrene, p-cymene, limonene, beta-ocimene, gamma-terpinene, terpinolene, and myristicin) of these oils, we showed that some of them had much higher selectivity than the oils themselves. Terpinolene was particularly active with an EC50 value of 0.035 mu g/rnL (0.26 mu M) and a selectivity index (SI) of 180. Four other compounds with EC50 in the range 1.0-6.0 mu g/mL (7.4-44 mu M) had also good SI: a-pinene (> 100), beta-ocimene (> 91), limonene (> 18) and sabinene ( > 17). In conclusion, these results highlight that the essential oils from the Apiaceae family are a reservoir of substances to be used as leading compounds for the development of natural drugs for the treatment of HAT.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
Apiaceae, Essential oils, Human African trypanosomiasis, Trypanosome brucei, BALB/3T3
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-150669 (URN)10.1016/j.ecoenv.2018.03.032 (DOI)000430519100019 ()29549739 (PubMedID)2-s2.0-85045436656 (Scopus ID)
Available from: 2018-08-17 Created: 2018-08-17 Last updated: 2018-08-17Bibliographically approved
Sut, S., Dall'Acqua, S., Baldan, V., Ngahang Kamte, S. L., Ranjbarian, F., Biapa Nya, P. C., . . . Petrelli, R. (2018). Identification of tagitinin C from Tithonia diversifolia as antitrypanosomal compound using bioactivity-guided fractionation. Fitoterapia (Milano), 124, 145-151
Open this publication in new window or tab >>Identification of tagitinin C from Tithonia diversifolia as antitrypanosomal compound using bioactivity-guided fractionation
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2018 (English)In: Fitoterapia (Milano), ISSN 0367-326X, E-ISSN 1873-6971, Vol. 124, p. 145-151Article in journal (Refereed) Published
Abstract [en]

Tithonia diversifolia (Asteraceae), is used as traditional medicine in tropical countries for the treatment of various diseases, including malaria. Although numerous studies have assessed the antimalarial properties, nothing is known about the effect of T. diversifolia extracts on trypanosomiasis. In this study extracts of T. diversifolia aerial parts were evaluated for their bioactivity against Trypanosoma brucei. The activity was studied against bloodstream forms of T. brucei (TC221), as well as against mammalian cells (BALB/3T3 mouse fibroblasts), as a counter-screen for toxicity. Both methanolic and aqueous extracts showed significant effects with IC50 values of 1.1 and 2.2 mu g/mL against T. brucei (TC221) and 5.2 and 3.7 mu g/mL against BALB/3T3 cells, respectively. A bioassay-guided fractionation on the methanolic extract yielded in identification of active fractions (F8 and F9) with IC50 values of 0.41 and 0.43 mu g/mL, respectively, against T. brucei (TC221) and 1.4 and 1.5 mu g/mL, respectively, against BALB/3T3 cells,. The phytochemical composition of the extracts and the purified fractions were investigated using HPLC-ESI-MS/MS and 1D and 2D NMR spectra showing the presence of sesquiterpene lactones that in turn were subjected to the isolation procedure. Tagitinin A and C were rather active but the latter presented a very strong inhibition on T. brucei (TC221) with an IC50 value of 0.0042 mu g/mL. This activity was 4.5 times better than that of the reference drug suramin. The results of this study shed light on the antitrypanosomal effects of T. diversifolia extracts and highlighted tagitinin C as one of the possible responsible for this effect. Further structure activity relationships studies on tagitinins are needed to consider this sesquiterpenes as lead compounds for the development of new antitrypanosomal drugs.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
BALB/3T3 mouse fibroblasts, Mexican sunflower, HPLC-ESI-MS/MS, NMR, Tagitinins A and C, squiterpene lactones
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-144971 (URN)10.1016/j.fitote.2017.11.002 (DOI)000423888000022 ()29146170 (PubMedID)
Available from: 2018-02-21 Created: 2018-02-21 Last updated: 2018-06-09Bibliographically approved
Benelli, G., Maggi, F., Pavela, R., Murugan, K., Govindarajan, M., Vaseeharan, B., . . . Higuchi, A. (2018). Mosquito control with green nanopesticides: towards the One Health approach? A review of non-target effects. Environmental science and pollution research international, 25(11), 10184-10206
Open this publication in new window or tab >>Mosquito control with green nanopesticides: towards the One Health approach? A review of non-target effects
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2018 (English)In: Environmental science and pollution research international, ISSN 0944-1344, E-ISSN 1614-7499, Vol. 25, no 11, p. 10184-10206Article, review/survey (Refereed) Published
Abstract [en]

The rapid spread of highly aggressive arboviruses, parasites, and bacteria along with the development of resistance in the pathogens and parasites, as well as in their arthropod vectors, represents a huge challenge in modern parasitology and tropical medicine. Eco-friendly vector control programs are crucial to fight, besides malaria, the spread of dengue, West Nile, chikungunya, and Zika virus, as well as other arboviruses such as St. Louis encephalitis and Japanese encephalitis. However, research efforts on the control of mosquito vectors are experiencing a serious lack of eco-friendly and highly effective pesticides, as well as the limited success of most biocontrol tools currently applied. Most importantly, a cooperative interface between the two disciplines is still lacking. To face this challenge, we have reviewed a wide number of promising results in the field of green-fabricated pesticides tested against mosquito vectors, outlining several examples of synergy with classic biological control tools. The non-target effects of green-fabricated nanopesticides, including acute toxicity, genotoxicity, and impact on behavioral traits of mosquito predators, have been critically discussed. In the final section, we have identified several key challenges at the interface between "green" nanotechnology and classic biological control, which deserve further research attention.

Keywords
Arbovirus, Biosafety, Dengue, Genotoxicity, Japanese encephalitis, Malaria, Nanosynthesis, West Nile rus, Zika virus
National Category
Microbiology
Identifiers
urn:nbn:se:umu:diva-147471 (URN)10.1007/s11356-017-9752-4 (DOI)000429810200004 ()28755145 (PubMedID)
Available from: 2018-05-22 Created: 2018-05-22 Last updated: 2018-06-09Bibliographically approved
Rozman Grinberg, I., Lundin, D., Hasan, M., Crona, M., Rao Jonna, V., Loderer, C., . . . Sjöberg, B.-M. (2018). Novel ATP-cone-driven allosteric regulation of ribonucleotide reductase via the radical-generating subunit. eLIFE, 7, Article ID e31529.
Open this publication in new window or tab >>Novel ATP-cone-driven allosteric regulation of ribonucleotide reductase via the radical-generating subunit
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2018 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 7, article id e31529Article in journal (Refereed) Published
Abstract [en]

Ribonucleotide reductases (RNRs) are key enzymes in DNA metabolism, with allosteric mechanisms controlling substrate specificity and overall activity. In RNRs, the activity master-switch, the ATP-cone, has been found exclusively in the catalytic subunit. In two class I RNR subclasses whose catalytic subunit lacks the ATP-cone, we discovered ATP-cones in the radical-generating subunit. The ATP-cone in the Leeuwenhoekiella blandensis radical-generating subunit regulates activity via quaternary structure induced by binding of nucleotides. ATP induces enzymatically competent dimers, whereas dATP induces non-productive tetramers, resulting in different holoenzymes. The tetramer forms by interactions between ATP-cones, shown by a 2.45 A crystal structure. We also present evidence for an (MnMnIV)-Mn-III metal center. In summary, lack of an ATP-cone domain in the catalytic subunit was compensated by transfer of the domain to the radical-generating subunit. To our knowledge, this represents the first observation of transfer of an allosteric domain between components of the same enzyme complex.

Place, publisher, year, edition, pages
ELIFE SCIENCES PUBLICATIONS LTD, 2018
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-144937 (URN)10.7554/eLife.31529 (DOI)000423786200001 ()
Available from: 2018-02-23 Created: 2018-02-23 Last updated: 2018-06-09Bibliographically approved
Grinberg, I., McGann, M., Lundin, D., Crona, M., Hasan, M., Jonna, V. R., . . . Sjöberg, B.-M. (2018). Novel ATP-Cone-Driven Allosteric Regulation of Ribonucleotide Reductase Via the Radical-Generating Subunit. Paper presented at 32nd Annual Symposium of the Protein-Society, JUL 09-12, 2018, Boston, MA. Protein Science, 27, 87-88
Open this publication in new window or tab >>Novel ATP-Cone-Driven Allosteric Regulation of Ribonucleotide Reductase Via the Radical-Generating Subunit
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2018 (English)In: Protein Science, ISSN 0961-8368, E-ISSN 1469-896X, Vol. 27, p. 87-88Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Wiley-Blackwell, 2018
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-154065 (URN)000450682700147 ()
Conference
32nd Annual Symposium of the Protein-Society, JUL 09-12, 2018, Boston, MA
Available from: 2018-12-19 Created: 2018-12-19 Last updated: 2018-12-19Bibliographically approved
Schmitt, A., Jiang, K., Camacho, M. I., Jonna, V. R., Hofer, A., Westerlund, F., . . . Berntsson, R.-A. P. (2018). PrgB promotes aggregation, biofilm formation, and conjugation through DNA binding and compaction. Molecular Microbiology, 109(3), 291-305
Open this publication in new window or tab >>PrgB promotes aggregation, biofilm formation, and conjugation through DNA binding and compaction
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2018 (English)In: Molecular Microbiology, ISSN 0950-382X, E-ISSN 1365-2958, Vol. 109, no 3, p. 291-305Article in journal (Refereed) Published
Abstract [en]

Gram-positive bacteria deploy type IV secretion systems (T4SSs) to facilitate horizontal gene transfer. The T4SSs of Gram-positive bacteria rely on surface adhesins as opposed to conjugative pili to facilitate mating. Enterococcus faecalis PrgB is a surface adhesin that promotes mating pair formation and robust biofilm development in an extracellular DNA (eDNA) dependent manner. Here, we report the structure of the adhesin domain of PrgB. The adhesin domain binds and compacts DNA in vitro. In vivo PrgB deleted of its adhesin domain does not support cellular aggregation, biofilm development and conjugative DNA transfer. PrgB also binds lipoteichoic acid (LTA), which competes with DNA binding. We propose that PrgB binding and compaction of eDNA facilitates cell aggregation and plays an important role in establishment of early biofilms in mono- or polyspecies settings. Within these biofilms, PrgB mediates formation and stabilization of direct cell-cell contacts through alternative binding of cell-bound LTA, which in turn promotes establishment of productive mating junctions and efficient intra- or inter-species T4SS-mediated gene transfer.

Place, publisher, year, edition, pages
John Wiley & Sons, 2018
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-152231 (URN)10.1111/mmi.13980 (DOI)000443810300005 ()29723434 (PubMedID)
Available from: 2018-10-25 Created: 2018-10-25 Last updated: 2018-10-25Bibliographically approved
Ranjbarian, F., Vodnala, M., Alzahrani, K. J. H., Ebiloma, G. U., de Koning, H. P. & Hofer, A. (2017). 9-(2 '-Deoxy-2 '-Fluoro-beta-D-Arabinofuranosyl) Adenine Is a Potent Antitrypanosomal Adenosine Analogue That Circumvents Transport-Related Drug Resistance. Antimicrobial Agents and Chemotherapy, 61(6), Article ID e02719-16.
Open this publication in new window or tab >>9-(2 '-Deoxy-2 '-Fluoro-beta-D-Arabinofuranosyl) Adenine Is a Potent Antitrypanosomal Adenosine Analogue That Circumvents Transport-Related Drug Resistance
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2017 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 61, no 6, article id e02719-16Article in journal (Refereed) Published
Abstract [en]

Current chemotherapy against African sleeping sickness, a disease caused by the protozoan parasite Trypanosoma brucei, is limited by toxicity, inefficacy, and drug resistance. Nucleoside analogues have been successfully used to cure T. brucei-infected mice, but they have the limitation of mainly being taken up by the P2 nucleoside transporter, which, when mutated, is a common cause of multidrug resistance in T. brucei. We report here that adenine arabinoside (Ara-A) and the newly tested drug 9-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl) adenine (FANA-A) are instead taken up by the P1 nucleoside transporter, which is not associated with drug resistance. Like Ara-A, FANA-A was found to be resistant to cleavage by methylthioadenosine phosphorylase, an enzyme that protects T. brucei against the antitrypanosomal effects of deoxyadenosine. Another important factor behind the selectivity of nucleoside analogues is how well they are phosphorylated within the cell. We found that the T. brucei adenosine kinase had a higher catalytic efficiency with FANA-A than the mammalian enzyme, and T. brucei cells treated with FANA-A accumulated high levels of FANA-A triphosphate, which even surpassed the level of ATP and led to cell cycle arrest, inhibition of DNA synthesis, and the accumulation of DNA breaks. FANA-A inhibited nucleic acid biosynthesis and parasite proliferation with 50% effective concentrations (EC(50)s) in the low nanomolar range, whereas mammalian cell proliferation was inhibited in the micromolar range. Both Ara-A and FANA-A, in combination with deoxycoformycin, cured T. brucei-infected mice, but FANA-A did so at a dose 100 times lower than that of Ara-A.

Place, publisher, year, edition, pages
American Society for Microbiology, 2017
Keywords
9-(2 '-deoxy-2 '-fluoro-beta-D-arabinofuranosyl) adenine, FANA-A, Trypanosoma brucei, adenosine kinase, drug resistance, methylthioadenosine phosphorylase, nucleoside transporters, trypanosome
National Category
Microbiology in the medical area Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-137649 (URN)10.1128/AAC.02719-16 (DOI)000403783400052 ()
Available from: 2017-07-18 Created: 2017-07-18 Last updated: 2018-06-09Bibliographically approved
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