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  1. Article ; Online: EPR Spectroscopic Studies of Lipoxygenases.

    Gaffney, Betty J

    Chemistry, an Asian journal

    2019  Volume 15, Issue 1, Page(s) 42–50

    Abstract: Polyunsaturated fatty acids are sources of diverse natural, and chemically designed products. The enzyme lipoxygenase selectively oxidizes fatty acid acyl chains using controlled free radical chemistry; the products are regio- and stereo-chemically ... ...

    Abstract Polyunsaturated fatty acids are sources of diverse natural, and chemically designed products. The enzyme lipoxygenase selectively oxidizes fatty acid acyl chains using controlled free radical chemistry; the products are regio- and stereo-chemically unique hydroperoxides. A conserved structural fold of ≈600 amino acids harbors a long and narrow substrate channel and a well-shielded catalytic iron. Oxygen, a co-substrate, is blocked from the active site until a hydrogen atom is abstracted from substrate bis-allylic carbon, in a non-heme iron redox cycle. EPR spectroscopy of ferric intermediates in lipoxygenase catalysis reveals changes in the metal coordination and leads to a proposal on the nature of the reactive intermediate. Remarkably, free radicals are so well controlled in lipoxygenase chemistry that spin label technology can be applied as well. The current level of understanding of steps in lipoxygenase catalysis, from the EPR perspective, will be reviewed.
    MeSH term(s) Biocatalysis ; Electron Spin Resonance Spectroscopy ; Fatty Acids, Unsaturated/chemistry ; Fatty Acids, Unsaturated/metabolism ; Humans ; Lipoxygenases/metabolism ; Molecular Structure
    Chemical Substances Fatty Acids, Unsaturated ; Lipoxygenases (EC 1.13.11.-)
    Language English
    Publishing date 2019-12-05
    Publishing country Germany
    Document type Journal Article ; Review
    ZDB-ID 2233006-9
    ISSN 1861-471X ; 1861-4728
    ISSN (online) 1861-471X
    ISSN 1861-4728
    DOI 10.1002/asia.201901461
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  2. Article ; Online: Connecting lipoxygenase function to structure by electron paramagnetic resonance.

    Gaffney, Betty J

    Accounts of chemical research

    2014  Volume 47, Issue 12, Page(s) 3588–3595

    Abstract: CONSPECTUS: Lipoxygenase enzymes insert oxygen in a polyunsaturated lipid, yielding a hydroperoxide product. When the acyl chain is arachidonate, with three cis-pentadiene units, 12 positionally and stereochemically different products might result. The ... ...

    Abstract CONSPECTUS: Lipoxygenase enzymes insert oxygen in a polyunsaturated lipid, yielding a hydroperoxide product. When the acyl chain is arachidonate, with three cis-pentadiene units, 12 positionally and stereochemically different products might result. The plant lipids, linoleate and linolenate, have, respectively, four and eight potential oxygen insertion sites. The puzzle of how specificity is achieved in these reactions grows as more and more protein structures confirm the conservation of a lipoxygenase protein fold in plants, animals, and bacteria. Lipoxygenases are large enough (60-100 kDa) that they provide a protein shell completely surrounding an active site cavity that has the shape of a long acyl chain and contains a catalytic metal (usually iron). This Account summarizes electron paramagnetic resonance (EPR) spectroscopic, and other, experiments designed to bridge the gap between lipid-lipoxygenase interactions in solution and crystal structures. Experiments with spin-labeled lipids give a picture of bound lipids tethered to protein by an acyl chain, but with a polar end emerging from the cavity to solvent exposure, where the headgroup is highly flexible. The location of a spin on the polar end of a lysolecithin was determined by pulsed, dipolar EPR measurements, by representing the protein structure as a five-point grid of spin-labels with coordinates derived from 10 distance determinations between spin pairs. Distances from the lipid spin to each grid site completed a six-point representation of the enzyme with a bound lipid. Insight into the dynamics that allow substrate/product to enter/exit the cavity was obtained with a different set of spin-labeled protein mutants. Once substrate enters the cavity, the rate-limiting step of catalysis involves redox cycling at the metal center. Here, a mononuclear iron cycles between ferric and ferrous (high-spin) forms. Two helices provide pairs of side-chain ligands to the iron, resulting in characteristic EPR signals. Quantitative comparison of EPR spectra of plant and bacterial lipoxygenases has suggested conservation of a unique geometry of lipoxygenase iron centers. High frequency (94 GHz) EPR is consistent with a similar metal center in a manganese version of lipoxygenase. Overall, established and emerging EPR experiments have been developed and applied to the lipoxygenase family of enzymes to elucidate changes in the solution structures that are related to function.
    MeSH term(s) Binding Sites ; Electron Spin Resonance Spectroscopy ; Lipoxygenase/chemistry ; Lipoxygenase/metabolism ; Models, Molecular ; Protein Structure, Tertiary ; Glycine max/enzymology
    Chemical Substances Lipoxygenase (EC 1.13.11.12)
    Language English
    Publishing date 2014-10-23
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1483291-4
    ISSN 1520-4898 ; 0001-4842
    ISSN (online) 1520-4898
    ISSN 0001-4842
    DOI 10.1021/ar500290r
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  3. Article: EPR of Mononuclear Non-Heme Iron Proteins.

    Gaffney, Betty J

    Biological magnetic resonance

    2010  Volume 28, Page(s) 233–268

    Abstract: Flexible geometry of three- to six-protein side-chain ligands to non-heme iron in proteins is the basis for widely diverse reactivites ranging from iron transport to redox chemistry. The gap between fixed states determined by x-ray analysis can be filled ...

    Abstract Flexible geometry of three- to six-protein side-chain ligands to non-heme iron in proteins is the basis for widely diverse reactivites ranging from iron transport to redox chemistry. The gap between fixed states determined by x-ray analysis can be filled by spectroscopic study of trapped intermediates. EPR is a versatile and relatively quick approach to defining intermediate states in terms of the geometry and electronic structures of iron. A number of examples in which the iron chemistry of non-heme proteins is understood through x-ray structures at subbond length resolution, refined calculations, and spectroscopy exist now. Some examples in which EPR has provided unique insight are summarized in Table 1. Assignment and quantitative evaluation of the EPR resonances in ferric, non-heme iron sites is the focus of the first section of this review. An earlier chapter in this series provides more background on the theory specific to EPR of S = 5/2 metal ions [1]. Besides EPR spectra of ferric mononuclear sites, EPR of ferrous iron coupled to a spin 1/2 radical, as it pertains to the categories mononuclear and non-heme, will also be covered, in the second half of this chapter. Examples include the quinone-ferrous interactions in photosynthetic reaction centers and nitric oxide complexes with non-heme ferrous iron. Other recent reviews of the biochemistry and spectroscopy of non-heme iron proteins provide additional background [2-6].
    Language English
    Publishing date 2010-04-12
    Publishing country United States
    Document type Journal Article
    ISSN 0192-6020
    ISSN 0192-6020
    DOI 10.1007/978-0-387-84856-3
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  4. Article: Anesthesia, analgesia, and euphoria.

    Gaffney, Betty J

    Biophysical journal

    2007  Volume 92, Issue 1, Page(s) 1–2

    MeSH term(s) Analgesia/methods ; Anesthesia/methods ; Anesthesiology/methods ; Animals ; Biophysics/methods ; Euphoria ; Humans ; Pain/drug therapy ; Protein Binding ; Receptors, N-Methyl-D-Aspartate/metabolism ; X-Ray Diffraction ; Xenon/chemistry
    Chemical Substances Receptors, N-Methyl-D-Aspartate ; Xenon (3H3U766W84)
    Language English
    Publishing date 2007-01-01
    Publishing country United States
    Document type Comment ; Journal Article
    ZDB-ID 218078-9
    ISSN 1542-0086 ; 0006-3495
    ISSN (online) 1542-0086
    ISSN 0006-3495
    DOI 10.1529/biophysj.106.096503
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  5. Article ; Online: Fluctuations of an exposed π-helix involved in lipoxygenase substrate recognition.

    Bradshaw, Miles D / Gaffney, Betty J

    Biochemistry

    2014  Volume 53, Issue 31, Page(s) 5102–5110

    Abstract: The second helix in lipoxygenases adapts to permit substrate access to the active site, but details of this process are varied and poorly understood. We therefore examined the dynamics of helix 2 in solutions of spin-labeled soybean lipoxygenase-1 and ... ...

    Abstract The second helix in lipoxygenases adapts to permit substrate access to the active site, but details of this process are varied and poorly understood. We therefore examined the dynamics of helix 2 in solutions of spin-labeled soybean lipoxygenase-1 and spin relaxation at 60 K of the spin-labels by catalytic iron. Helix 2 in soybean lipoxygenase structures is surface-exposed and contains one turn of π-helix, centrally located. A site-directed spin-label scan of 18 of the 21 helix 2 residues, and electron paramagnetic resonance, showed that the π-helical segment became unusually mobile, on a nanosecond time scale, under conditions favoring substrate binding (pH 9 and lipid addition), while segments before and after had relatively unchanged dynamics. Backbone dynamics of residues in the π-helical segment appeared to be correlated, at pH 9. Samples also were frozen to examine the polarity and proticity of the local environments, the effect of the local environment on intrinsic relaxation, and dipolar relaxation by two symmetries of catalytic iron. The average hyperfine tensor component, Azz, of four π-helix residues decreased by 1.75 G, with an increase in pH from 7 to 9, while it remained unaffected for nearby buried residues. Power saturation data suggested the change in polarity specific to the π-helix altered the intrinsic relaxation rates. Different symmetries of iron contributed to distance-dependent magnetic relaxation. We interpret these data to mean that a π-helix in the second helix of plant lipoxygenases is highly dynamic and is the site where lipid chains penetrate to inner helices that outline the substrate pocket.
    MeSH term(s) Amino Acid Sequence ; Amino Acid Substitution ; Catalytic Domain/genetics ; Electron Spin Resonance Spectroscopy ; Kinetics ; Lipoxygenase/chemistry ; Lipoxygenase/genetics ; Lipoxygenase/metabolism ; Lysophosphatidylcholines/metabolism ; Models, Molecular ; Molecular Sequence Data ; Mutagenesis, Site-Directed ; Plant Proteins/chemistry ; Plant Proteins/genetics ; Plant Proteins/metabolism ; Protein Conformation ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Glycine max/enzymology ; Glycine max/genetics ; Substrate Specificity
    Chemical Substances Lysophosphatidylcholines ; Plant Proteins ; Recombinant Proteins ; lipoxygenase L-1 (EC 1.13.11.-) ; Lipoxygenase (EC 1.13.11.12)
    Language English
    Publishing date 2014-07-29
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1108-3
    ISSN 1520-4995 ; 0006-2960
    ISSN (online) 1520-4995
    ISSN 0006-2960
    DOI 10.1021/bi500768c
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  6. Article ; Online: Toxicity analysis of busulfan pharmacokinetic therapeutic dose monitoring.

    Gaffney, Kelly J / Urban, Theresa A / Lucena, Mariana / Anwer, Faiz / Dean, Robert M / Gerds, Aaron T / Hamilton, Betty K / Jagadeesh, Deepa / Kalaycio, Matt E / Khouri, Jack / Pohlman, Brad / Sobecks, Ronald / Winter, Allison / Rybicki, Lisa / Majhail, Navneet S / Hill, Brian T

    Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners

    2022  , Page(s) 10781552221104422

    Abstract: Busulfan-based conditioning regimens are associated with serious toxicities and literature reports increased risk of toxicities when daily area under the curve concentrations exceed 6000 µM-minute. We implemented real time pharmacokinetic-guided ... ...

    Abstract Busulfan-based conditioning regimens are associated with serious toxicities and literature reports increased risk of toxicities when daily area under the curve concentrations exceed 6000 µM-minute. We implemented real time pharmacokinetic-guided therapeutic drug monitoring of busulfan for myeloablative conditioning regimens. The objective was to compare toxicity of intravenous busulfan before and after therapeutic drug monitoring implementation. The primary endpoint was incidence of hepatotoxicity. Medical records were retrospectively reviewed with weight-based dose Busulfan/Cyclophosphamide (BuCy) conditioning from August 2017 through March 2018 (
    Language English
    Publishing date 2022-06-07
    Publishing country England
    Document type Journal Article
    ZDB-ID 1330764-2
    ISSN 1477-092X ; 1078-1552
    ISSN (online) 1477-092X
    ISSN 1078-1552
    DOI 10.1177/10781552221104422
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  7. Article: Fluctuations of an Exposed π-Helix Involved in Lipoxygenase Substrate Recognition

    Bradshaw, Miles D / Gaffney Betty J

    Biochemistry. 2014 Aug. 12, v. 53, no. 31

    2014  

    Abstract: The second helix in lipoxygenases adapts to permit substrate access to the active site, but details of this process are varied and poorly understood. We therefore examined the dynamics of helix 2 in solutions of spin-labeled soybean lipoxygenase-1 and ... ...

    Abstract The second helix in lipoxygenases adapts to permit substrate access to the active site, but details of this process are varied and poorly understood. We therefore examined the dynamics of helix 2 in solutions of spin-labeled soybean lipoxygenase-1 and spin relaxation at 60 K of the spin-labels by catalytic iron. Helix 2 in soybean lipoxygenase structures is surface-exposed and contains one turn of π-helix, centrally located. A site-directed spin-label scan of 18 of the 21 helix 2 residues, and electron paramagnetic resonance, showed that the π-helical segment became unusually mobile, on a nanosecond time scale, under conditions favoring substrate binding (pH 9 and lipid addition), while segments before and after had relatively unchanged dynamics. Backbone dynamics of residues in the π-helical segment appeared to be correlated, at pH 9. Samples also were frozen to examine the polarity and proticity of the local environments, the effect of the local environment on intrinsic relaxation, and dipolar relaxation by two symmetries of catalytic iron. The average hyperfine tensor component, Azz, of four π-helix residues decreased by 1.75 G, with an increase in pH from 7 to 9, while it remained unaffected for nearby buried residues. Power saturation data suggested the change in polarity specific to the π-helix altered the intrinsic relaxation rates. Different symmetries of iron contributed to distance-dependent magnetic relaxation. We interpret these data to mean that a π-helix in the second helix of plant lipoxygenases is highly dynamic and is the site where lipid chains penetrate to inner helices that outline the substrate pocket.
    Keywords active sites ; electron paramagnetic resonance spectroscopy ; iron ; lipids ; lipoxygenase ; pH ; soybeans
    Language English
    Dates of publication 2014-0812
    Size p. 5102-5110.
    Publishing place American Chemical Society
    Document type Article
    ZDB-ID 1108-3
    ISSN 1520-4995 ; 0006-2960
    ISSN (online) 1520-4995
    ISSN 0006-2960
    DOI 10.1021%2Fbi500768c
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  8. Article: Dynamic behavior of fatty acid spin labels within a binding site of soybean lipoxygenase-1.

    Wu, Fayi / Gaffney, Betty J

    Biochemistry

    2006  Volume 45, Issue 41, Page(s) 12510–12518

    Abstract: The putative substrate-binding site in lipoxygenases is long and internal. There is little direct evidence about how the unsaturated fatty acid substrates enter and move within the cavity to position themselves correctly for electron transfer reactions ... ...

    Abstract The putative substrate-binding site in lipoxygenases is long and internal. There is little direct evidence about how the unsaturated fatty acid substrates enter and move within the cavity to position themselves correctly for electron transfer reactions with the catalytic non-heme iron. An EPR spectroscopy approach, with spin-labeled fatty acids, is taken here to investigate dynamic behavior of fatty acids bound to soybean lipoxygenase-1. The probes are labeled on C5, C8, C10, C12, and C16 of stearic acid. The EPR-determined affinity for the enzyme increases as the length of the alkyl end of the probe increases, with a DeltaDeltaG of -190 cal/methylene. The probes in the series exhibit similar enhanced paramagnetic relaxation by the iron center. These results indicate that the members of the series have a common binding site. All of the bound probes undergo considerable local mobility. The stearate spin-labeled at C5 has the highest affinity for the lipoxygenase, and it is a competitive inhibitor, with a K(i) of 9 muM. Surprisingly, this stearate labeled near the carboxyl end undergoes more local motion than those labeled in the middle of the chain, when it is bound. This shows that the carboxyl end of the fatty-acid spin label is not rigidly docked on the protein. During catalysis, repositioning of the substrate carboxyl on the protein surface may be coupled to motion of portions of the chain undergoing reaction.
    MeSH term(s) Catalytic Domain ; Electron Spin Resonance Spectroscopy ; Fatty Acids/metabolism ; Kinetics ; Lipoxygenase/chemistry ; Lipoxygenase/metabolism ; Models, Molecular ; Protein Conformation ; Glycine max/enzymology ; Spin Labels ; Stearic Acids/metabolism ; Thermodynamics
    Chemical Substances Fatty Acids ; Spin Labels ; Stearic Acids ; Lipoxygenase (EC 1.13.11.12)
    Language English
    Publishing date 2006-10-06
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1108-3
    ISSN 1520-4995 ; 0006-2960
    ISSN (online) 1520-4995
    ISSN 0006-2960
    DOI 10.1021/bi061415l
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  9. Article ; Online: Locating a lipid at the portal to the lipoxygenase active site.

    Gaffney, Betty J / Bradshaw, Miles D / Frausto, Stephen D / Wu, Fayi / Freed, Jack H / Borbat, Peter

    Biophysical journal

    2012  Volume 103, Issue 10, Page(s) 2134–2144

    Abstract: Lipoxygenase enzymes initiate diverse signaling pathways by specifically directing oxygen to different carbons of arachidonate and other polyunsaturated acyl chains, but structural origins of this specificity have remained unclear. We therefore ... ...

    Abstract Lipoxygenase enzymes initiate diverse signaling pathways by specifically directing oxygen to different carbons of arachidonate and other polyunsaturated acyl chains, but structural origins of this specificity have remained unclear. We therefore determined the nature of the lipoxygenase interaction with the polar-end of a paramagnetic lipid by electron paramagnetic resonance spectroscopy. Distances between selected grid points on soybean seed lipoxygenase-1 (SBL1) and a lysolecithin spin-labeled on choline were measured by pulsed (electron) dipolar spectroscopy. The protein grid was designed by structure-based modeling so that five natural side chains were replaced with spin labels. Pairwise distances in 10 doubly spin-labeled mutants were examined by pulsed dipolar spectroscopy, and a fit to the model was optimized. Finally, experimental distances between the lysolecithin spin and each single spin site on SBL1 were also obtained. With these 15 distances, distance geometry localized the polar-end and the spin of the lysolecithin to the region between the two domains in the SBL1 structure, nearest to E236, K260, Q264, and Q544. Mutation of a nearby residue, E256A, relieved the high pH requirement for enzyme activity of SBL1 and allowed lipid binding at pH 7.2. This general approach could be used to locate other flexible molecules in macromolecular complexes.
    MeSH term(s) Catalytic Domain ; Cyclic N-Oxides/chemistry ; Cyclic N-Oxides/metabolism ; Electron Spin Resonance Spectroscopy ; Hydrogen-Ion Concentration ; Lecithins/chemistry ; Lecithins/metabolism ; Lipids/chemistry ; Lipoxygenase/chemistry ; Lipoxygenase/metabolism ; Mutant Proteins/chemistry ; Mutant Proteins/metabolism ; Mutation/genetics ; Solutions ; Glycine max/enzymology ; Spin Labels ; Substrate Specificity ; Time Factors
    Chemical Substances Cyclic N-Oxides ; Lecithins ; Lipids ; Mutant Proteins ; Solutions ; Spin Labels ; tempocholine (50669-92-6) ; lipoxygenase L-1 (EC 1.13.11.-) ; Lipoxygenase (EC 1.13.11.12)
    Language English
    Publishing date 2012-11-20
    Publishing country United States
    Document type Journal Article ; Research Support, American Recovery and Reinvestment Act ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 218078-9
    ISSN 1542-0086 ; 0006-3495
    ISSN (online) 1542-0086
    ISSN 0006-3495
    DOI 10.1016/j.bpj.2012.10.002
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  10. Article ; Online: Deep sequencing reveals a DAP1 regulatory haplotype that potentiates autoimmunity in systemic lupus erythematosus.

    Raj, Prithvi / Song, Ran / Zhu, Honglin / Riediger, Linley / Jun, Dong-Jae / Liang, Chaoying / Arana, Carlos / Zhang, Bo / Gao, Yajing / Wakeland, Benjamin E / Dozmorov, Igor / Zhou, Jinchun / Kelly, Jennifer A / Lauwerys, Bernard R / Guthridge, Joel M / Olsen, Nancy J / Nath, Swapan K / Pasare, Chandrashekhar / van Oers, Nicolai /
    Gilkeson, Gary / Tsao, Betty P / Gaffney, Patrick M / Gregersen, Peter K / James, Judith A / Zuo, Xiaoxia / Karp, David R / Li, Quan-Zhen / Wakeland, Edward K

    Genome biology

    2020  Volume 21, Issue 1, Page(s) 281

    Abstract: Background: Systemic lupus erythematosus (SLE) is a clinically heterogeneous autoimmune disease characterized by the development of anti-nuclear antibodies. Susceptibility to SLE is multifactorial, with a combination of genetic and environmental risk ... ...

    Abstract Background: Systemic lupus erythematosus (SLE) is a clinically heterogeneous autoimmune disease characterized by the development of anti-nuclear antibodies. Susceptibility to SLE is multifactorial, with a combination of genetic and environmental risk factors contributing to disease development. Like other polygenic diseases, a significant proportion of estimated SLE heritability is not accounted for by common disease alleles analyzed by SNP array-based GWASs. Death-associated protein 1 (DAP1) was implicated as a candidate gene in a previous familial linkage study of SLE and rheumatoid arthritis, but the association has not been explored further.
    Results: We perform deep sequencing across the DAP1 genomic segment in 2032 SLE patients, and healthy controls, and discover a low-frequency functional haplotype strongly associated with SLE risk in multiple ethnicities. We find multiple cis-eQTLs embedded in a risk haplotype that progressively downregulates DAP1 transcription in immune cells. Decreased DAP1 transcription results in reduced DAP1 protein in peripheral blood mononuclear cells, monocytes, and lymphoblastoid cell lines, leading to enhanced autophagic flux in immune cells expressing the DAP1 risk haplotype. Patients with DAP1 risk allele exhibit significantly higher autoantibody titers and altered expression of the immune system, autophagy, and apoptosis pathway transcripts, indicating that the DAP1 risk allele mediates enhanced autophagy, leading to the survival of autoreactive lymphocytes and increased autoantibody.
    Conclusions: We demonstrate how targeted sequencing captures low-frequency functional risk alleles that are missed by SNP array-based studies. SLE patients with the DAP1 genotype have distinct autoantibody and transcription profiles, supporting the dissection of SLE heterogeneity by genetic analysis.
    MeSH term(s) Alleles ; Apoptosis Regulatory Proteins/genetics ; Arthritis, Rheumatoid ; Autoimmunity/genetics ; Autophagy ; Dendritic Cells ; Down-Regulation ; Gene Expression ; Gene Expression Profiling ; Gene Frequency ; Genetic Predisposition to Disease/genetics ; Genotype ; Haplotypes ; High-Throughput Nucleotide Sequencing ; Humans ; Leukocytes, Mononuclear ; Lupus Erythematosus, Systemic/genetics ; Polymorphism, Single Nucleotide ; Sequence Alignment
    Chemical Substances Apoptosis Regulatory Proteins ; DAP protein, human
    Language English
    Publishing date 2020-11-19
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2040529-7
    ISSN 1474-760X ; 1474-760X
    ISSN (online) 1474-760X
    ISSN 1474-760X
    DOI 10.1186/s13059-020-02184-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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