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352. Preface

Author

Tyrrell, D. A. J. and Pereira, H. G.

Published
1980

354. HCV796: A selective nonstructural protein 5B polymerase inhibitor with potent anti-hepatitis C virus activity In Vitro, in mice with chimeric human livers, and in humans infected with hepatitis C virus

Author

Kneteman, Norman M., primary, Howe, Anita Y. M., additional, Gao, Tiejun, additional, Lewis, Jamie, additional, Pevear, Dan, additional, Lund, Gary, additional, Douglas, Donna, additional, Mercer, David F., additional, Tyrrell, D. Lorne J., additional, Immermann, Frederick, additional, Chaudhary, Inder, additional, Speth, John, additional, Villano, Stephen A., additional, O'Connell, John, additional, and Collett, Marc, additional

Published
2008
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355. The Discovery of Pyrano[3,4-b]indole-Based Allosteric Inhibitors of HCV NS5B Polymerase with In Vivo Activity

Author

LaPorte, Matthew G., primary, Jackson, Randy W., additional, Draper, Tandy L., additional, Gaboury, Janet A., additional, Galie, Kristin, additional, Herbertz, Torsten, additional, Hussey, Alison R., additional, Rippin, Susan R., additional, Benetatos, Christopher A., additional, Chunduru, Srinivas K., additional, Christensen, Joel S., additional, Coburn, Glen A., additional, Rizzo, Christopher J., additional, Rhodes, Gerry, additional, O'Connell, John, additional, Howe, Anita Y. M., additional, Mansour, Tarek S., additional, Collett, Marc S., additional, Pevear, Daniel C., additional, Young, Dorothy C., additional, Gao, Tiejun, additional, Tyrrell, D. Lorne J., additional, Kneteman, Norman M., additional, Burns, Christopher J., additional, and Condon, Stephen M., additional

Published
2008
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361. A simple ultrasound-guided approach for intra-articular injection of the canine hip joint.

Author

Wernham, B. G. J., Tyrrell, D., Whittem, T., and Ryan, S.

Subjects
CANINE hip dysplasia, ANIMAL diseases, ULTRASONIC imaging, INTRA-articular injections, DOG anatomy, DIAGNOSIS
Abstract

AIMS To describe the sonoanatomy of the canine hip joint and determine the feasibility of an ultrasound-guided technique for intra-articular hip injection. METHODS Six fresh-frozen canine cadavers and five live dogs were used to describe the sonoanatomy of the hip and develop an ultrasound-guided intra-articular injection technique of the hip joint. The hip joints of five canine cadavers were injected with 1 mL of coloured liquid latex under ultrasound guidance. The results of injection were determined via dissection after injection and the injection technique modified and refined. Once an appropriate technique had been developed, a single cadaver was frozen, sectioned and the anatomical and sonoanatomical landmarks compared. RESULTS The regional sonoanatomy of the canine hip joint could be easily determined and correlated well with cryosections. The hip joint could be accurately injected under ultrasound guidance using a caudoventrolateral approach. Initial imaging of the hip joint was achieved by placing the transducer immediately proximal to the palpable greater trochanter, perpendicular to the spine. Appropriate transducer positioning for targeting the hip joint was then achieved by rotating the transducer approximately 30 degrees clockwise or anticlockwise to inject the left or right hip, respectively. CONCLUSIONS Ultrasound-guided hip injection using a caudoventrolateral approach is feasible in the canine cadaver. CLINICAL RELEVANCE Although this technique remains to be performed in clinical cases, it has the potential to facilitate the diagnosis of coxofemoral pain, septic arthritis and the accurate delivery of intra-articular therapeutic agents. [ABSTRACT FROM AUTHOR]

Published
2015

362. The Pekin duck programmed death-ligand 1: cDNA cloning, genomic structure, molecular characterization and mRNA expression analysis.

Author

Yao, Q., Fischer, K. P., Tyrrell, D. L., and Gutfreund, K. S.

Subjects
LIGANDS (Biochemistry), MOLECULAR cloning, ANTISENSE DNA, IMMUNE response, STRUCTURAL genomics, MESSENGER RNA
Abstract

Programmed death ligand-1 ( PD-L1) plays an important role in the attenuation of adaptive immune responses in higher vertebrates. Here, we describe the identification of the Pekin duck PD-L1 orthologue (du PD-L1) and its gene structure. The du PD-L1 cDNA encodes a 311-amino acid protein that has an amino acid identity of 78% and 42% with chicken and human PD-L1, respectively. Mapping of the du PD-L1 cDNA with duck genomic sequences revealed an exonic structure of its coding sequence similar to those of other vertebrates but lacked a noncoding exon 1. Homology modelling of the du PD-L1 extracellular domain was compatible with the tandem IgV-like and IgC-like Ig SF domain structure of human PD-L1 ( PDB ID: 3 BIS). Residues known to be important for receptor binding of human PD-L1 were mostly conserved in du PD-L1 within the N-terminus and the G sheet, and partially conserved within the F sheet but not within sheets C and C'. Du PD-L1 mRNA was constitutively expressed in all tissues examined with highest expression levels in lung and spleen and very low levels of expression in muscle, kidney and brain. Mitogen stimulation of duck peripheral blood mononuclear cells transiently increased du PD-L1 mRNA expression. Our observations demonstrate evolutionary conservation of the exonic structure of its coding sequence, the extracellular domain structure and residues implicated in receptor binding, but the role of the longer cytoplasmic tail in avian PD-L1 proteins remains to be determined. [ABSTRACT FROM AUTHOR]

Published
2015
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366. Host-Specific Response to HCV Infection in the Chimeric SCID-beige/Alb-uPA Mouse Model: Role of the Innate Antiviral Immune Response

Author

Walters, Kathie-Anne, primary, Joyce, Michael A, additional, Thompson, Jill C, additional, Smith, Maria W, additional, Yeh, Matthew M, additional, Proll, Sean, additional, Zhu, Lin-Fu, additional, Gao, T. J, additional, Kneteman, Norman M, additional, Tyrrell, D. Lorne, additional, and Katze, Michael G, additional

Published
2006
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373. Anti-HCV therapies in chimericscid-Alb/uPA mice parallel outcomes in human clinical application

Author

Kneteman, Norman M., primary, Weiner, Amy J., additional, O'Connell, John, additional, Collett, Marc, additional, Gao, Tiejun, additional, Aukerman, Lea, additional, Kovelsky, Rosemary, additional, Ni, Zhi-Jie, additional, Hashash, Ahmad, additional, Kline, Janine, additional, Hsi, Belinda, additional, Schiller, Daniel, additional, Douglas, Donna, additional, Tyrrell, D Lorne J, additional, and Mercer, David F., additional

Published
2006
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374. Coccidioidal meningitis acquired during holidays in Arizona

Author

Taylor, G D, Boettger, D W, Miedzinski, L J, and Tyrrell, D L

Subjects
Male, Travel, Coccidioidomycosis, Coccidioides, Arizona, Administration, Oral, Alberta, Amphotericin B, Humans, Female, Meningitis, Fluconazole, Injections, Spinal, Research Article, Aged
Published
1990

380. Application of functional genomics to the chimeric mouse model of HCV infection: optimization of microarray protocols and genomics analysis

Author

Smith Maria W, Wallace James, Proll Sean, Thompson Jill C, Joyce Michael A, Walters Kathie-Anne, Furlong Jeff, Tyrrell D Lorne, and Katze Michael G

Subjects
Chimera, Methodology, Computational Biology, Gene Expression, Nucleic Acid Hybridization, Reproducibility of Results, Genomics, Hepacivirus, Mice, SCID, Lipid Metabolism, Hepatitis C, Polymerase Chain Reaction, lcsh:Infectious and parasitic diseases, Disease Models, Animal, Mice, Liver, Succinate-CoA Ligases, Animals, Humans, RNA, lcsh:RC109-216, Oligonucleotide Array Sequence Analysis
Abstract

Background Many model systems of human viral disease involve human-mouse chimeric tissue. One such system is the recently developed SCID-beige/Alb-uPA mouse model of hepatitis C virus (HCV) infection which involves a human-mouse chimeric liver. The use of functional genomics to study HCV infection in these chimeric tissues is complicated by the potential cross-hybridization of mouse mRNA on human oligonucleotide microarrays. To identify genes affected by mouse liver mRNA hybridization, mRNA from identical human liver samples labeled with either Cy3 or Cy5 was compared in the presence and absence of known amounts of mouse liver mRNA labeled in only one dye. Results The results indicate that hybridization of mouse mRNA to the corresponding human gene probe on Agilent Human 22 K oligonucleotide microarray does occur. The number of genes affected by such cross-hybridization was subsequently reduced to approximately 300 genes both by increasing the hybridization temperature and using liver samples which contain at least 80% human tissue. In addition, Real Time quantitative RT-PCR using human specific probes was shown to be a valid method to verify the expression level in human cells of known cross-hybridizing genes. Conclusion The identification of genes affected by cross-hybridization of mouse liver RNA on human oligonucleotide microarrays makes it feasible to use functional genomics approaches to study the chimeric SCID-beige/Alb-uPA mouse model of HCV infection. This approach used to study cross-species hybridization on oligonucleotide microarrays can be adapted to other chimeric systems of viral disease to facilitate selective analysis of human gene expression.

Published
2006

383. The Effect of Deuteration and Homologation of the Lactam Ring of Nirmatrelvir on Its Biochemical Properties and Oxidative Metabolism

Author

Arutyunova, Elena, Belovodskiy, Alexandr, Chen, Pu, Khan, Muhammad Bashir, Joyce, Michael, Saffran, Holly, Lu, Jimmy, Turner, Zoe, Bai, Bing, Lamer, Tess, Young, Howard S., Vederas, John C., Tyrrell, D. Lorne, Lemieux, M. Joanne, and Nieman, James A.

Abstract

This study explores the relationship between structural alterations of nirmatrelvir, such as homologation and deuteration, and metabolic stability of newly synthesized derivatives. We developed a reliable synthetic protocol toward dideutero-nirmatrelvir and its homologated analogues with high isotopic incorporation. Deuteration of the primary metabolic site of nirmatrelvir provides a 3-fold improvement of its human microsomal stability but is accompanied by an increased metabolism rate at secondary sites. Homologation of the lactam ring allows the capping group modification to decrease and delocalize the molecule’s lipophilicity, reducing the metabolic rate at secondary sites. The effect of deuteration was less pronounced for the 6-membered lactam than for its 5-membered analogue in human microsomes, but the trend is reversed in the case of mouse microsomes. X-ray data revealed that the homologation of the lactam ring favors the orientation of the drug’s nitrile warhead for interaction with the catalytic sulfur of the SARS-CoV-2 Mpro, improving its binding. Comparable potency against SARS-CoV-2 Mprofrom several variants of concern and selectivity over human cysteine proteases cathepsin B, L, and S was observed for the novel deuterated/homologated derivative and nirmatrelvir. Synthesized compounds displayed a large interspecies variability in hamster, rat, and human hepatocyte stability assays. Overall, we aimed to apply a rational approach in changing the physicochemical properties of the drug to refine its biochemical and biological parameters.

Published
2023
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384. Bovine Serum Albumin-Protected Gold Nanoclusters for Sensing of SARS-CoV-2 Antibodies and Virus

Author

Shen, Qiming, Hossain, Faisal, Fang, Changhao, Shu, Tong, Zhang, Xueji, Law, John Lok Man, Logan, Michael, Houghton, Michael, Tyrrell, D. Lorne, Joyce, Michael A., and Serpe, Michael J.

Abstract

An approach to assess severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (and past infection) was developed. For virus detection, the SARS-CoV-2 virus nucleocapsid protein (NP) was targeted. To detect the NP, antibodies were immobilized on magnetic beads to capture the NPs, which were subsequently detected using rabbit anti-SARS-CoV-2 nucleocapsid antibodies and alkaline phosphatase (AP)-conjugated anti-rabbit antibodies. A similar approach was used to assess SARS-CoV-2-neutralizing antibody levels by capturing spike receptor-binding domain (RBD)-specific antibodies utilizing RBD protein-modified magnetic beads and detecting them using AP-conjugated anti-human IgG antibodies. The sensing mechanism for both assays is based on cysteamine etching-induced fluorescence quenching of bovine serum albumin-protected gold nanoclusters where cysteamine is generated in proportion to the amount of either SARS-CoV-2 virus or anti-SARS-CoV-2 receptor-binding domain-specific immunoglobulin antibodies (anti-RBD IgG antibodies). High sensitivity can be achieved in 5 h 15 min for the anti-RBD IgG antibody detection and 6 h 15 min for virus detection, although the assay can be run in “rapid” mode, which takes 1 h 45 min for the anti-RBD IgG antibody detection and 3 h 15 min for the virus. By spiking the anti-RBD IgG antibodies and virus in serum and saliva, we demonstrate that the assay can detect the anti-RBD IgG antibodies with a limit of detection (LOD) of 4.0 and 2.0 ng/mL in serum and saliva, respectively. For the virus, we can achieve an LOD of 8.5 × 105RNA copies/mL and 8.8 × 105RNA copies/mL in serum and saliva, respectively. Interestingly, this assay can be easily modified to detect myriad analytes of interest.

Published
2023
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385. Evaluation of the antirhinovirus chalcone Ro 09-0415 given orally to volunteers.

Author

Phillpotts, R. J., Higgins, P. G., Willman, J. S., Tyrrell, D. A. J., Lenox-Smith, I., and Tyrrell, D A

Abstract

Ro 09-0415, a phosphorylated ‘pro-drug’ of the potent antirhinovirus compound, 4′ ethoxy-2′-hydroxy-4, 6′ dimethoxy-chalcone (Ro 09-0410) was tested in a double-blind placebo-controlled trial for its protective effect against experimental rhinovirus infection. The maximum dose, 1200 mg bd, based on considerations of practicality and tolerance was given orally both before and after challenge with a sensitive rhinovirus, type 9. Plasma concentrations of active compound in excess of those required for the inhibition of rhinovirus type 9 were achieved, but there was no evidence to suggest that treatment with Ro 09-0415 had a beneficial effect. It is concluded that Ro 09-0415 given orally is unlikely to be of value in the prophylaxis or therapy of human rhinovirus infection. [ABSTRACT FROM PUBLISHER]

Published
1984

386. Role of viruses in febrile convulsions.

Author

LEWIS, HELEN M., PARRY, JOHN V., PARRY, RUTH P., DAVIES, HEATHER A., SANDERSON, P. J., TYRRELL, D. A. J., VALMAN, H. B., Lewis, H M, Parry, J V, Parry, R P, Davies, H A, and Tyrrell, D A

Abstract

A disseminated viral illness was demonstrated by isolating a virus from the CSF, blood or urine in 27% of 73 children who were admitted to hospital after a first febrile convulsion. However, a viral aetiology could be implicated for 86% of the children after combining results of tissue culture, electron microscopy, mouse inoculation, complement fixation tests, and interferon assay. Parallel bacterial cultures showed a possible pathogen in 29% of children, but in only 4% was the pathogen isolated from the CSF, blood, or urine. No correlation was found between the nature of the pathogen (or evidence of its dissemination) and the severity of the convulsion, degree of fever, CSF protein, CSF white cells, or the WBC. The results suggest that a febrile convulsion could be a response to invasion of the blood stream or central nervous system by a micro-organism which is usually a virus. Invasion may be of such brief duration that successful isolation of the virus from the blood, CSF, or urine in not more commonly achieved. [ABSTRACT FROM AUTHOR]

Published
1979
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387. A year's experience of the rotavirus syndrome and its association with respiratory illness.

Author

LEWIS, HELEN M., PARRY, J. V., DAVIES, HEATHER A., PARRY, RUTH P., MOTT, ANGELA, DOURMASHKIN, R. R., SANDERSON, P. J., TYRRELL, D. A. J., VALMAN, H. B., Lewis, H M, Davies, H A, Parry, R P, Mott, A, and Tyrrell, D A

Abstract

In a hospital study rotavirus was identified in 51% of 152 children with diarrhoea. These patients showed a clinical pattern that was distinct from patients in whom the diarrhoea was associated with bacteria, other viruses, or no pathogens. A respiratory illness was described in 66% of rotavirus patients and usually preceded the gastrointestinal symptoms. Vomiting lasted between one and 3 days and was curtailed by substituting the normal diet with clear fluids. Watery diarrhoes continued for 4 or 5 days, even when rehydration was by the intravenous rather than the oral route. Prolonged diarrhoea was rare. Most children infected with rotavirus were under 2 years of age, but dehydration was most severe in infants aged between 12 and 18 months. A clinician can thus recognise the rotavirus syndrome and expect spontaneous recovery if adequate rehydration is maintained for a critical few days. [ABSTRACT FROM AUTHOR]

Published
1979

388. Echovirus encephalitis and myositis in primary immunoglobulin deficiency.

Author

WEBSTER, A. D. B., TRIPP, J. H., HAYWARD, A. R., DAYAN, A. D., DOSHI, R., MACINTYRE, E. H., TYRRELL, D. A. J., Webster, A D, and Tyrrell, D A

Abstract

Two children are described with primary hypogammaglobulinaemia and encephalitis associated with echovirus infection. One also developed a condition resembling dermatomyositis which improved after he was given infusions of plasma containing antibody to the echovirus. Although both died of their encephalitis, the course of the brain disease in one of them may have been prolonged by treatment with specific antibody. These cases, together with another briefly mentioned case in an adult with congenital hypogammaglobulinaemia and echovirus infection, indicate that these patients are particularly susceptible to echoviruses. [ABSTRACT FROM AUTHOR]

Published
1978
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390. Editorial

Author

Norrby, E., Rowe, W. P., Scholtissek, C., Tyrrell, D. A. J., and Vilček, J.

Published
1975
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393. ChemInform Abstract: Nucleic Acid Related Compounds. Part 114. Synthesis of 2,6‐(Disubstituted)purine 2′,3′‐Dideoxynucleosides [cf. (V)] and Selected Cytotoxic, Anti‐Hepatitis B, and Adenosine Deaminase Substrate Activities.

Author

Robins, Morris J., primary, Wilson, John S., additional, Madej, Danuta, additional, Tyrrell, D. Lorne J., additional, Gati, Wendy P., additional, Lindmark, R. J., additional, and Wnuk, Stanislaw F., additional

Published
2002
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