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Article ; Online: Brown adipose tissue CoQ deficiency activates the integrated stress response and FGF21-dependent mitohormesis.

Chang, Ching-Fang / Gunawan, Amanda L / Liparulo, Irene / Zushin, Peter-James H / Vitangcol, Kaitlyn / Timblin, Greg A / Saijo, Kaoru / Wang, Biao / Parlakgül, Güneş / Arruda, Ana Paula / Stahl, Andreas

The EMBO journal

2024 Volume 43, Issue 2, Page(s) 168–195

Abstract: Coenzyme Q (CoQ) is essential for mitochondrial respiration and required for thermogenic activity in brown adipose tissues (BAT). CoQ deficiency leads to a wide range of pathological manifestations, but mechanistic consequences of CoQ deficiency in ... ...

Abstract	Coenzyme Q (CoQ) is essential for mitochondrial respiration and required for thermogenic activity in brown adipose tissues (BAT). CoQ deficiency leads to a wide range of pathological manifestations, but mechanistic consequences of CoQ deficiency in specific tissues, such as BAT, remain poorly understood. Here, we show that pharmacological or genetic CoQ deficiency in BAT leads to stress signals causing accumulation of cytosolic mitochondrial RNAs and activation of the eIF2α kinase PKR, resulting in activation of the integrated stress response (ISR) with suppression of UCP1 but induction of FGF21 expression. Strikingly, despite diminished UCP1 levels, BAT CoQ deficiency displays increased whole-body metabolic rates at room temperature and thermoneutrality resulting in decreased weight gain on high-fat diets (HFD). In line with enhanced metabolic rates, BAT and inguinal white adipose tissue (iWAT) interorgan crosstalk caused increased browning of iWAT in BAT-specific CoQ deficient animals. This mitohormesis-like effect depends on the ATF4-FGF21 axis and BAT-secreted FGF21, revealing an unexpected role for CoQ in the modulation of whole-body energy expenditure with wide-ranging implications for primary and secondary CoQ deficiencies.
MeSH term(s)	Animals ; Mice ; Adipose Tissue, Brown/metabolism ; Ubiquinone/metabolism ; Ubiquinone/pharmacology ; Mitochondrial Diseases/metabolism ; Thermogenesis/genetics ; Mice, Inbred C57BL ; Ataxia ; Fibroblast Growth Factors ; Muscle Weakness
Chemical Substances	fibroblast growth factor 21 ; Ubiquinone (1339-63-5) ; Fibroblast Growth Factors (62031-54-3)
Language	English
Publishing date	2024-01-11
Publishing country	England
Document type	Journal Article
ZDB-ID	586044-1
ISSN	1460-2075 ; 0261-4189
ISSN (online)	1460-2075
ISSN	0261-4189
DOI	10.1038/s44318-023-00008-x
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Article: The microenvironment dictates glycocalyx construction and immune surveillance.

Tharp, Kevin M / Park, Sangwoo / Timblin, Greg A / Richards, Alicia L / Berg, Jordan A / Twells, Nicholas M / Riley, Nicholas M / Peltan, Egan L / Shon, D Judy / Stevenson, Erica / Tsui, Kimberly / Palomba, Francesco / Lefebvre, Austin E Y T / Soens, Ross W / Ayad, Nadia M E / Hoeve-Scott, Johanna Ten / Healy, Kevin / Digman, Michelle / Dillin, Andrew /

Bertozzi, Carolyn R / Swaney, Danielle L / Mahal, Lara K / Cantor, Jason R / Paszek, Matthew J / Weaver, Valerie M

Research square

2023

Abstract: Efforts to identify anti-cancer therapeutics and understand tumor-immune interactions are built ... ...

Abstract	Efforts to identify anti-cancer therapeutics and understand tumor-immune interactions are built with
Language	English
Publishing date	2023-08-16
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3164966/v1
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Article ; Online: Ebf1 and c-Myb repress rag transcription downstream of Stat5 during early B cell development.

Timblin, Greg A / Schlissel, Mark S

Journal of immunology (Baltimore, Md. : 1950)

2013 Volume 191, Issue 9, Page(s) 4676–4687

Abstract: The temporal control of RAG (Rag) expression in developing lymphocytes prevents DNA breaks during periods of proliferation that could threaten genomic integrity. In developing B cells, the IL-7R and precursor B cell Ag receptor (pre-BCR) synergize to ... ...

Abstract	The temporal control of RAG (Rag) expression in developing lymphocytes prevents DNA breaks during periods of proliferation that could threaten genomic integrity. In developing B cells, the IL-7R and precursor B cell Ag receptor (pre-BCR) synergize to induce proliferation and the repression of Rag at the protein and mRNA levels for a brief period following successful Ig H chain gene rearrangement. Whereas the mechanism of RAG2 protein downregulation is well defined, little is known about the pathways and transcription factors that mediate transcriptional repression of Rag. Using Abelson murine leukemia virus-transformed B cells to model this stage of development, we identified early B cell factor 1 (Ebf1) as a strong repressor of Rag transcription. Short hairpin RNA-mediated knockdown of either Ebf1 or its downstream target c-Myb was sufficient to induce Rag transcription in these highly proliferative cells. Ebf1 and c-Myb antagonize Rag transcription by negatively regulating the binding of Foxo1 to the Rag locus. Ebf1 accomplishes this through both direct negative regulation of Foxo1 expression and direct positive regulation of Gfi1b expression. Ebf1 expression is driven by the IL-7R downstream effector Stat5, providing a link between the negative regulation of Rag transcription by IL-7 and a novel repressive pathway involving Ebf1 and c-Myb.
MeSH term(s)	Animals ; B-Lymphocytes/metabolism ; Cell Differentiation/immunology ; Cell Proliferation ; Cells, Cultured ; DNA-Binding Proteins/genetics ; Forkhead Box Protein O1 ; Forkhead Transcription Factors/biosynthesis ; Forkhead Transcription Factors/metabolism ; Homeodomain Proteins/genetics ; Interleukin-7 ; Mice ; Mice, Inbred C57BL ; Proto-Oncogene Proteins/biosynthesis ; Proto-Oncogene Proteins c-myb/genetics ; Proto-Oncogene Proteins c-myb/metabolism ; RNA Interference ; RNA, Small Interfering ; Repressor Proteins/biosynthesis ; STAT5 Transcription Factor/genetics ; Signal Transduction ; Trans-Activators/genetics ; Trans-Activators/metabolism ; Transcription, Genetic
Chemical Substances	DNA-Binding Proteins ; Ebf1 protein, mouse ; Forkhead Box Protein O1 ; Forkhead Transcription Factors ; Foxo1 protein, mouse ; Gfi1b protein, mouse ; Homeodomain Proteins ; Interleukin-7 ; Proto-Oncogene Proteins ; Proto-Oncogene Proteins c-myb ; RNA, Small Interfering ; Repressor Proteins ; STAT5 Transcription Factor ; Trans-Activators ; V(D)J recombination activating protein 2 ; RAG-1 protein (128559-51-3)
Language	English
Publishing date	2013-09-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.1301675
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Article ; Online: Dual Mechanism of

Timblin, Greg A / Xie, Liangqi / Tjian, Robert / Schlissel, Mark S

Molecular and cellular biology

2017 Volume 37, Issue 12

Abstract: Developing B lymphocytes undergo clonal expansion following successful immunoglobulin heavy chain gene rearrangement. During this proliferative burst, expression of ... ...

Abstract	Developing B lymphocytes undergo clonal expansion following successful immunoglobulin heavy chain gene rearrangement. During this proliferative burst, expression of the
MeSH term(s)	Animals ; Binding Sites ; CRISPR-Cas Systems/genetics ; Cell Proliferation ; DNA-Binding Proteins/metabolism ; Enhancer Elements, Genetic/genetics ; Forkhead Box Protein O1/metabolism ; Gene Expression Regulation ; Homeodomain Proteins/metabolism ; Mice ; Models, Biological ; Mutation/genetics ; Precursor Cells, B-Lymphoid/cytology ; Precursor Cells, B-Lymphoid/metabolism ; Protein Binding ; Proto-Oncogene Proteins c-myb/metabolism ; Repressor Proteins/metabolism ; Transcription, Genetic
Chemical Substances	DNA-Binding Proteins ; Forkhead Box Protein O1 ; Homeodomain Proteins ; Proto-Oncogene Proteins c-myb ; Rag2 protein, mouse ; Repressor Proteins ; RAG-1 protein (128559-51-3)
Language	English
Publishing date	2017-05-31
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	779397-2
ISSN	1098-5549 ; 0270-7306
ISSN (online)	1098-5549
ISSN	0270-7306
DOI	10.1128/MCB.00437-16
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Article ; Online: Versatile Histochemical Approach to Detection of Hydrogen Peroxide in Cells and Tissues Based on Puromycin Staining.

Yik-Sham Chung, Clive / Timblin, Greg A / Saijo, Kaoru / Chang, Christopher J

Journal of the American Chemical Society

2018 Volume 140, Issue 19, Page(s) 6109–6121

Abstract: Hydrogen peroxide ( ... ...

Abstract	Hydrogen peroxide (H
MeSH term(s)	Animals ; Diet, High-Fat/adverse effects ; Fluorescent Dyes/chemistry ; HeLa Cells ; Histocytochemistry ; Humans ; Hydrogen Peroxide/analysis ; Male ; Mice ; Mice, Inbred C57BL ; Microscopy, Confocal ; Molecular Structure ; Non-alcoholic Fatty Liver Disease/chemically induced ; Non-alcoholic Fatty Liver Disease/diagnostic imaging ; Puromycin/analogs & derivatives ; Puromycin/analysis ; Puromycin/chemistry ; Staining and Labeling ; Tumor Cells, Cultured
Chemical Substances	Fluorescent Dyes ; peroxymycin-1 ; Puromycin (4A6ZS6Q2CL) ; Hydrogen Peroxide (BBX060AN9V)
Language	English
Publishing date	2018-05-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/jacs.8b02279
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Article ; Online: Dual Mechanism of Rag Gene Repression by c-Myb during Pre-B Cell Proliferation

Timblin, Greg A. / Xie, Liangqi / Tjian, Robert / Schlissel, Mark S.

Molecular and Cellular Biology. 2017 June 1, v. 37, no. 12 p.e00437-16-

2017

Abstract: Developing B lymphocytes undergo clonal expansion following successful immunoglobulin heavy chain gene rearrangement. During this proliferative burst, expression of the Rag genes is transiently repressed to prevent the generation of double-stranded DNA ( ... ...

Abstract	Developing B lymphocytes undergo clonal expansion following successful immunoglobulin heavy chain gene rearrangement. During this proliferative burst, expression of the Rag genes is transiently repressed to prevent the generation of double-stranded DNA (dsDNA) breaks in cycling large pre-B cells. The Rag genes are then reexpressed in small, resting pre-B cells for immunoglobulin light chain gene rearrangement. We previously identified c-Myb as a repressor of Rag transcription during clonal expansion using Abelson murine leukemia virus-transformed B cells. Nevertheless, the molecular mechanisms by which c-Myb achieved precise spatiotemporal repression of Rag expression remained obscure. Here, we identify two mechanisms by which c-Myb represses Rag transcription. First, c-Myb negatively regulates the expression of the Rag activator Foxo1, an activity dependent on M303 in c-Myb's transactivation domain, and likely the recruitment of corepressors to the Foxo1 locus by c-Myb. Second, c-Myb represses Rag transcription directly by occupying the Erag enhancer and antagonizing Foxo1 binding to a consensus forkhead site in this cis-regulatory element that we show is crucial for Rag expression in Abelson pre-B cell lines. This work provides important mechanistic insight into how spatiotemporal expression of the Rag genes is tightly controlled during B lymphocyte development to prevent mistimed dsDNA breaks and their deleterious consequences.
Keywords	B-lymphocytes ; DNA ; cell proliferation ; gene rearrangement ; genes ; immunoglobulin heavy chains ; immunoglobulin light chains ; leukemia ; loci ; mice ; transcriptional activation ; B cell development ; V(D)J recombination ; c-Myb ; chromatin remodeling ; transcriptional regulation
Language	English
Dates of publication	2017-0601
Publishing place	Taylor & Francis
Document type	Article ; Online
ZDB-ID	779397-2
ISSN	1098-5549 ; 0270-7306
ISSN (online)	1098-5549
ISSN	0270-7306
DOI	10.1128/MCB.00437-16
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Article ; Online: Mitohormesis reprogrammes macrophage metabolism to enforce tolerance.

Timblin, Greg A / Tharp, Kevin M / Ford, Breanna / Winchester, Janet M / Wang, Jerome / Zhu, Stella / Khan, Rida I / Louie, Shannon K / Iavarone, Anthony T / Ten Hoeve, Johanna / Nomura, Daniel K / Stahl, Andreas / Saijo, Kaoru

Nature metabolism

2021 Volume 3, Issue 5, Page(s) 618–635

Abstract: Macrophages generate mitochondrial reactive oxygen species and mitochondrial reactive electrophilic species as antimicrobials during Toll-like receptor (TLR)-dependent inflammatory responses. Whether mitochondrial stress caused by these molecules impacts ...

Abstract	Macrophages generate mitochondrial reactive oxygen species and mitochondrial reactive electrophilic species as antimicrobials during Toll-like receptor (TLR)-dependent inflammatory responses. Whether mitochondrial stress caused by these molecules impacts macrophage function is unknown. Here, we demonstrate that both pharmacologically driven and lipopolysaccharide (LPS)-driven mitochondrial stress in macrophages triggers a stress response called mitohormesis. LPS-driven mitohormetic stress adaptations occur as macrophages transition from an LPS-responsive to LPS-tolerant state wherein stimulus-induced pro-inflammatory gene transcription is impaired, suggesting tolerance is a product of mitohormesis. Indeed, like LPS, hydroxyoestrogen-triggered mitohormesis suppresses mitochondrial oxidative metabolism and acetyl-CoA production needed for histone acetylation and pro-inflammatory gene transcription, and is sufficient to enforce an LPS-tolerant state. Thus, mitochondrial reactive oxygen species and mitochondrial reactive electrophilic species are TLR-dependent signalling molecules that trigger mitohormesis as a negative feedback mechanism to restrain inflammation via tolerance. Moreover, bypassing TLR signalling and pharmacologically triggering mitohormesis represents a new anti-inflammatory strategy that co-opts this stress response to impair epigenetic support of pro-inflammatory gene transcription by mitochondria.
MeSH term(s)	Acetyl Coenzyme A/metabolism ; Anti-Inflammatory Agents/pharmacology ; Cellular Reprogramming ; Energy Metabolism ; Estrogens/metabolism ; Gene Expression Regulation ; Immune Tolerance ; Lipopolysaccharides/immunology ; Macrophage Activation ; Macrophages/immunology ; Macrophages/metabolism ; Mitochondria/metabolism ; Models, Biological ; Reactive Oxygen Species/metabolism ; Stress, Physiological
Chemical Substances	Anti-Inflammatory Agents ; Estrogens ; Lipopolysaccharides ; Reactive Oxygen Species ; Acetyl Coenzyme A (72-89-9)
Language	English
Publishing date	2021-05-20
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2522-5812
ISSN (online)	2522-5812
DOI	10.1038/s42255-021-00392-w
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Article ; Online: Adhesion-mediated mechanosignaling forces mitohormesis.

Tharp, Kevin M / Higuchi-Sanabria, Ryo / Timblin, Greg A / Ford, Breanna / Garzon-Coral, Carlos / Schneider, Catherine / Muncie, Jonathon M / Stashko, Connor / Daniele, Joseph R / Moore, Andrew S / Frankino, Phillip A / Homentcovschi, Stefan / Manoli, Sagar S / Shao, Hao / Richards, Alicia L / Chen, Kuei-Ho / Hoeve, Johanna Ten / Ku, Gregory M / Hellerstein, Marc /

Nomura, Daniel K / Saijo, Karou / Gestwicki, Jason / Dunn, Alexander R / Krogan, Nevan J / Swaney, Danielle L / Dillin, Andrew / Weaver, Valerie M

Cell metabolism

2021 Volume 33, Issue 7, Page(s) 1322–1341.e13

Abstract: Mitochondria control eukaryotic cell fate by producing the energy needed to support life and the signals required to execute programed cell death. The biochemical milieu is known to affect mitochondrial function and contribute to the dysfunctional ... ...

Abstract	Mitochondria control eukaryotic cell fate by producing the energy needed to support life and the signals required to execute programed cell death. The biochemical milieu is known to affect mitochondrial function and contribute to the dysfunctional mitochondrial phenotypes implicated in cancer and the morbidities of aging. However, the physical characteristics of the extracellular matrix are also altered in cancerous and aging tissues. Here, we demonstrate that cells sense the physical properties of the extracellular matrix and activate a mitochondrial stress response that adaptively tunes mitochondrial function via solute carrier family 9 member A1-dependent ion exchange and heat shock factor 1-dependent transcription. Overall, our data indicate that adhesion-mediated mechanosignaling may play an unappreciated role in the altered mitochondrial functions observed in aging and cancer.
MeSH term(s)	Adult ; Animals ; Animals, Genetically Modified ; Caenorhabditis elegans ; Cell Adhesion/physiology ; Cell Respiration ; Cells, Cultured ; Extracellular Matrix/metabolism ; Female ; HEK293 Cells ; Humans ; Hyperglycemia/metabolism ; Hyperglycemia/pathology ; Hyperglycemia/physiopathology ; Integrins/physiology ; Ion Exchange ; Mechanotransduction, Cellular/physiology ; Mice ; Microscopy, Confocal ; Middle Aged ; Mitochondria/metabolism ; Mitochondria/physiology ; Mitochondrial Dynamics/physiology ; Oxidative Stress/physiology ; Reactive Oxygen Species/metabolism ; Signal Transduction/physiology ; Sodium-Hydrogen Exchanger 1/physiology ; Time-Lapse Imaging
Chemical Substances	Integrins ; Reactive Oxygen Species ; Sodium-Hydrogen Exchanger 1
Language	English
Publishing date	2021-05-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Video-Audio Media
ZDB-ID	2176834-1
ISSN	1932-7420 ; 1550-4131
ISSN (online)	1932-7420
ISSN	1550-4131
DOI	10.1016/j.cmet.2021.04.017
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Article: Versatile Histochemical Approach to Detection of Hydrogen Peroxide in Cells and Tissues Based on Puromycin Staining

Yik-Sham Chung, Clive / Timblin, Greg A / Saijo, Kaoru / Chang, Christopher J

Journal of the American Chemical Society. 2018 May 03, v. 140, no. 19

2018

Abstract: Hydrogen peroxide (H2O2) is a central reactive oxygen species (ROS) that contributes to diseases from obesity to cancer to neurodegeneration but is also emerging as an important signaling molecule. We now report a versatile histochemical approach for ... ...

Abstract	Hydrogen peroxide (H2O2) is a central reactive oxygen species (ROS) that contributes to diseases from obesity to cancer to neurodegeneration but is also emerging as an important signaling molecule. We now report a versatile histochemical approach for detection of H2O2 that can be employed across a broad range of cell and tissue specimens in both healthy and disease states. We have developed a first-generation H2O2-responsive analogue named Peroxymycin-1, which is based on the classic cell-staining molecule puromycin and enables covalent staining of biological samples and retains its signal after fixation. H2O2-mediated boronate cleavage uncages the puromycin aminonucleoside, which leaves a permanent and dose-dependent mark on treated biological specimens that can be detected with high sensitivity and precision through a standard immunofluorescence assay. Peroxymycin-1 is selective and sensitive enough to image both exogenous and endogenous changes in cellular H2O2 levels and can be exploited to profile resting H2O2 levels across a panel of cell lines to distinguish metastatic, invasive cancer cells from less invasive cancer and nontumorigenic counterparts, based on correlations with ROS status. Moreover, we establish that Peroxymycin-1 is an effective histochemical probe for in vivo H2O2 analysis, as shown through identification of aberrant elevations in H2O2 levels in liver tissues in a murine model of nonalcoholic fatty liver disease, thus demonstrating the potential of this approach for studying disease states and progression associated with H2O2. This work provides design principles that should enable development of a broader range of histochemical probes for biological use that operate via activity-based sensing.
Keywords	animal models ; cell lines ; dose response ; fatty liver ; fluorescent antibody technique ; hydrogen peroxide ; image analysis ; liver ; metastasis ; neoplasm cells ; neoplasms ; neurodegenerative diseases ; obesity ; puromycin ; staining ; tissues
Language	English
Dates of publication	2018-0503
Size	p. 6109-6121.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/jacs.8b02279
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Article ; Online: The proximal J kappa germline-transcript promoter facilitates receptor editing through control of ordered recombination.

Vettermann, Christian / Timblin, Greg A / Lim, Vivian / Lai, Ernest C / Schlissel, Mark S

PloS one

2015 Volume 10, Issue 1, Page(s) e0113824

Abstract: V(D)J recombination creates antibody light chain diversity by joining a Vκ gene segment with one of four Jκ segments. Two Jκ germline-transcript (GT) promoters control Vκ-Jκ joining, but the mechanisms that govern Jκ choice are unclear. Here, we show in ... ...

Abstract	V(D)J recombination creates antibody light chain diversity by joining a Vκ gene segment with one of four Jκ segments. Two Jκ germline-transcript (GT) promoters control Vκ-Jκ joining, but the mechanisms that govern Jκ choice are unclear. Here, we show in gene-targeted mice that the proximal GT promoter helps targeting rearrangements to Jκ1 by preventing premature DNA breaks at Jκ2. Consequently, cells lacking the proximal GT promoter show a biased utilization of downstream Jκ segments, resulting in a diminished potential for receptor editing. Surprisingly, the proximal--in contrast to the distal--GT promoter is transcriptionally inactive prior to Igκ recombination, indicating that its role in Jκ choice is independent of classical promoter function. Removal of the proximal GT promoter increases H3K4me3 levels at Jκ segments, suggesting that this promoter could act as a suppressor of recombination by limiting chromatin accessibility to RAG. Our findings identify the first cis-element critical for Jκ choice and demonstrate that ordered Igκ recombination facilitates receptor editing.
MeSH term(s)	Animals ; B-Lymphocytes/immunology ; B-Lymphocytes/metabolism ; Cells, Cultured ; Female ; Flow Cytometry ; Gene Expression/immunology ; Germ Cells/immunology ; Germ Cells/metabolism ; Histones/immunology ; Histones/metabolism ; Immunoglobulin Joining Region/genetics ; Immunoglobulin Joining Region/immunology ; Immunoglobulin Variable Region/genetics ; Immunoglobulin Variable Region/immunology ; Immunoglobulin kappa-Chains/genetics ; Immunoglobulin kappa-Chains/immunology ; Lysine/immunology ; Lysine/metabolism ; Male ; Methylation ; Mice, Inbred C57BL ; Mice, Knockout ; Promoter Regions, Genetic/genetics ; Promoter Regions, Genetic/immunology ; Receptors, Antigen, B-Cell/genetics ; Receptors, Antigen, B-Cell/immunology ; Reverse Transcriptase Polymerase Chain Reaction ; V(D)J Recombination/genetics ; V(D)J Recombination/immunology
Chemical Substances	Histones ; Immunoglobulin Joining Region ; Immunoglobulin Variable Region ; Immunoglobulin kappa-Chains ; Receptors, Antigen, B-Cell ; Lysine (K3Z4F929H6)
Language	English
Publishing date	2015-01-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0113824
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