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Full-Text Articles in Medicine and Health Sciences
Structural Insights Into The Disruption Of Tnf-Tnfr1 Signalling By Small Molecules Stabilising A Distorted Tnf, David Mcmillan, Carlos Martinez-Fleites, John Porter, David Fox, Rachel E. Davis, Prashant Mori, Tom Ceska, Bruce Carrington, Alastair Lawson, Tim Bourne, James O'Connell
Structural Insights Into The Disruption Of Tnf-Tnfr1 Signalling By Small Molecules Stabilising A Distorted Tnf, David Mcmillan, Carlos Martinez-Fleites, John Porter, David Fox, Rachel E. Davis, Prashant Mori, Tom Ceska, Bruce Carrington, Alastair Lawson, Tim Bourne, James O'Connell
Faculty Publications
Tumour necrosis factor (TNF) is a trimeric protein which signals through two membrane receptors, TNFR1 and TNFR2. Previously, we identified small molecules that inhibit human TNF by stabilising a distorted trimer and reduce the number of receptors bound to TNF from three to two. Here we present a biochemical and structural characterisation of the small molecule-stabilised TNF-TNFR1 complex, providing insights into how a distorted TNF trimer can alter signalling function. We demonstrate that the inhibitors reduce the binding affinity of TNF to the third TNFR1 molecule. In support of this, we show by X-ray crystallography that the inhibitor-bound, distorted, TNF …
Megf10 Deficiency Impairs Skeletal Muscle Stem Cell Migration And Muscle Regeneration, Chengcheng Li, Dorianmarie Vargas-Franco, Madhurima Saha, Rachel M. Davis, Kelsey A. Manko, Isabelle Draper, Christina A. Pacak, Peter B. Kang
Megf10 Deficiency Impairs Skeletal Muscle Stem Cell Migration And Muscle Regeneration, Chengcheng Li, Dorianmarie Vargas-Franco, Madhurima Saha, Rachel M. Davis, Kelsey A. Manko, Isabelle Draper, Christina A. Pacak, Peter B. Kang
Faculty Publications
Biallelic loss-of-function MEGF10 mutations lead to MEGF10 myopathy, also known as early onset myopathy with areflexia, respiratory distress, and dysphagia (EMARDD). MEGF10 is expressed in muscle satellite cells, but the contribution of satellite cell dysfunction to MEGF10 myopathy is unclear. Myofibers and satellite cells were isolated and examined from Megf10 and wild-type mice. A separate set of mice underwent repeated intramuscular barium chloride injections. Megf10 muscle satellite cells showed reduced proliferation and migration, while Megf10 mouse skeletal muscles showed impaired regeneration. Megf10 deficiency is associated with impaired muscle regeneration, due in part to defects in satellite cell function. Efforts to …
Small Molecules That Inhibit Tnf Signalling By Stabilising An Asymmetric Form Of The Trimer, James O'Connell, John Porter, Boris Kroeplien, Tim Norman, Stephen Rapecki, Rachel E. Davis, David Mcmillan, Tracy Arakaki, Alex Burgin, David Fox Iii, Tom Ceska, Fabien Lecomte, Alison Maloney, Alex Vugler, Bruce Carrington, Benjamin P. Cossins, Tim Bourne, Alastair Lawson
Small Molecules That Inhibit Tnf Signalling By Stabilising An Asymmetric Form Of The Trimer, James O'Connell, John Porter, Boris Kroeplien, Tim Norman, Stephen Rapecki, Rachel E. Davis, David Mcmillan, Tracy Arakaki, Alex Burgin, David Fox Iii, Tom Ceska, Fabien Lecomte, Alison Maloney, Alex Vugler, Bruce Carrington, Benjamin P. Cossins, Tim Bourne, Alastair Lawson
Faculty Publications
Tumour necrosis factor (TNF) is a cytokine belonging to a family of trimeric proteins; it has been shown to be a key mediator in autoimmune diseases such as rheumatoid arthritis and Crohn's disease. While TNF is the target of several successful biologic drugs, attempts to design small molecule therapies directed to this cytokine have not led to approved products. Here we report the discovery of potent small molecule inhibitors of TNF that stabilise an asymmetrical form of the soluble TNF trimer, compromising signalling and inhibiting the functions of TNF in vitro and in vivo. This discovery paves the way for …
Virus-Specific Memory T Cells Populate Tumors And Can Be Repurposed For Tumor Immunotherapy, Pamela C. Rosato, Sathi Wijeyesinghe, J Michael Stolley, Christine E. Nelson, Rachel Davis, Luke S. Manlove, Christopher A. Pennell, Bruce R. Blazar, Clark C. Chen, Melissa A. Geller, Vaiva Vezys, David Masopust
Virus-Specific Memory T Cells Populate Tumors And Can Be Repurposed For Tumor Immunotherapy, Pamela C. Rosato, Sathi Wijeyesinghe, J Michael Stolley, Christine E. Nelson, Rachel Davis, Luke S. Manlove, Christopher A. Pennell, Bruce R. Blazar, Clark C. Chen, Melissa A. Geller, Vaiva Vezys, David Masopust
Faculty Publications
The immunosuppressive tumor microenvironment limits the success of current immunotherapies. The host retains memory T cells specific for previous infections throughout the entire body that are capable of executing potent and immediate immunostimulatory functions. Here we show that virus-specific memory T cells extend their surveillance to mouse and human tumors. Reactivating these antiviral T cells can arrest growth of checkpoint blockade-resistant and poorly immunogenic tumors in mice after injecting adjuvant-free non-replicating viral peptides into tumors. Peptide mimics a viral reinfection event to memory CD8+ T cells, triggering antigen presentation and cytotoxic pathways within the tumor, activating dendritic cells and natural …
A Requirement For Slc15a4 In Imiquimod-Induced Systemic Inflammation And Psoriasiform Inflammation In Mice, Alexis D. Griffith, Asifa K. Zaidi, Ashley Pietro, Matthew Hadiono, Jessica S. Yang, Rachel Davis, Daniel L. Popkin
A Requirement For Slc15a4 In Imiquimod-Induced Systemic Inflammation And Psoriasiform Inflammation In Mice, Alexis D. Griffith, Asifa K. Zaidi, Ashley Pietro, Matthew Hadiono, Jessica S. Yang, Rachel Davis, Daniel L. Popkin
Faculty Publications
There is competing evidence that plasmacytoid dendritic cells (pDC), the most potent source of IFN-I, may initiate psoriasis. We targeted pDC function using the slc15a4 loss-of-function mouse whose pDC are unresponsive to TLR agonists. slc15a4 treated with the topical TLR7-agonist imiquimod (IMQ) demonstrated decreased epidermal thickening 24 hours post-treatment which was more pronounced by day 5 as compared to wildtype mice. These findings were specific to the acute IMQ model and not the protracted IL23 model that drives inflammation downstream of TLR activation. Systemically, slc15a4 was required for IMQ-induced weight loss and cutaneous accumulation of CD4+ and Siglec H+, but …
Clinically Relevant Behavioral Endpoints In A Recurrent Nitroglycerin Migraine Model In Rats, Kenneth J. Sufka, Stephanie M. Staszko, Ainslee P. Johnson, Morgan E. Davis, Rachel E. Davis, Todd A. Smitherman
Clinically Relevant Behavioral Endpoints In A Recurrent Nitroglycerin Migraine Model In Rats, Kenneth J. Sufka, Stephanie M. Staszko, Ainslee P. Johnson, Morgan E. Davis, Rachel E. Davis, Todd A. Smitherman
Faculty Publications
BACKGROUND: This research sought to further validate the rat nitroglycerin (NTG) migraine model by comparing the effects of single versus recurrent NTG episodes on behavioral endpoints that mirror ICHD-3 diagnostic criteria for migraine, and to determine if the altered behavioral endpoints are reduced after administration of sumatriptan. METHODS: Separate cohorts of rats were administered NTG (10 mg/kg/2 ml) or saline (Experiment 1: single injection; Experiment 2: repeated injections; Experiment 3: repeated injections with sumatriptan [0.0, 0.3 and 1.0 mg/kg/ml] rescue. Behavioral endpoints were assessed 2 h after final NTG administration and included time in light/dark chambers for photophobia and activity, …
Pharmacokinetics Of Once-Daily Amikacin In Healthy Foals And Therapeutic Drug Monitoring In Hospitalized Equine Neonates, Erica Paige Bucki, Steeve Giguère, Margo Macpherson, Rachel E. Davis
Pharmacokinetics Of Once-Daily Amikacin In Healthy Foals And Therapeutic Drug Monitoring In Hospitalized Equine Neonates, Erica Paige Bucki, Steeve Giguère, Margo Macpherson, Rachel E. Davis
Faculty Publications
The objectives of this study were to investigate the pharmacokinetics of once-daily amikacin in healthy neonates, to determine amikacin concentrations in hospitalized foals, and to determine the minimum inhibitory concentrations (MICs) of amikacin against gram-negative isolates from blood cultures in septic foals. Median half-life, clearance, and volume of distribution of amikacin in healthy 2- to 3-day-old foals after administration of an intravenous bolus of amikacin (25 mg/kg) were 5.07 hours (4.86-5.45 hours), 1.82 mL/min/kg (1.35-1.97 mL/min/kg), and 0.785 L/kg (0.638-0.862 L/kg), respectively. Statistically significant (P or = 3 microg/mL between the 2 groups. An initial dose at 25 mg/kg is …