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Article ; Online: Biological Evaluation of DNA Biomarkers in a Chemically Defined and Site-Specific Manner.

Bian, Ke / Delaney, James C / Zhou, Xianhao / Li, Deyu

2019 Volume 7, Issue 2

Abstract: As described elsewhere in this Special Issue on biomarkers, much progress has been made in the detection of modified DNA within organisms at endogenous and exogenous levels of exposure to chemical species, including putative carcinogens and ... ...

Abstract	As described elsewhere in this Special Issue on biomarkers, much progress has been made in the detection of modified DNA within organisms at endogenous and exogenous levels of exposure to chemical species, including putative carcinogens and chemotherapeutic agents. Advances in the detection of damaged or unnatural bases have been able to provide correlations to support or refute hypotheses between the level of exposure to oxidative, alkylative, and other stresses, and the resulting DNA damage (lesion formation). However, such stresses can form a plethora of modified nucleobases, and it is therefore difficult to determine the individual contribution of a particular modification to alter a cell's genetic fate, as measured in the form of toxicity by stalled replication past the damage, by subsequent mutation, and by lesion repair. Chemical incorporation of a modification at a specific site within a vector (site-specific mutagenesis) has been a useful tool to deconvolute what types of damage quantified in biologically relevant systems may lead to toxicity and/or mutagenicity, thereby allowing researchers to focus on the most relevant biomarkers that may impact human health. Here, we will review a sampling of the DNA modifications that have been studied by shuttle vector techniques.
Language	English
Publishing date	2019-06-25
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2733883-6
ISSN	2305-6304 ; 2305-6304
ISSN (online)	2305-6304
ISSN	2305-6304
DOI	10.3390/toxics7020036
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Article ; Online: Development of an antibody fused with an antimicrobial peptide targeting Pseudomonas aeruginosa: A new approach to prevent and treat bacterial infections.

Johnson, Kenneth / Delaney, James C / Guillard, Thomas / Reffuveille, Fany / Varin-Simon, Jennifer / Li, Kai / Wollacott, Andrew / Frapy, Eric / Mong, Surin / Tissire, Hamid / Viswanathan, Karthik / Touti, Faycal / Babcock, Gregory J / Shriver, Zachary / Pentelute, Bradley L / Plante, Obadiah / Skurnik, David

PLoS pathogens

2023 Volume 19, Issue 9, Page(s) e1011612

Abstract: The increase in emerging drug resistant Gram-negative bacterial infections is a global concern. In addition, there is growing recognition that compromising the microbiota through the use of broad-spectrum antibiotics can impact long term patient outcomes. ...

Abstract	The increase in emerging drug resistant Gram-negative bacterial infections is a global concern. In addition, there is growing recognition that compromising the microbiota through the use of broad-spectrum antibiotics can impact long term patient outcomes. Therefore, there is the need to develop new bactericidal strategies to combat Gram-negative infections that would address these specific issues. In this study, we report and characterize one such approach, an antibody-drug conjugate (ADC) that combines (i) targeting the surface of a specific pathogenic organism through a monoclonal antibody with (ii) the high killing activity of an antimicrobial peptide. We focused on a major pathogenic Gram-negative bacterium associated with antibacterial resistance: Pseudomonas aeruginosa. To target this organism, we designed an ADC by fusing an antimicrobial peptide to the C-terminal end of the VH and/or VL-chain of a monoclonal antibody, VSX, that targets the core of P. aeruginosa lipopolysaccharide. This ADC demonstrates appropriately minimal levels of toxicity against mammalian cells, rapidly kills P. aeruginosa strains, and protects mice from P. aeruginosa lung infection when administered therapeutically. Furthermore, we found that the ADC was synergistic with several classes of antibiotics. This approach described in this study might result in a broadly useful strategy for targeting specific pathogenic microorganisms without further augmenting antibiotic resistance.
MeSH term(s)	Animals ; Mice ; Pseudomonas aeruginosa ; Immunoconjugates ; Bacterial Infections ; Antibodies, Monoclonal/pharmacology ; Anti-Bacterial Agents/pharmacology ; Antimicrobial Peptides ; Mammals
Chemical Substances	Immunoconjugates ; Antibodies, Monoclonal ; Anti-Bacterial Agents ; Antimicrobial Peptides
Language	English
Publishing date	2023-09-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1011612
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Article: Characterization of an Antibody Recognizing the Conserved Inner Core of Pseudomonas aeruginosa Lipopolysaccharides

Elli, Stefano / Alekseeva, Anna / Ramakrishnan, Boopathy / Koch, Tyree / Wollacott, Andrew / Viswanathan, Karthik / Li, Kai / Delaney, James C / Shriver, Zachary / Plante, Obadiah / Guerrini, Marco

Biochemistry. 2020 Oct. 21, v. 59, no. 43

2020

Abstract: Bacterial infections are a growing public health threat with carbapenem-resistant Pseudomonas aeruginosa being classified as a Priority 1 critical threat by the World Health Organization. Antibody-based therapeutics can serve as an alternative and in ... ...

Abstract	Bacterial infections are a growing public health threat with carbapenem-resistant Pseudomonas aeruginosa being classified as a Priority 1 critical threat by the World Health Organization. Antibody-based therapeutics can serve as an alternative and in some cases supplement antibiotics for the treatment of bacterial infections. The glycans covering the bacterial cell surface have been proposed as intriguing targets for binding by antibodies; however, antibodies that can engage with high affinity and specificity with glycans are much less common compared to antibodies that engage with protein antigens. In this study, we sought to characterize an antibody that targets a conserved glycan epitope on the surface of Pseudomonas. First, we characterized the breadth of binding of VSX, demonstrating that the VSX is specific to Pseudomonas but can bind across multiple serotypes of the organism. Next, we provide insight into how VSX engages with its target epitope, using a combination of biolayer interferometry and nuclear magnetic resonance, and verify our results using site-directed mutagenesis experiments. We demonstrate that the antibody, with limited somatic hypermutation of the complementarity-determining regions (CDRs) and with a characteristic set of arginines within the CDRs, specifically targets the conserved inner core of Pseudomonas lipopolysaccharides. Our results provide important additional context to antibody–glycan contacts and provide insight useful for the construction of vaccines and therapeutics against Pseudomonas aeruginosa, an important human pathogen.
Keywords	Pseudomonas aeruginosa ; World Health Organization ; animal pathogens ; antibiotics ; antibodies ; bacteria ; bacterial infections ; epitopes ; interferometry ; lipopolysaccharides ; nuclear magnetic resonance spectroscopy ; public health ; serotypes ; site-directed mutagenesis ; therapeutics ; vaccines
Language	English
Dates of publication	2020-1021
Size	p. 4202-4211.
Publishing place	American Chemical Society
Document type	Article
Note	NAL-light
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/acs.biochem.0c00642
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Article: Biological properties of single chemical-DNA adducts: a twenty year perspective.

Delaney, James C / Essigmann, John M

Chemical research in toxicology

2007 Volume 21, Issue 1, Page(s) 232–252

Abstract: The genome and its nucleotide precursor pool are under sustained attack by radiation, reactive oxygen and nitrogen species, chemical carcinogens, hydrolytic reactions, and certain drugs. As a result, a large and heterogeneous population of damaged ... ...

Abstract	The genome and its nucleotide precursor pool are under sustained attack by radiation, reactive oxygen and nitrogen species, chemical carcinogens, hydrolytic reactions, and certain drugs. As a result, a large and heterogeneous population of damaged nucleotides forms in all cells. Some of the lesions are repaired, but for those that remain, there can be serious biological consequences. For example, lesions that form in DNA can lead to altered gene expression, mutation, and death. This perspective examines systems developed over the past 20 years to study the biological properties of single DNA lesions.
MeSH term(s)	Animals ; DNA/chemistry ; DNA/genetics ; DNA Adducts/chemistry ; DNA Adducts/genetics ; DNA Repair ; Humans ; Kinetics ; Mutagenesis ; Nucleotides/chemistry ; Oligonucleotides/chemical synthesis ; Oligonucleotides/chemistry
Chemical Substances	DNA Adducts ; Nucleotides ; Oligonucleotides ; DNA (9007-49-2)
Language	English
Publishing date	2007-12-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	639353-6
ISSN	1520-5010 ; 0893-228X
ISSN (online)	1520-5010
ISSN	0893-228X
DOI	10.1021/tx700292a
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Article ; Online: Characterization of an Antibody Recognizing the Conserved Inner Core of

Elli, Stefano / Alekseeva, Anna / Ramakrishnan, Boopathy / Koch, Tyree / Wollacott, Andrew / Viswanathan, Karthik / Li, Kai / Delaney, James C / Shriver, Zachary / Plante, Obadiah / Guerrini, Marco

Biochemistry

2020 Volume 59, Issue 43, Page(s) 4202–4211

Abstract: Bacterial infections are a growing public health threat with carbapenem- ... ...

Abstract	Bacterial infections are a growing public health threat with carbapenem-resistant
MeSH term(s)	Antibodies, Bacterial/metabolism ; Epitopes/immunology ; Epitopes/metabolism ; Lipopolysaccharides/immunology ; Lipopolysaccharides/metabolism ; Polysaccharides/immunology ; Polysaccharides/metabolism ; Pseudomonas Infections/immunology ; Pseudomonas Infections/metabolism ; Pseudomonas aeruginosa/immunology ; Pseudomonas aeruginosa/metabolism
Chemical Substances	Antibodies, Bacterial ; Epitopes ; Lipopolysaccharides ; Polysaccharides
Language	English
Publishing date	2020-10-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/acs.biochem.0c00642
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Article: Assays for determining lesion bypass efficiency and mutagenicity of site-specific DNA lesions in vivo.

Delaney, James C / Essigmann, John M

Methods in enzymology

2006 Volume 408, Page(s) 1–15

Abstract: DNA damage, if left unrepaired, may hinder translesion synthesis, leading to cytotoxicity, and instruct a DNA polymerase to incorporate an incorrect incipient base opposite the damage, leading to mutagenicity. This chapter describes technology used to ... ...

Abstract	DNA damage, if left unrepaired, may hinder translesion synthesis, leading to cytotoxicity, and instruct a DNA polymerase to incorporate an incorrect incipient base opposite the damage, leading to mutagenicity. This chapter describes technology used to measure quantitatively the degree to which a specific type of DNA damage impedes DNA replication. The technology also quantifies the mutation frequency and specificity of such damage after replication within cells. If cells with defined defects in DNA repair are used as hosts for replication, one can pinpoint the specific enzymes or pathways of repair that are operative on specific types of DNA damage.
MeSH term(s)	Bacteriophage M13/genetics ; Biological Assay/methods ; DNA Damage ; DNA Repair ; DNA Replication ; DNA, Viral ; Genome, Viral ; Mutagenesis
Chemical Substances	DNA, Viral
Language	English
Publishing date	2006
Publishing country	United States
Document type	Journal Article
ISSN	0076-6879
ISSN	0076-6879
DOI	10.1016/S0076-6879(06)08001-3
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Article ; Online: The AlkB Family of Fe(II)/α-Ketoglutarate-dependent Dioxygenases: Repairing Nucleic Acid Alkylation Damage and Beyond.

Fedeles, Bogdan I / Singh, Vipender / Delaney, James C / Li, Deyu / Essigmann, John M

The Journal of biological chemistry

2015 Volume 290, Issue 34, Page(s) 20734–20742

Abstract: The AlkB family of Fe(II)- and α-ketoglutarate-dependent dioxygenases is a class of ubiquitous direct reversal DNA repair enzymes that remove alkyl adducts from nucleobases by oxidative dealkylation. The prototypical and homonymous family member is an ... ...

Abstract	The AlkB family of Fe(II)- and α-ketoglutarate-dependent dioxygenases is a class of ubiquitous direct reversal DNA repair enzymes that remove alkyl adducts from nucleobases by oxidative dealkylation. The prototypical and homonymous family member is an Escherichia coli "adaptive response" protein that protects the bacterial genome against alkylation damage. AlkB has a wide variety of substrates, including monoalkyl and exocyclic bridged adducts. Nine mammalian AlkB homologs exist (ALKBH1-8, FTO), but only a subset functions as DNA/RNA repair enzymes. This minireview presents an overview of the AlkB proteins including recent data on homologs, structural features, substrate specificities, and experimental strategies for studying DNA repair by AlkB family proteins.
MeSH term(s)	AlkB Homolog 4, Lysine Demethylase ; Alkylation ; DNA Damage ; DNA Repair ; DNA, Single-Stranded/genetics ; DNA, Single-Stranded/metabolism ; Dioxygenases/genetics ; Dioxygenases/metabolism ; Escherichia coli/enzymology ; Escherichia coli/genetics ; Escherichia coli Proteins/genetics ; Escherichia coli Proteins/metabolism ; Gene Expression ; Humans ; Iron/metabolism ; Isoenzymes/genetics ; Isoenzymes/metabolism ; Ketoglutaric Acids/metabolism ; Mixed Function Oxygenases/genetics ; Mixed Function Oxygenases/metabolism ; Models, Molecular ; Multigene Family ; Oxidation-Reduction ; Substrate Specificity
Chemical Substances	DNA, Single-Stranded ; Escherichia coli Proteins ; Isoenzymes ; Ketoglutaric Acids ; Iron (E1UOL152H7) ; Mixed Function Oxygenases (EC 1.-) ; Dioxygenases (EC 1.13.11.-) ; AlkB protein, E coli (EC 1.14.11.-) ; ALKBH4 protein, human (EC 1.14.11.27) ; AlkB Homolog 4, Lysine Demethylase (EC 1.14.11.27)
Language	English
Publishing date	2015-07-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.R115.656462
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Article: Mutagenesis, genotoxicity, and repair of 1-methyladenine, 3-alkylcytosines, 1-methylguanine, and 3-methylthymine in alkB Escherichia coli.

Delaney, James C / Essigmann, John M

Proceedings of the National Academy of Sciences of the United States of America

2004 Volume 101, Issue 39, Page(s) 14051–14056

Abstract: AlkB repairs 1-alkyladenine and 3-methylcytosine lesions in DNA by directly reversing the base damage. Although repair studies with randomly alkylated substrates have been performed, the miscoding nature of these and related individually alkylated bases ... ...

Abstract	AlkB repairs 1-alkyladenine and 3-methylcytosine lesions in DNA by directly reversing the base damage. Although repair studies with randomly alkylated substrates have been performed, the miscoding nature of these and related individually alkylated bases and the suppression of mutagenesis by AlkB within cells have not yet been explored. Here, we address the miscoding potential of 1-methyldeoxyadenosine (m1A), 3-methyldeoxycytidine (m3C), 3-ethyldeoxycytidine (e3C), 1-methyldeoxyguanosine (m1G), and 3-methyldeoxythymidine (m3T) by synthesizing single-stranded vectors containing each alkylated base, followed by vector passage through Escherichia coli. In SOS(-), AlkB-deficient cells, m1A was only 1% mutagenic; however, m3C and e3C were 30% mutagenic, rising to 70% in SOS(+) cells. In contrast, the mutagenicity of m1G and m3T in AlkB(-) cells dropped slightly when SOS polymerases were expressed (m1G from 80% to 66% and m3T from 60% to 53%). Mutagenicity was abrogated for m1A, m3C, and e3C in wild-type (AlkB(+)) cells, whereas m3T mutagenicity was only partially reduced. Remarkably, m1G mutagenicity was also eliminated in AlkB(+) cells, establishing it as a natural AlkB substrate. All lesions were blocks to replication in AlkB-deficient cells. The m1A, m3C, and e3C blockades were completely removed in wild-type cells; the m1G blockade was partially removed and that for m3T was unaffected by the presence of AlkB. All lesions demonstrated enhanced bypass when SOS polymerases were induced. This work provides direct evidence that AlkB suppresses both genotoxicity and mutagenesis by physiologically realistic low doses of 1-alkylpurine and 3-alkylpyrimidine DNA damage in vivo.
MeSH term(s)	Adenine/analogs & derivatives ; Adenine/physiology ; Base Sequence ; Cytosine/analogs & derivatives ; Cytosine/physiology ; DNA Adducts/genetics ; DNA Adducts/metabolism ; DNA Damage/physiology ; DNA Methylation ; DNA Repair/physiology ; DNA Replication/physiology ; DNA, Bacterial/physiology ; DNA, Single-Stranded/genetics ; DNA, Single-Stranded/metabolism ; Escherichia coli/enzymology ; Escherichia coli Proteins/physiology ; Genetic Techniques ; Guanine/analogs & derivatives ; Guanine/physiology ; Mutagenesis/physiology ; Nucleotides/physiology ; SOS Response (Genetics)/physiology ; Thymine/analogs & derivatives ; Thymine/physiology
Chemical Substances	DNA Adducts ; DNA, Bacterial ; DNA, Single-Stranded ; Escherichia coli Proteins ; Nucleotides ; 1-methylguanine (1ATY0M8242) ; 1-methylthymine (4160-72-9) ; 1-methyladenine (5142-22-3) ; Guanine (5Z93L87A1R) ; Cytosine (8J337D1HZY) ; Adenine (JAC85A2161) ; Thymine (QR26YLT7LT)
Language	English
Publishing date	2004-09-28
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.0403489101
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Article ; Online: Implications for damage recognition during Dpo4-mediated mutagenic bypass of m1G and m3C lesions.

Rechkoblit, Olga / Delaney, James C / Essigmann, John M / Patel, Dinshaw J

Structure (London, England : 1993)

2011 Volume 19, Issue 6, Page(s) 821–832

Abstract: DNA is susceptible to alkylation damage by a number of environmental agents that modify the Watson-Crick edge of the bases. Such lesions, if not repaired, may be bypassed by Y-family DNA polymerases. The bypass polymerase Dpo4 is strongly inhibited by 1- ... ...

Abstract	DNA is susceptible to alkylation damage by a number of environmental agents that modify the Watson-Crick edge of the bases. Such lesions, if not repaired, may be bypassed by Y-family DNA polymerases. The bypass polymerase Dpo4 is strongly inhibited by 1-methylguanine (m1G) and 3-methylcytosine (m3C), with nucleotide incorporation opposite these lesions being predominantly mutagenic. Further, extension after insertion of both correct and incorrect bases, introduces additional base substitution and deletion errors. Crystal structures of the Dpo4 ternary extension complexes with correct and mismatched 3'-terminal primer bases opposite the lesions reveal that both m1G and m3C remain positioned within the DNA template/primer helix. However, both correct and incorrect pairing partners exhibit pronounced primer terminal nucleotide distortion, being primarily evicted from the DNA helix when opposite m1G or misaligned when pairing with m3C. Our studies provide insights into mechanisms related to hindered and mutagenic bypass of methylated lesions and models associated with damage recognition by repair demethylases.
MeSH term(s)	Catalytic Domain ; Crystallography, X-Ray ; DNA Adducts/chemistry ; DNA Polymerase beta/chemistry ; DNA Repair ; Enzyme Assays ; Escherichia coli/enzymology ; Escherichia coli Proteins/chemistry ; Hydrogen Bonding ; Models, Molecular ; Mutagenesis ; Nucleic Acid Conformation ; Oligonucleotides/chemistry
Chemical Substances	DNA Adducts ; Escherichia coli Proteins ; Oligonucleotides ; Dpo4 protein, E coli (EC 2.7.7.-) ; DNA Polymerase beta (EC 2.7.7.7)
Language	English
Publishing date	2011-05-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1213087-4
ISSN	1878-4186 ; 0969-2126
ISSN (online)	1878-4186
ISSN	0969-2126
DOI	10.1016/j.str.2011.03.020
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Article: Chemical-biological fingerprinting: probing the properties of DNA lesions formed by peroxynitrite.

Delaney, Sarah / Delaney, James C / Essigmann, John M

Chemical research in toxicology

2007 Volume 20, Issue 11, Page(s) 1718–1729

Abstract: DNA-damaging agents usually produce a vast collection of lesions within the genome. Analysis of these lesions from the structural and biological viewpoints is often complicated by the reality that some of the lesions are chemically fragile, leading to an ...

Abstract	DNA-damaging agents usually produce a vast collection of lesions within the genome. Analysis of these lesions from the structural and biological viewpoints is often complicated by the reality that some of the lesions are chemically fragile, leading to an even larger set of secondary and tertiary products. In an effort to deconvolute complex DNA-damage spectra, a strategy is presented whereby an oligonucleotide containing a specific target for chemical reaction is allowed to react with a DNA-damaging agent. A large collection of HPLC-resolvable modified oligonucleotides is generated, and chromatographically distinct members of the set are then individually characterized using chemical, spectroscopic, biochemical, and genetic probes. The biological component of this "chemical-biological fingerprinting" tool is the use of polymerase bypass in vivo in cells having defined replication status and quantitative and qualitative patterns of lesion-directed mutagenesis, as key properties that complement physical analysis of modified DNA. This approach was applied to the complex product spectrum generated by peroxynitrite in the presence of CO2; peroxynitrite is a powerful oxidizing and nitrating agent generated as part of immune response. An oligonucleotide containing the primary oxidation product, 7,8-dihydro-8-oxoguanine (8-oxoGua), which is highly susceptible to further oxidation and/or nitration, was treated with peroxynitrite. Using mass spectrometry, coelution with authentic standards, sensitivity to piperidine, recognition and strand cleavage by the DNA repair enzyme MutM, and mutagenicity and genotoxicity in vivo, a matrix was created that defined the properties of the secondary DNA lesions formed when 3-morpholinosydnonimine (SIN-1) delivered a low, constant flux of peroxynitrite to an oligonucleotide containing 8-oxoGua. Two lesions were identified as the diastereomers of spiroiminodihydantoin (Sp), which had been observed previously in nucleoside-based experiments employing SIN-1. A third lesion, triazine, was tentatively identified. However, in addition to these lesions, a number of secondary lesions were generated that had chemical-biological fingerprints inconsistent with that of any known 8-oxoGua-derived lesion described to date. In vitro experiments showed that while some of these newly characterized secondary lesions were removed from DNA by MutM, others were in fact very poor substrates for this repair enzyme. These 8-oxoGua-derived lesions also showed varying degrees of sensitivity to piperidine. Furthermore, all of the secondary lesions observed in this work were potently mutagenic and genotoxic in Escherichia coli. Therefore, while 8-oxoGua itself is nontoxic and only mildly mutagenic in repair-proficient cells, peroxynitrite reveals the promutagenic potential and triggers the covert nature of this DNA lesion.
MeSH term(s)	Chromatography, High Pressure Liquid ; DNA Damage ; Escherichia coli/drug effects ; Escherichia coli/genetics ; Guanine/analogs & derivatives ; Guanine/metabolism ; Molsidomine/analogs & derivatives ; Molsidomine/toxicity ; Mutation ; Peroxynitrous Acid/toxicity ; SOS Response, Genetics ; Spectrometry, Mass, Electrospray Ionization
Chemical Substances	7,8-dihydro-8-oxoguanine ; Peroxynitrous Acid (14691-52-2) ; linsidomine (5O5U71P6VQ) ; Guanine (5Z93L87A1R) ; Molsidomine (D46583G77X)
Language	English
Publishing date	2007-10-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	639353-6
ISSN	1520-5010 ; 0893-228X
ISSN (online)	1520-5010
ISSN	0893-228X
DOI	10.1021/tx700273u
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