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Article ; Online: Cyclin D3 restricts SARS-CoV-2 envelope incorporation into virions and interferes with viral spread.

Gupta, Ravi K / Mlcochova, Petra

2022 Volume 41, Issue 22, Page(s) e111653

Abstract: The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a great threat to human health. The interplay between the virus and host plays a crucial role in successful virus replication and transmission. ... ...

Abstract	The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a great threat to human health. The interplay between the virus and host plays a crucial role in successful virus replication and transmission. Understanding host-virus interactions are essential for the development of new COVID-19 treatment strategies. Here, we show that SARS-CoV-2 infection triggers redistribution of cyclin D1 and cyclin D3 from the nucleus to the cytoplasm, followed by proteasomal degradation. No changes to other cyclins or cyclin-dependent kinases were observed. Further, cyclin D depletion was independent of SARS-CoV-2-mediated cell cycle arrest in the early S phase or S/G2/M phase. Cyclin D3 knockdown by small-interfering RNA specifically enhanced progeny virus titres in supernatants. Finally, cyclin D3 co-immunoprecipitated with SARS-CoV-2 envelope (E) and membrane (M) proteins. We propose that cyclin D3 impairs the efficient incorporation of envelope protein into virions during assembly and is depleted during SARS-CoV-2 infection to restore efficient assembly and release of newly produced virions.
MeSH term(s)	Humans ; SARS-CoV-2 ; Cyclin D3 ; COVID-19 ; Pandemics ; Cell Line ; Virion ; COVID-19 Drug Treatment
Chemical Substances	Cyclin D3
Language	English
Publishing date	2022-10-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	586044-1
ISSN	1460-2075 ; 0261-4189
ISSN (online)	1460-2075
ISSN	0261-4189
DOI	10.15252/embj.2022111653
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Article ; Online: Cell cycle independent role of cyclin D3 in host restriction of SARS-CoV-2 infection

Gupta, Ravi K. / Mlcochova, Petra

bioRxiv

Abstract: The COVID-19 pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) presents a great threat to human health. The interplay between the virus and host plays a crucial role in successful virus replication and transmission. ... ...

Abstract	The COVID-19 pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) presents a great threat to human health. The interplay between the virus and host plays a crucial role in successful virus replication and transmission. Understanding host-virus interactions is essential for development of new COVID-19 treatment strategies. Here we show that SARS-CoV-2 infection triggers redistribution of cyclin D1 and cyclin D3 from the nucleus to the cytoplasm, followed by its proteasomal degradation. No changes to other cyclins or cyclin dependent kinases were observed. Further, cyclin D depletion was independent from SARS-CoV-2 mediated cell cycle arrest in early S phase or S/G2/M phase. Cyclin D3 knockdown by small interfering RNA specifically enhanced progeny virus titres in supernatants. Finally, cyclin D3 co-immunoprecipitated with SARS-CoV-2 Envelope and Membrane proteins. We propose that cyclin D3 inhibits virion assembly and is depleted during SARS-CoV-2 infection to restore efficient assembly and release of newly produced virions.
Keywords	covid19
Language	English
Publishing date	2022-05-08
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2022.05.07.491022
Database	COVID19

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Article ; Online: TLR4-Mediated Pathway Triggers Interferon-Independent G0 Arrest and Antiviral SAMHD1 Activity in Macrophages.

Mlcochova, Petra / Winstone, Helena / Zuliani-Alvarez, Lorena / Gupta, Ravindra K

Cell reports

2020 Volume 30, Issue 12, Page(s) 3972–3980.e5

Abstract: Macrophages exist predominantly in two distinct states, G0 and a G1-like state that is accompanied by phosphorylation of SAMHD1 at T592. Here, we demonstrate that Toll-like receptor 4 (TLR4) activation can potently induce G0 arrest and SAMHD1 ... ...

Abstract	Macrophages exist predominantly in two distinct states, G0 and a G1-like state that is accompanied by phosphorylation of SAMHD1 at T592. Here, we demonstrate that Toll-like receptor 4 (TLR4) activation can potently induce G0 arrest and SAMHD1 antiretroviral activity by an interferon (IFN)-independent pathway. This pathway requires TLR4 engagement with TRIF, but not involvement of TBK1 or IRF3. Exclusive Myd88 activators are unable to trigger G0 arrest or SAMHD1 dephosphorylation, demonstrating this arrest is also Myd88/nuclear factor κB (NF-κB) independent. The G0 arrest is accompanied by p21 upregulation and CDK1 depletion, consistent with the observed SAMHD1 dephosphorylation at T592. Furthermore, we show by SAMHD1 knockdown that the TLR4-activated pathway potently blocks HIV-1 infection in macrophages specifically via SAMHD1. Together, these data demonstrate that macrophages can mobilize an intrinsic cell arrest and anti-viral state by activating TLR4 prior to IFN secretion, thereby highlighting the importance of cell-cycle regulation as a response to pathogen-associated danger signals in macrophages.
MeSH term(s)	Antiviral Agents/metabolism ; Cell Cycle Checkpoints/drug effects ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Escherichia coli/metabolism ; Female ; HIV Infections/pathology ; Humans ; Interferons/metabolism ; Lipopolysaccharides/pharmacology ; Macrophages/metabolism ; Macrophages/virology ; Male ; Myeloid Differentiation Factor 88/metabolism ; Resting Phase, Cell Cycle/drug effects ; SAM Domain and HD Domain-Containing Protein 1/metabolism ; Signal Transduction/drug effects ; Toll-Like Receptor 4/metabolism ; Toll-Like Receptor 5/metabolism ; Up-Regulation/drug effects
Chemical Substances	Antiviral Agents ; Cyclin-Dependent Kinase Inhibitor p21 ; Lipopolysaccharides ; Myeloid Differentiation Factor 88 ; Toll-Like Receptor 4 ; Toll-Like Receptor 5 ; Interferons (9008-11-1) ; SAM Domain and HD Domain-Containing Protein 1 (EC 3.1.5.-)
Language	English
Publishing date	2020-03-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2020.03.008
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Article ; Online: Cell Cycle Regulation in Macrophages and Susceptibility to HIV-1.

Ferreira, Isabella A T M / Porterfield, J Zachary / Gupta, Ravindra K / Mlcochova, Petra

Viruses

2020 Volume 12, Issue 8

Abstract: Macrophages are the first line of defence against invading pathogens. They play a crucial role in immunity but also in regeneration and homeostasis. Their remarkable plasticity in their phenotypes and function provides them with the ability to quickly ... ...

Abstract	Macrophages are the first line of defence against invading pathogens. They play a crucial role in immunity but also in regeneration and homeostasis. Their remarkable plasticity in their phenotypes and function provides them with the ability to quickly respond to environmental changes and infection. Recent work shows that macrophages undergo cell cycle transition from a G0/terminally differentiated state to a G1 state. This G0-to-G1 transition presents a window of opportunity for HIV-1 infection. Macrophages are an important target for HIV-1 but express high levels of the deoxynucleotide-triphosphate hydrolase SAMHD1, which restricts viral DNA synthesis by decreasing levels of dNTPs. While the G0 state is non-permissive to HIV-1 infection, a G1 state is very permissive to HIV-1 infection. This is because macrophages in a G1 state switch off the antiviral restriction factor SAMHD1 by phosphorylation, thereby allowing productive HIV-1 infection. Here, we explore the macrophage cell cycle and the interplay between its regulation and permissivity to HIV-1 infection.
MeSH term(s)	Animals ; Cell Cycle ; Cell Cycle Checkpoints ; Cells, Cultured ; DNA Damage ; G1 Phase ; Gram-Negative Bacteria/immunology ; HIV-1/physiology ; Histone Deacetylase Inhibitors/pharmacology ; Humans ; Macrophages/immunology ; Macrophages/physiology ; Macrophages/virology ; Phosphorylation ; Resting Phase, Cell Cycle ; SAM Domain and HD Domain-Containing Protein 1/metabolism ; vif Gene Products, Human Immunodeficiency Virus/metabolism ; vpr Gene Products, Human Immunodeficiency Virus/metabolism
Chemical Substances	Histone Deacetylase Inhibitors ; vif Gene Products, Human Immunodeficiency Virus ; vif protein, Human immunodeficiency virus 1 ; vpr Gene Products, Human Immunodeficiency Virus ; vpr protein, Human immunodeficiency virus 1 ; SAM Domain and HD Domain-Containing Protein 1 (EC 3.1.5.-)
Language	English
Publishing date	2020-07-31
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v12080839
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Article: Cell Cycle Regulation in Macrophages and Susceptibility to HIV-1

Ferreira, Isabella A. T. M / Porterfield, J. Zachary / Gupta, Ravindra K / Mlcochova, Petra

Viruses. 2020 July 31, v. 12, no. 8

2020

Abstract	Macrophages are the first line of defence against invading pathogens. They play a crucial role in immunity but also in regeneration and homeostasis. Their remarkable plasticity in their phenotypes and function provides them with the ability to quickly respond to environmental changes and infection. Recent work shows that macrophages undergo cell cycle transition from a G0/terminally differentiated state to a G1 state. This G0-to-G1 transition presents a window of opportunity for HIV-1 infection. Macrophages are an important target for HIV-1 but express high levels of the deoxynucleotide-triphosphate hydrolase SAMHD1, which restricts viral DNA synthesis by decreasing levels of dNTPs. While the G0 state is non-permissive to HIV-1 infection, a G1 state is very permissive to HIV-1 infection. This is because macrophages in a G1 state switch off the antiviral restriction factor SAMHD1 by phosphorylation, thereby allowing productive HIV-1 infection. Here, we explore the macrophage cell cycle and the interplay between its regulation and permissivity to HIV-1 infection.
Keywords	DNA replication ; HIV infections ; Human immunodeficiency virus 1 ; cell cycle ; homeostasis ; hydrolases ; immunity ; macrophages ; pathogens ; phenotype ; phenotypic plasticity ; phosphorylation
Language	English
Dates of publication	2020-0731
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2516098-9
ISSN	1999-4915
ISSN	1999-4915
DOI	10.3390/v12080839
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Extended in vitro inactivation of SARS-CoV-2 by titanium dioxide surface coating

Mlcochova, Petra / Chadha, Ambika / Hesselhoj, Timi / Fraternali, Franca / Ramsden, Jeremy / Gupta, Ravindra K

bioRxiv

Abstract: SARS-CoV-2 transmission occurs via airborne droplets and surface contamination. We show tiles coated with TiO2 120 days previously can inactivate SARS-CoV-2 under ambient indoor lighting with 87% reduction in titres at 1h and complete loss by 5h exposure. ...

Abstract	SARS-CoV-2 transmission occurs via airborne droplets and surface contamination. We show tiles coated with TiO2 120 days previously can inactivate SARS-CoV-2 under ambient indoor lighting with 87% reduction in titres at 1h and complete loss by 5h exposure. TiO2 coatings could be an important tool in containing SARS-CoV-2.
Keywords	covid19
Language	English
Publishing date	2020-12-08
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2020.12.08.415018
Database	COVID19

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Article ; Online: The IRE1α-XBP1 arm of the unfolded protein response is a host factor activated in SARS-CoV-2 infection.

Fernández, Jose Javier / Marín, Arturo / Rosales, Romel / Penrice-Randal, Rebekah / Mlcochova, Petra / Alvarez, Yolanda / Villalón-Letelier, Fernando / Yildiz, Soner / Pérez, Enrique / Rathnasinghe, Raveen / Cupic, Anastasija / Kehrer, Thomas / Uccellini, Melissa B / Alonso, Sara / Martínez, Fernando / McGovern, Briana Lynn / Clark, Jordan J / Sharma, Parul / Bayón, Yolanda /

Alonso, Andrés / Albrecht, Randy A / White, Kris M / Schotsaert, Michael / Miorin, Lisa / Stewart, James P / Hiscox, Julian A / Gupta, Ravindra K / Irigoyen, Nerea / García-Sastre, Adolfo / Crespo, Mariano Sánchez / Fernández, Nieves

Biochimica et biophysica acta. Molecular basis of disease

2024 Volume 1870, Issue 5, Page(s) 167193

Abstract: SARS-CoV-2 infection can cause severe pneumonia, wherein exacerbated inflammation plays a major role. This is reminiscent of the process commonly termed cytokine storm, a condition dependent on a disproportionated production of cytokines. This state ... ...

Abstract	SARS-CoV-2 infection can cause severe pneumonia, wherein exacerbated inflammation plays a major role. This is reminiscent of the process commonly termed cytokine storm, a condition dependent on a disproportionated production of cytokines. This state involves the activation of the innate immune response by viral patterns and coincides with the biosynthesis of the biomass required for viral replication, which may overwhelm the capacity of the endoplasmic reticulum and drive the unfolded protein response (UPR). The UPR is a signal transduction pathway composed of three branches that is initiated by a set of sensors: inositol-requiring protein 1 (IRE1), protein kinase RNA-like ER kinase (PERK), and activating transcription factor 6 (ATF6). These sensors control adaptive processes, including the transcriptional regulation of proinflammatory cytokines. Based on this background, the role of the UPR in SARS-CoV-2 replication and the ensuing inflammatory response was investigated using in vivo and in vitro models of infection. Mice and Syrian hamsters infected with SARS-CoV-2 showed a sole activation of the Ire1α-Xbp1 arm of the UPR associated with a robust production of proinflammatory cytokines. Human lung epithelial cells showed the dependence of viral replication on the expression of UPR-target proteins branching on the IRE1α-XBP1 arm and to a lower extent on the PERK route. Likewise, activation of the IRE1α-XBP1 branch by Spike (S) proteins from different variants of concern was a uniform finding. These results show that the IRE1α-XBP1 system enhances viral replication and cytokine expression and may represent a potential therapeutic target in SARS-CoV-2 severe pneumonia.
Language	English
Publishing date	2024-04-20
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	60-7
ISSN	1879-260X ; 1879-2596 ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-260X ; 1879-2596 ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbadis.2024.167193
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Article ; Online: DNA damage induced by topoisomerase inhibitors activates SAMHD1 and blocks HIV-1 infection of macrophages.

Mlcochova, Petra / Caswell, Sarah J / Taylor, Ian A / Towers, Greg J / Gupta, Ravindra K

The EMBO journal

2017 Volume 37, Issue 1, Page(s) 50–62

Abstract: We report that DNA damage induced by topoisomerase inhibitors, including etoposide (ETO), results in a potent block to HIV-1 infection in human monocyte-derived macrophages (MDM). SAMHD1 suppresses viral reverse transcription (RT) through depletion of ... ...

Abstract	We report that DNA damage induced by topoisomerase inhibitors, including etoposide (ETO), results in a potent block to HIV-1 infection in human monocyte-derived macrophages (MDM). SAMHD1 suppresses viral reverse transcription (RT) through depletion of cellular dNTPs but is naturally switched off by phosphorylation in a subpopulation of MDM found in a G1-like state. We report that SAMHD1 was activated by dephosphorylation following ETO treatment, along with loss of expression of MCM2 and CDK1, and reduction in dNTP levels. Suppression of infection occurred after completion of viral DNA synthesis, at the step of 2LTR circle and provirus formation. The ETO-induced block was completely rescued by depletion of SAMHD1 in MDM Concordantly, infection by HIV-2 and SIVsm encoding the SAMHD1 antagonist Vpx was insensitive to ETO treatment. The mechanism of DNA damage-induced blockade of HIV-1 infection involved activation of p53, p21, decrease in CDK1 expression, and SAMHD1 dephosphorylation. Therefore, topoisomerase inhibitors regulate SAMHD1 and HIV permissivity at a post-RT step, revealing a mechanism by which the HIV-1 reservoir may be limited by chemotherapeutic drugs.
MeSH term(s)	Cells, Cultured ; DNA Damage/drug effects ; Etoposide/pharmacology ; HIV Infections/drug therapy ; HIV Infections/virology ; HIV-1/drug effects ; Humans ; Macrophages/drug effects ; Macrophages/metabolism ; Macrophages/virology ; Nucleotides/metabolism ; Phosphorylation/drug effects ; SAM Domain and HD Domain-Containing Protein 1/metabolism ; Topoisomerase II Inhibitors/pharmacology ; Virus Replication/drug effects
Chemical Substances	Nucleotides ; Topoisomerase II Inhibitors ; Etoposide (6PLQ3CP4P3) ; SAM Domain and HD Domain-Containing Protein 1 (EC 3.1.5.-) ; SAMHD1 protein, human (EC 3.1.5.-)
Language	English
Publishing date	2017-10-30
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	586044-1
ISSN	1460-2075 ; 0261-4189
ISSN (online)	1460-2075
ISSN	0261-4189
DOI	10.15252/embj.201796880
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Article ; Online: Macrophages: the neglected barrier to eradication.

Watters, Sarah A / Mlcochova, Petra / Gupta, Ravindra K

Current opinion in infectious diseases

2013 Volume 26, Issue 6, Page(s) 561–566

Abstract: Purpose of review: There has been a shift towards HIV-1 eradication research in the last three years, yet much is still unknown about the precise role that macrophages will play in any such strategy. This review attempts to summarize the latest data on ... ...

Abstract	Purpose of review: There has been a shift towards HIV-1 eradication research in the last three years, yet much is still unknown about the precise role that macrophages will play in any such strategy. This review attempts to summarize the latest data on this subject. Recent findings: A new generation of histone deacetylase inhibitors, ITF2357, belinostat, givinostat, panobinostat, and the cancer drug JQ1, have been shown to induce viral reactivation in a monocyte cell line. In macrophages chronically infected with HIV-1 in vitro, drugs blocking pre-integration steps have demonstrated poor efficacy in controlling viral replication in comparison to protease inhibitors, thus questioning whether drugs can control this reservoir following histone deacetylase inhibition. Finally, non-human primate data suggest that CD8+ T cells may not be able to clear infected macrophages. Summary: Given these data highlighting the barriers to addressing the macrophage reservoir, functional rather than sterilizing cure may be a realistic goal. More research on macrophages is needed and animal models may prove useful in future HIV-1 eradication studies by offering a clinically relevant way to study macrophage infection in vivo.
MeSH term(s)	Animals ; Anti-Retroviral Agents/pharmacology ; Disease Reservoirs/virology ; HIV Infections/drug therapy ; HIV-1/drug effects ; HIV-1/physiology ; Histone Deacetylase Inhibitors/pharmacology ; Humans ; Macrophages/virology ; Monocytes/virology ; Virus Activation/drug effects ; Virus Replication/drug effects
Chemical Substances	Anti-Retroviral Agents ; Histone Deacetylase Inhibitors
Language	English
Publishing date	2013-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	645085-4
ISSN	1473-6527 ; 1535-3877 ; 0951-7375 ; 1355-834X
ISSN (online)	1473-6527 ; 1535-3877
ISSN	0951-7375 ; 1355-834X
DOI	10.1097/QCO.0000000000000014
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Article ; Online: Organization and regulation of intracellular plasma membrane-connected HIV-1 assembly compartments in macrophages.

Mlcochova, Petra / Pelchen-Matthews, Annegret / Marsh, Mark

BMC biology

2013 Volume 11, Page(s) 89

Abstract: Background: In HIV-1-infected human monocyte-derived macrophages (MDMs), virus particles assemble primarily on intracellularly sequestered plasma membrane domains termed intracellular plasma membrane-connected compartments (IPMCs). Despite their clear ... ...

Abstract	Background: In HIV-1-infected human monocyte-derived macrophages (MDMs), virus particles assemble primarily on intracellularly sequestered plasma membrane domains termed intracellular plasma membrane-connected compartments (IPMCs). Despite their clear role in virus formation, little is known of the organization, composition, dynamics or function of these compartments. Results: We have used amphipathic membrane dyes to reveal the complex three-dimensional structure of IPMCs in whole MDMs and to visualize connections between IPMCs and the cell surface. The observation of similar IPMC structures in both infected and uninfected cells indicates that these compartments are not induced by virus infection, but are present constitutively in MDMs. By expressing a phospholipase Cδ pleckstrin homology domain linked to green fluorescent protein, we demonstrate that IPMCs contain phosphatidylinositol 4,5-bisphosphate. Live cell imaging of cells expressing this probe shows that IPMCs are dynamic, but relatively stable, sub-domains of the plasma membrane. As recent electron microscopy studies indicated that portions of IPMCs are coated with β2 integrin-containing focal adhesion-like complexes linked to actin, we investigated whether the actin cytoskeleton is required for the organization of IPMCs. In MDMs treated with the actin polymerization inhibitor latrunculin, the normally compact IPMCs dispersed into smaller structures that remained connected to the plasma membrane. Moreover, latrunculin enhanced the release of preformed, mature HIV-1 particles from infected MDMs. Conclusions: IPMCs are constitutive features of MDMs that are continuous with the plasma membrane and are used as unique sites for the assembly of new virions following infection by HIV-1. A functionally intact actin cytoskeleton is required to maintain the organization of the IPMCs and, in HIV-1-infected cells, perturbation of the actin cytoskeleton influences both the organization of the compartment and the release of sequestered virus.
MeSH term(s)	Actin Cytoskeleton/metabolism ; Actins/metabolism ; Bridged Bicyclo Compounds, Heterocyclic/pharmacology ; Cell Compartmentation/drug effects ; Cell Membrane/drug effects ; Cell Membrane/virology ; Cell Survival/drug effects ; Coloring Agents/pharmacology ; Fluorescence Recovery After Photobleaching ; Green Fluorescent Proteins/metabolism ; HIV Infections/pathology ; HIV Infections/virology ; HIV-1/drug effects ; HIV-1/physiology ; Humans ; Image Processing, Computer-Assisted ; Intracellular Membranes/drug effects ; Intracellular Membranes/virology ; Lipids/chemistry ; Macrophages/metabolism ; Macrophages/ultrastructure ; Macrophages/virology ; Monocytes/cytology ; Phosphatidylinositol 4,5-Diphosphate/metabolism ; Phosphatidylinositol Phosphates/metabolism ; Polymerization/drug effects ; Thiazolidines/pharmacology ; Virus Assembly/drug effects ; Virus Assembly/physiology
Chemical Substances	Actins ; Bridged Bicyclo Compounds, Heterocyclic ; Coloring Agents ; Lipids ; Phosphatidylinositol 4,5-Diphosphate ; Phosphatidylinositol Phosphates ; Thiazolidines ; phosphatidylinositol 3-phosphate ; Green Fluorescent Proteins (147336-22-9) ; latrunculin A (SRQ9WWM084)
Language	English
Publishing date	2013-08-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2133020-7
ISSN	1741-7007 ; 1741-7007
ISSN (online)	1741-7007
ISSN	1741-7007
DOI	10.1186/1741-7007-11-89
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