Biology subjects

Terry, R.

Publications and source records attributed to Terry, R..

6 recordsLinked to original sources

bioRxiv2025

Progression of the cardiac phenotype of the DE50-MD dog model of Duchenne Muscular Dystrophy, corroborating results of cardiac magnetic resonance imaging with pathology up to 36 months of age.

Cardiomyopathy is an expected consequence of the invariably fatal, X-linked muscle-wasting disease, Duchenne Muscular Dystrophy, (DMD) but onset and progression vary between individuals. Cardiac magnetic resonance imaging (CMR) is invaluable for identification of subclinical myocardial abnormalities, to stratify disease and to identify patients needing early therapeutic intervention. The dystrophin-deficient DE50-MD canine model harbours a mutation in the major hot spot region for mutations in DMD patients and mimics the preclinical cardiac and skeletal muscle of DMD boys. We performed serial parametric (T1, T2 and extracellular volume) mapping and late gadolinium enhancement (LGE) studies to characterise myocardial pathology in 15-to-36-month-old DE50-MD, (n=8) and wild type (WT, n=6) dogs. In 6/8 DE50-MD dogs left ventricular (LV) subepicardial LGE identified myocardial fibrofatty infiltration, (confirmed with histopathology post-mortem) with the characteristic distribution reported in DMD cardiomyopathy. Parametric mapping techniques exposed diffuse myocardial pathology that was most pronounced in DE50-MD dogs of 30 months and older and supported extracellular matrix expansion due to fibrosis, with or without regional myocardial oedema and /or fatty infiltration in individual dogs. All CMR markers of fibrosis worsened with age in DE50-MD dogs and paralleled deterioration in ventricular function evaluated with conventional and speckle tracking (circumferential strain) echocardiography, the burden of fragmented QRS complexes in 12-lead electrocardiography studies and the severity of pathological lesions. LGE and parametric mapping studies accurately identified a spectrum of myocardial abnormalities encountered in young DE50-MD dogs, further validating the relevance of these dogs as a preclinical model of DMD cardiomyopathy.

pathology↗

bioRxiv2025

The preclinical cardiac phenotype of the DE50-MD dog model of Duchenne muscular dystrophy.

Cardiomyopathy is the leading cause of death in the X-linked disorder, Duchenne Muscular Dystrophy (DMD) yet optimal management strategies remain undetermined. Advances in the search for novel DMD treatments, particularly at cell and molecular levels, rely heavily on the use of translational animal models. It is crucial that these models faithfully recapitulate the human clinical phenotype to best expedite the development of promising treatments. We sought comprehensively to describe the cardiac phenotype of DE50-MD dogs, a novel dystrophin-deficient model that harbours a mutation within the principal DMD mutational hotspot. Cardiac magnetic resonance imaging and echocardiographic studies were performed at approximately 12-week intervals in male, 3- to 18-month-old DE50-MD (n=17) and age-matched littermates, wild type (WT, n=14) dogs. Late gadolinium enhancement (LGE) imaging was performed in a subpopulation of DE50-MD (n=10) and WT (n=11) dogs aged 9 to 18 months. The DE50-MD dogs had smaller left ventricular (LV) mass and LV dimensions than WT dogs. While global ventricular systolic function was preserved, DE50-MD dogs showed early differences in strain and strain rate parameters. Only DE50-MD dogs demonstrated LGE (3/8 dogs studied at 18 months); the subepicardial to transmural, mid-to-basal LV LGE distribution resembling that of DMD patients and of other dystrophic dog models. Histopathological assessment confirmed that LGE corresponded to fibrofatty myocardial scarring, as described in DMD patients and other canine models of dystrophin-deficient cardiomyopathy. The DE50-MD early preclinical cardiac phenotype shares key features of DMD cardiomyopathy prior to onset of global LV systolic dysfunction. Their disproportionately low LV volume to mass supports possible combined physiological hypotrophy and tonic contraction in affected animals.

pathology↗

bioRxiv2022

A novel transcriptional signature identifies T-cell infiltration in high-risk paediatric cancer

Molecular profiling of the tumour immune microenvironment (TIME) has enabled the rational choice of immunotherapies in some adult cancers. In contrast, the TIME of paediatric cancers is relatively unexplored. We speculated that a more refined appreciation of the TIME in childhood cancers, rather than a reliance on commonly used biomarkers such as tumour mutation burden (TMB), neoantigen load and PD-L1 expression, is an essential prerequisite for improved immunotherapies in childhood solid cancers. We combined immunohistochemistry (IHC) and molecular profiling to develop an alternative, expression-based signature associated with CD8+ T-cell infiltration of the TIME in high-risk paediatric tumours. Using this novel 15-gene immune signature, Immune Paediatric Signature Score (IPASS), we estimate up to 31% of high-risk cancers harbour infiltrating T-cells. Our data provides new insights into the variable immune-suppressive mechanisms dampening responses in paediatric solid cancers. Effective immune-based interventions in high-risk paediatric cancer will require individualised analysis of the TIME.

cancer biology↗

bioRxiv2021

BACE1, but not BACE2, function is critical for metabolic disorders induced by high-fat diets in C57BL/6N mice

Aims/hypothesisBeta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is required for the production of toxic amyloid peptides and is highly expressed in the brain, but also to a lesser extent in major peripheral organs such as muscle and liver. In contrast, BACE2 is mainly expressed in peripheral tissues and is enriched in pancreatic beta cells, where it regulates beta- cell function and mass. Previous reports demonstrated that loss of BACE1 function decreases body weight, protects against diet-induced obesity and enhances insulin sensitivity in mice, whereas mice lacking Bace2 exhibit reduced blood glucose levels, improved intraperitoneal glucose tolerance and increased beta-cell mass. Impaired glucose homeostasis and insulin resistance are hallmarks of type 2 diabetes and have been implicated in Alzheimers disease. Therefore, we tested the contribution of the individual BACE isoforms to those metabolic phenotypes by placing Bace1 knockout (KO), Bace2 KO, Bace1/2 double knockout (dKO) and wild-type (WT) mice on a high-fat high-cholesterol diet (HFD) for 16 weeks. MethodsBace1 KO (n = 18), Bace2 KO (n = 18), Bace1/2 dKO (n = 18) and WT C57BL/6N mice (n = 54) were fed a HFD for 16 weeks (age 9-25 weeks). Body composition was measured before initiation of the HFD and after 11 weeks of HFD. Oral glucose tolerance and insulin sensitivity tests were performed after 12 and 13 weeks of HFD, respectively, and full blood chemistry was analyzed after 16 weeks of HFD. The effects of subchronic BACE1/2 inhibition were assessed by administration of 10 mg/kg/day of the dual BACE1/2 inhibitor MBi-3 in a HFD fed to C57BL/6N mice for 3 weeks. ResultsBace1 KO and Bace1/2 dKO mice showed decreased body weight and improved glucose tolerance and insulin resistance vs. WT mice. Conversely, Bace2 KO mice did not show any significant differences in body weight, glucose tolerance or insulin resistance under our experimental conditions. Finally, subchronic MBi-3-mediated BACE1/2 inhibition in mice in conjunction with a HFD resulted in a modest improvement of glucose tolerance. Conclusions/interpretationOur data indicate that lack of BACE1 - but not BACE2 - function contributes mainly to the metabolic phenotypic changes observed in Bace1/2 dKO mice, suggesting that inhibition of BACE1 has the greater role (vs. BACE2) in any potential improvements in metabolic homeostasis. HIGHLIGHTSO_LIInsulin resistance may develop in the brains of patients with Alzheimers disease (83/85 characters) C_LIO_LIBACE1 and BACE2 may play a role in glucose homeostasis and insulin sensitivity (80/85 characters) C_LIO_LIBody weight in mice decreased with Bace1 KO and Bace1/2 KO but not Bace2 KO alone (83/85 characters) C_LIO_LIBace1 and Bace1/2, but not Bace2, KO improved glucose tolerance/insulin resistance (84/85 characters) C_LIO_LIImproved metabolic homeostasis may follow loss of BACE1 rather than BACE 2 activity (85/85 characters) C_LI

physiology↗

bioRxiv2020

Development of a small molecule that corrects misfolding and increases secretion of Z α1-antitrypsin

Severe 1-antitrypsin deficiency results from the Z allele (Glu342Lys) that causes the accumulation of homopolymers of mutant 1-antitrypsin within the endoplasmic reticulum of hepatocytes in association with liver disease. We have used a DNA-encoded chemical library to undertake a high throughput screen to identify small molecules that bind to, and stabilise Z 1-antitrypsin. The lead compound blocks Z 1-antitrypsin polymerisation in vitro, reduces intracellular polymerisation and increases the secretion of Z 1-antitrypsin three-fold in mammalian cells including an iPSC model of disease. Crystallographic and biophysical analyses demonstrate that GSK716 and related molecules bind to a cryptic binding pocket, negate the local effects of the Z mutation and stabilise the bound state against progression along the polymerization pathway. Oral dosing of transgenic mice at 100 mg/kg three times a day for 20 days increased the secretion of Z 1-antitrypsin into the plasma by 7-fold. There was no observable clearance of hepatic inclusions with respect to controls. This study provides proof-of-principle that mutation ameliorating small molecules are a viable approach to treat protein conformational diseases.

pharmacology and toxicology↗

bioRxiv2020

A standardized and reproducible method to measure decision-making in mice

Progress in science requires standardized assays whose results can be readily shared, compared, and reproduced across laboratories. Reproducibility, however, has been a concern in neuroscience, particularly for measurements of mouse behavior. Here we show that a standardized task to probe decision-making in mice produces reproducible results across multiple laboratories. We designed a task for head-fixed mice that combines established assays of perceptual and value-based decision making, and we standardized training protocol and experimental hardware, software, and procedures. We trained 140 mice across seven laboratories in three countries, and we collected 5 million mouse choices into a publicly available database. Learning speed was variable across mice and laboratories, but once training was complete there were no significant differences in behavior across laboratories. Mice in different laboratories adopted similar reliance on visual stimuli, on past successes and failures, and on estimates of stimulus prior probability to guide their choices. These results reveal that a complex mouse behavior can be successfully reproduced across multiple laboratories. They establish a standard for reproducible rodent behavior, and provide an unprecedented dataset and open-access tools to study decision-making in mice. More generally, they indicate a path towards achieving reproducibility in neuroscience through collaborative open-science approaches.

neuroscience↗