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Article ; Online: Bisphenol S induces Agrp expression through GPER1 activation and alters transcription factor expression in immortalized hypothalamic neurons: A mechanism distinct from BPA-induced upregulation.

Xu, Katherine J / Loganathan, Neruja / Belsham, Denise D

2022 Volume 552, Page(s) 111630

Abstract: The increasing prevalence of obesity around the world has brought concern upon ubiquitously present obesogenic environmental compounds, such as bisphenol A (BPA). Increasingly tightened regulations on the industrial use of BPA have prompted a transition ... ...

Abstract	The increasing prevalence of obesity around the world has brought concern upon ubiquitously present obesogenic environmental compounds, such as bisphenol A (BPA). Increasingly tightened regulations on the industrial use of BPA have prompted a transition to a structurally similar alternative, bisphenol S (BPS). BPS displays endocrine-disrupting behaviours similar to those of BPA and increases body weight, food intake and the hypothalamic expression of Agrp in vivo. However, the mechanisms behind this deleterious effect are unclear. Here, we report an increase in the mRNA level of Agrp at 4 h following BPS treatment in immortalized murine hypothalamic cell lines of embryonic and adult origin (mHypoE-41, mHypoA-59). BPS-induced changes in the expression of transcription factors and estrogen receptors that occurred concurrently with Agrp upregulation demonstrated similarities to BPA-induced changes, however, there were also changes that were unique to BPS. Specifically, while Chop, Atf3, Atf4, Atf6, Klf4, and Creb1 were upregulated and Gper1 was downregulated by both BPA and BPS, Esr1 mRNA levels were upregulated and Foxo1 and Stat3 levels remained unchanged by BPS. Finally, inhibition of GPER1 by G15 prevented BPS-mediated Agrp upregulation, independent of Atf3 and Klf4 upregulation. Overall, our results demonstrate the ability of BPS to increase Agrp mRNA expression through GPER1 signaling and to alter transcription factor expression in hypothalamic neurons, further elucidating the endocrine-disrupting potential of this alternative industrial chemical.
MeSH term(s)	Agouti-Related Protein/metabolism ; Animals ; Benzhydryl Compounds/toxicity ; Mice ; Neurons/metabolism ; Phenols ; RNA, Messenger/metabolism ; Receptors, Estrogen/metabolism ; Receptors, G-Protein-Coupled/metabolism ; Sulfones ; Transcription Factors/metabolism ; Up-Regulation
Chemical Substances	Agouti-Related Protein ; Benzhydryl Compounds ; GPER1 protein, mouse ; Phenols ; RNA, Messenger ; Receptors, Estrogen ; Receptors, G-Protein-Coupled ; Sulfones ; Transcription Factors ; bis(4-hydroxyphenyl)sulfone (80-09-1) ; bisphenol A (MLT3645I99)
Language	English
Publishing date	2022-05-13
Publishing country	Ireland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	187438-x
ISSN	1872-8057 ; 0303-7207
ISSN (online)	1872-8057
ISSN	0303-7207
DOI	10.1016/j.mce.2022.111630
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Article ; Online: Identification of a short, highly conserved, motif required for picornavirus capsid precursor processing at distal sites.

Kristensen, Thea / Belsham, Graham J

PLoS pathogens

2019 Volume 15, Issue 1, Page(s) e1007509

Abstract: ... of 60 copies of three or four different capsid proteins. For the aphthoviruses (e.g. FMDV) and ... plus 2A. For enteroviruses, e.g. poliovirus, the capsid precursor is P1 alone, which is cleaved ...

Abstract	Many picornaviruses cause important diseases in humans and other animals including poliovirus, rhinoviruses (causing the common cold) and foot-and-mouth disease virus (FMDV). These small, non-enveloped viruses comprise a positive-stranded RNA genome (ca. 7-9 kb) enclosed within a protein shell composed of 60 copies of three or four different capsid proteins. For the aphthoviruses (e.g. FMDV) and cardioviruses, the capsid precursor, P1-2A, is cleaved by the 3C protease (3Cpro) to generate VP0, VP3 and VP1 plus 2A. For enteroviruses, e.g. poliovirus, the capsid precursor is P1 alone, which is cleaved by the 3CD protease to generate just VP0, VP3 and VP1. The sequences required for correct processing of the FMDV capsid protein precursor in mammalian cells were analyzed. Truncation of the P1-2A precursor from its C-terminus showed that loss of the 2A peptide (18 residues long) and 27 residues from the C-terminus of VP1 (211 residues long) resulted in a precursor that cannot be processed by 3Cpro although it still contained two unmodified internal cleavage sites (VP0/VP3 and VP3/VP1 junctions). Furthermore, introduction of small deletions within P1-2A identified residues 185-190 within VP1 as being required for 3Cpro-mediated processing and for optimal accumulation of the precursor. Within this C-terminal region of VP1, five of these residues (YCPRP), are very highly conserved in all FMDVs and are also conserved amongst other picornaviruses. Mutant FMDV P1-2A precursors with single amino acid substitutions within this motif were highly resistant to cleavage at internal junctions. Such substitutions also abrogated virus infectivity. These results can explain earlier observations that loss of the C-terminus (including the conserved motif) from the poliovirus capsid precursor conferred resistance to processing. Thus, this motif seems essential for maintaining the correct structure of picornavirus capsid precursors prior to processing and subsequent capsid assembly; it may represent a site that interacts with cellular chaperones.
MeSH term(s)	Amino Acid Motifs/genetics ; Amino Acid Sequence/genetics ; Amino Acid Substitution ; Capsid/metabolism ; Capsid Proteins/genetics ; Capsid Proteins/metabolism ; Conserved Sequence ; Picornaviridae/genetics ; Picornaviridae/metabolism ; Picornaviridae Infections/genetics ; Picornaviridae Infections/metabolism ; Protein Precursors/genetics ; Protein Processing, Post-Translational ; Sequence Homology, Amino Acid ; Viral Proteins/metabolism ; Viral Structural Proteins/genetics ; Viral Structural Proteins/metabolism
Chemical Substances	Capsid Proteins ; Protein Precursors ; Viral Proteins ; Viral Structural Proteins
Language	English
Publishing date	2019-01-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7366
ISSN (online)	1553-7374
ISSN	1553-7366
DOI	10.1371/journal.ppat.1007509
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Molecular epidemiology, evolution and phylogeny of foot-and-mouth disease virus.

Jamal, Syed M / Belsham, Graham J

Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases

2018 Volume 59, Page(s) 84–98

Abstract: ... genome, the virus continuously evolves and new strains frequently arise (e.g. with modified antigenicity ...

Abstract	Foot-and-mouth disease virus (FMDV) is responsible for one of the most economically important infectious diseases of livestock. The virus spreads very easily and continues to affect many countries (mainly in Africa and Asia). The risks associated with the introduction of FMDV result in major barriers to trade in animals and their products. Seven antigenically distinct forms of the virus are known, called serotypes, but serotype C has not been detected anywhere for many years and may now be extinct. The serotypes have been further divided into topotypes (except for serotype Asia-1 viruses, which comprise a single topotype), genotypes, lineages and sub-lineages, which are usually restricted to specific geographical regions. However, sometimes, trans-regional spread of some strains occurs. Due to the error-prone replication of the RNA genome, the virus continuously evolves and new strains frequently arise (e.g. with modified antigenicity). Using nucleotide sequencing technologies, this rapid evolution of the viral genome can be followed. This allows the tracing of virus transmission pathways within an outbreak of disease if (near) full-length genome sequences can be generated. Furthermore, the movement of distinct virus lineages, from one country to another can be analyzed. Some important examples of the spread of new strains of FMD virus are described.
MeSH term(s)	Animals ; Evolution, Molecular ; Foot-and-Mouth Disease/epidemiology ; Foot-and-Mouth Disease/virology ; Foot-and-Mouth Disease Virus/classification ; Foot-and-Mouth Disease Virus/genetics ; Genome, Viral/genetics ; Livestock/virology ; Molecular Epidemiology ; Phylogeny ; RNA, Viral/genetics
Chemical Substances	RNA, Viral
Language	English
Publishing date	2018-02-03
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2037068-4
ISSN	1567-7257 ; 1567-1348
ISSN (online)	1567-7257
ISSN	1567-1348
DOI	10.1016/j.meegid.2018.01.020
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Zs.A 5645: Show issues

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Article ; Online: Foot-and-mouth disease virus: Prospects for using knowledge of virus biology to improve control of this continuing global threat.

Belsham, Graham J / Kristensen, Thea / Jackson, Terry

Virus research

2020 Volume 281, Page(s) 197909

Abstract: ... shortcomings, have been used very successfully (e.g. in Europe) to control the disease but it still remains ...

Abstract	Understanding of the biology of foot-and-mouth disease virus (FMDV) has grown considerably since the nucleotide sequence of the viral RNA was determined. The ability to manipulate the intact genome and also to express specific parts of the genome individually has enabled detailed analyses of viral components, both RNA and protein. Such studies have identified the requirements for specific functional elements for virus replication and pathogenicity. Furthermore, information about the functions of individual virus proteins has enabled the rational design of cDNA cassettes to express non-infectious empty capsid particles that can induce protective immunity in the natural host animals and thus represent new vaccine candidates. Similarly, attempts to block specific virus activities using antiviral agents have also been performed. However, currently, only the well-established, chemically inactivated FMDV vaccines are commercially available and suitable for use to combat this important disease of livestock animals. These vaccines, despite certain shortcomings, have been used very successfully (e.g. in Europe) to control the disease but it still remains endemic in much of Africa, southern Asia and the Middle East. Hence there remains a significant risk of reintroduction of the disease into highly susceptible animal populations with enormous economic consequences.
MeSH term(s)	Animals ; Foot-and-Mouth Disease/genetics ; Foot-and-Mouth Disease/prevention & control ; Foot-and-Mouth Disease/virology ; Foot-and-Mouth Disease Virus/genetics ; Foot-and-Mouth Disease Virus/immunology ; Genome, Viral/genetics ; Viral Proteins/genetics ; Viral Proteins/immunology ; Viral Vaccines/immunology
Chemical Substances	Viral Proteins ; Viral Vaccines
Language	English
Publishing date	2020-02-29
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	605780-9
ISSN	1872-7492 ; 0168-1702
ISSN (online)	1872-7492
ISSN	0168-1702
DOI	10.1016/j.virusres.2020.197909
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Article: Foot-and-mouth disease virus: Prospects for using knowledge of virus biology to improve control of this continuing global threat

Belsham, Graham J / Kristensen, Thea / Jackson, Terry

Virus research. 2020 May, v. 281

2020

Abstract: ... shortcomings, have been used very successfully (e.g. in Europe) to control the disease but it still remains ...

Abstract	Understanding of the biology of foot-and-mouth disease virus (FMDV) has grown considerably since the nucleotide sequence of the viral RNA was determined. The ability to manipulate the intact genome and also to express specific parts of the genome individually has enabled detailed analyses of viral components, both RNA and protein. Such studies have identified the requirements for specific functional elements for virus replication and pathogenicity. Furthermore, information about the functions of individual virus proteins has enabled the rational design of cDNA cassettes to express non-infectious empty capsid particles that can induce protective immunity in the natural host animals and thus represent new vaccine candidates. Similarly, attempts to block specific virus activities using antiviral agents have also been performed. However, currently, only the well-established, chemically inactivated FMDV vaccines are commercially available and suitable for use to combat this important disease of livestock animals. These vaccines, despite certain shortcomings, have been used very successfully (e.g. in Europe) to control the disease but it still remains endemic in much of Africa, southern Asia and the Middle East. Hence there remains a significant risk of reintroduction of the disease into highly susceptible animal populations with enormous economic consequences.
Keywords	Foot-and-mouth disease virus ; RNA ; animals ; antiviral agents ; capsid ; disease control ; economic impact ; genome ; immunity ; livestock diseases ; nucleotide sequences ; pathogenicity ; risk ; vaccines ; viral proteins ; virus replication ; viruses ; Africa ; Europe ; Middle East ; South Asia
Language	English
Dates of publication	2020-05
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	605780-9
ISSN	1872-7492 ; 0168-1702
ISSN (online)	1872-7492
ISSN	0168-1702
DOI	10.1016/j.virusres.2020.197909
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Separation of foot-and-mouth disease virus leader protein activities; identification of mutants that retain efficient self-processing activity but poorly induce eIF4G cleavage.

Guan, Su Hua / Belsham, Graham J

The Journal of general virology

2017 Volume 98, Issue 4, Page(s) 671–680

Abstract: ... This study characterizes mutant viruses that are deficient in blocking host cell responses to infection (e.g ...

Abstract	Foot-and-mouth disease virus is a picornavirus and its RNA genome encodes a large polyprotein. The N-terminal part of this polyprotein is the leader protein, a cysteine protease, termed Lpro. The virus causes the rapid inhibition of host cell cap-dependent protein synthesis within infected cells. This results from the Lpro-dependent cleavage of the cellular translation initiation factor eIF4G. Lpro also releases itself from the virus capsid precursor by cleaving the L/P1 junction. Using site-directed mutagenesis of the Lpro coding sequence, we have investigated the role of 51 separate amino acid residues in the functions of this protein. These selected residues either are highly conserved or are charged and exposed on the protein surface. Using transient expression assays, within BHK-21 cells, it was found that residues around the active site (W52, L53 and A149) of Lpro and others located elsewhere (K38, K39, R44, H138 and W159) are involved in the induction of eIF4G cleavage but not in the processing of the L/P1 junction. Modified viruses, encoding such amino acid substitutions within Lpro, can replicate in BHK-21 cells but did not grow well in primary bovine thyroid cells. This study characterizes mutant viruses that are deficient in blocking host cell responses to infection (e.g. interferon induction) and can assist in the rational design of antiviral agents targeting this process and in the production of attenuated viruses.
MeSH term(s)	Animals ; Cattle ; Cells, Cultured ; Cricetinae ; DNA Mutational Analysis ; Endopeptidases/genetics ; Endopeptidases/metabolism ; Eukaryotic Initiation Factor-4G/metabolism ; Foot-and-Mouth Disease Virus/enzymology ; Foot-and-Mouth Disease Virus/genetics ; Foot-and-Mouth Disease Virus/physiology ; Mutagenesis, Site-Directed ; Mutant Proteins/genetics ; Mutant Proteins/metabolism ; Proteolysis
Chemical Substances	Eukaryotic Initiation Factor-4G ; Mutant Proteins ; Endopeptidases (EC 3.4.-) ; leader proteinase, foot-and-mouth disease virus (EC 3.4.99.-)
Language	English
Publishing date	2017-04
Publishing country	England
Document type	Journal Article
ZDB-ID	219316-4
ISSN	1465-2099 ; 0022-1317
ISSN (online)	1465-2099
ISSN	0022-1317
DOI	10.1099/jgv.0.000747
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Article ; Online: Identification of a short, highly conserved, motif required for picornavirus capsid precursor processing at distal sites.

Thea Kristensen / Graham J Belsham

PLoS Pathogens, Vol 15, Iss 1, p e

2019 Volume 1007509

Abstract	Many picornaviruses cause important diseases in humans and other animals including poliovirus, rhinoviruses (causing the common cold) and foot-and-mouth disease virus (FMDV). These small, non-enveloped viruses comprise a positive-stranded RNA genome (ca. 7-9 kb) enclosed within a protein shell composed of 60 copies of three or four different capsid proteins. For the aphthoviruses (e.g. FMDV) and cardioviruses, the capsid precursor, P1-2A, is cleaved by the 3C protease (3Cpro) to generate VP0, VP3 and VP1 plus 2A. For enteroviruses, e.g. poliovirus, the capsid precursor is P1 alone, which is cleaved by the 3CD protease to generate just VP0, VP3 and VP1. The sequences required for correct processing of the FMDV capsid protein precursor in mammalian cells were analyzed. Truncation of the P1-2A precursor from its C-terminus showed that loss of the 2A peptide (18 residues long) and 27 residues from the C-terminus of VP1 (211 residues long) resulted in a precursor that cannot be processed by 3Cpro although it still contained two unmodified internal cleavage sites (VP0/VP3 and VP3/VP1 junctions). Furthermore, introduction of small deletions within P1-2A identified residues 185-190 within VP1 as being required for 3Cpro-mediated processing and for optimal accumulation of the precursor. Within this C-terminal region of VP1, five of these residues (YCPRP), are very highly conserved in all FMDVs and are also conserved amongst other picornaviruses. Mutant FMDV P1-2A precursors with single amino acid substitutions within this motif were highly resistant to cleavage at internal junctions. Such substitutions also abrogated virus infectivity. These results can explain earlier observations that loss of the C-terminus (including the conserved motif) from the poliovirus capsid precursor conferred resistance to processing. Thus, this motif seems essential for maintaining the correct structure of picornavirus capsid precursors prior to processing and subsequent capsid assembly; it may represent a site that interacts with cellular ...
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2019-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Animal Models for COVID-19: More to the Picture Than ACE2, Rodents, Ferrets, and Non-human Primates. A Case for Porcine Respiratory Coronavirus and the Obese Ossabaw Pig

Heegaard, P. M. H. / Sturek, M. / Alloosh, M. / Belsham, G. J.

Frontiers in Microbiology

Abstract: The ongoing COVID-19 pandemic caused by infection with SARS-CoV-2 has created an urgent need for animal models to enable study of basic infection and disease mechanisms and for development of vaccines, therapeutics, and diagnostics Most research on ... ...

Abstract	The ongoing COVID-19 pandemic caused by infection with SARS-CoV-2 has created an urgent need for animal models to enable study of basic infection and disease mechanisms and for development of vaccines, therapeutics, and diagnostics Most research on animal models for COVID-19 has been directed toward rodents, transgenic rodents, and non-human primates The primary focus has been on the angiotensin-converting enzyme 2 (ACE2), which is a host cell receptor for SARS-CoV-2 Among investigated species, irrespective of ACE2 spike protein binding, only mild (or no) disease has occurred following infection with SARS-CoV-2, suggesting that ACE2 may be necessary for infection but is not sufficient to determine the outcome of infection The common trait of all species investigated as COVID models is their healthy status prior to virus challenge In contrast, the vast majority of severe COVID-19 cases occur in people with chronic comorbidities such as diabetes, obesity, and/or cardiovascular disease Healthy pigs express ACE2 protein that binds the viral spike protein but they are not susceptible to infection with SARS-CoV-2 However, certain pig breeds, such as the Ossabaw pig, can reproducibly be made obese and show most aspects of the metabolic syndrome, thus resembling the more than 80% of the critically ill COVID-19 patients admitted to hospitals We urge considering infection with porcine respiratory coronavirus of metabolic syndrome pigs, such as the obese Ossabaw pig, as a highly relevant animal model of severe COVID-19
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #874505
Database	COVID19

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Article ; Online: Veterinær betydning af COVID-19

Belsham, Graham John / Rasmussen, Thomas Bruun / Bøtner, Anette Gleitze

Belsham , G J , Rasmussen , T B & Bøtner , A G 2020 , ' Veterinær betydning af COVID-19 ' , Dansk Veterinaertidsskrift , bind 2020 , nr. 04 , s. 16-17 .

2020

Abstract: SARS-CoV-2 er påvist hos flere dyr, men der er foreløbig ingen dokumentation for, at hverken kæledyr eller produktionsdyr spiller nogen rolle i forbindelse med spredningen af COVID-19 i ... ...

Abstract	SARS-CoV-2 er påvist hos flere dyr, men der er foreløbig ingen dokumentation for, at hverken kæledyr eller produktionsdyr spiller nogen rolle i forbindelse med spredningen af COVID-19 i mennesker
Keywords	covid19
Language	Danish
Publishing country	dk
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Diagnostic comparison of serum and EDTA-stabilized blood samples for the detection of foot-and-mouth disease virus RNA by RT-qPCR.

Fontél, Kristina S / Bøtner, Anette / Belsham, Graham J / Lohse, Louise

Journal of virological methods

2019 Volume 270, Page(s) 120–125

Abstract: ... occasional recent outbreaks in Europe, e.g. in the U.K. in 2001, U.K. 2007 and Bulgaria 2010/2011 ...

Abstract	Foot-and-mouth disease (FMD) remains a globally important disease but there have only been occasional recent outbreaks in Europe, e.g. in the U.K. in 2001, U.K. 2007 and Bulgaria 2010/2011. However, this infection still poses a threat to Europe as the disease occurs close to its borders and incursions can occur through importation of contaminated animal products and through the air. To deal with a suspected outbreak, fast sampling, transportation and accurate laboratory diagnosis are critical; testing for FMDV is normally performed on epithelium samples or serum. Assessment of the use of stabilized blood in assays for FMDV RNA is useful as this sample material can be prepared on site for safe transportation and rapid analysis at the laboratory. Such samples are also collected for diagnosis of other diseases giving similar clinical signs. Testing serum and EDTA-stabilized blood samples from FMDV-infected cattle and pigs, using real time quantitative RT-PCR assays, yielded similar results. However, detection of FMDV RNA was less sensitive (about 10-fold) when using EDTA-stabilized blood compared to serum. Thus, diagnosis of FMD can be achieved using EDTA-stabilized blood samples in an outbreak situation on a herd basis, but serum is preferred at the single animal level for optimal sensitivity.
MeSH term(s)	Animals ; Cattle ; Cattle Diseases/diagnosis ; Cattle Diseases/epidemiology ; Cattle Diseases/virology ; Disease Outbreaks/veterinary ; Edetic Acid ; Europe/epidemiology ; Foot-and-Mouth Disease/diagnosis ; Foot-and-Mouth Disease/epidemiology ; Foot-and-Mouth Disease Virus/isolation & purification ; RNA, Viral/genetics ; Real-Time Polymerase Chain Reaction/veterinary ; Sensitivity and Specificity ; Specimen Handling ; Swine ; Swine Diseases/diagnosis ; Swine Diseases/epidemiology ; Swine Diseases/virology
Chemical Substances	RNA, Viral ; Edetic Acid (9G34HU7RV0)
Language	English
Publishing date	2019-05-13
Publishing country	Netherlands
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	8013-5
ISSN	1879-0984 ; 0166-0934
ISSN (online)	1879-0984
ISSN	0166-0934
DOI	10.1016/j.jviromet.2019.05.003
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