Dominic Burg

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Address: Southampton, Southampton, United Kingdom

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Data from Activation of Thermogenesis in Brown Adipose Tissue and Dysregulated Lipid Metabolism Associated with Cancer Cachexia in Mice

Speaker Abstracts

Drug Metabolism Reviews, Nov 1, 2011

SC2. Examples and challenges in the translation of in-vitro to in-vivo results for therapeutic pr... more

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A chemically modified α-amylase with a molten-globule state has entropically driven enhanced thermal stability†

Protein Engineering Design & Selection, Aug 9, 2010

The thermostability properties of TAA were investigated by chemically modifying carboxyl groups o... more The thermostability properties of TAA were investigated by chemically modifying carboxyl groups on the surface of the enzyme with AMEs. The TAA MOD exhibited a 200% improvement in starch-hydrolyzing productivity at 608 8 8 8 8C. By studying the kinetic, thermodynamic and biophysical properties, we found that TAA MOD had formed a thermostable, MG state, in which the unfolding of the tertiary structure preceded that of the secondary structure by at least 208 8 8 8 8C. The X-ray crystal structure of TAA MOD revealed no new permanent interactions (electrostatic or other) resulting from the modification. By deriving thermodynamic activation parameters of TAA MOD , we rationalised that thermostabilisation have been caused by a decrease in the entropy of the transition state, rather than being enthalpically driven. Far-UV CD shows that the origin of decreased entropy may have arisen from a higher helical content of TAA MOD. This study provides new insight into the intriguing properties of an MG state resulting from the chemical modification of TAA.

format_quoteTAA MOD exhibited a 28-fold higher thermal inactivation half-life compared to TAA UM at 50°C, indicating significant improvements in stability.format_quote

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Supplementary Figure Legends 1-3 from Activation of Thermogenesis in Brown Adipose Tissue and Dysregulated Lipid Metabolism Associated with Cancer Cachexia in Mice

PDF file - 72K

Supplementary Figure 2 from Activation of Thermogenesis in Brown Adipose Tissue and Dysregulated Lipid Metabolism Associated with Cancer Cachexia in Mice

PDF file - 229K, Expression of nuclear transcription factor genes and target genes involved in li... more

Supplementary Figure Legends 1-3 from Activation of Thermogenesis in Brown Adipose Tissue and Dysregulated Lipid Metabolism Associated with Cancer Cachexia in Mice

PDF file - 72K

Supplementary Figure 2 from Activation of Thermogenesis in Brown Adipose Tissue and Dysregulated Lipid Metabolism Associated with Cancer Cachexia in Mice

PDF file - 229K, Expression of nuclear transcription factor genes and target genes involved in li... more

Supplementary Figure 1 from Activation of Thermogenesis in Brown Adipose Tissue and Dysregulated Lipid Metabolism Associated with Cancer Cachexia in Mice

PDF file - 175K, Effects of tumor C26 inoculation and food restriction on energy expenditure of mice

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Supplementary Figure 3 from Activation of Thermogenesis in Brown Adipose Tissue and Dysregulated Lipid Metabolism Associated with Cancer Cachexia in Mice

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Thermal

A chemically modified a-amylase with a molten-

Medication Adherence in Patients With Severe Asthma Prescribed Oral Corticosteroids in the U-BIOPRED Cohort

Chest, 2021

BACKGROUND Whilst estimates of sub-optimal adherence to oral corticosteroids in asthma range from... more BACKGROUND Whilst estimates of sub-optimal adherence to oral corticosteroids in asthma range from 30 to 50%, no ideal method for measurement exists; the impact of poor adherence in severe asthma is likely to be particularly high. RESEARCH QUESTIONS 1. What is the prevalence of suboptimal adherence detected using self-reporting and direct measures? 2. Is suboptimal adherence associated with disease activity? STUDY DESIGN AND METHODS Data were included from individuals with severe asthma taking part in the U-BIOPRED study prescribed daily oral corticosteroids. Participants completed the MARS, a five-item questionnaire used to grade adherence on a scale from 1 to 5, and provided a urine sample for analysis of prednisolone and metabolites by liquid-chromatography mass spectrometry. RESULTS Data from 166 participants were included in this study, mean (SD) age 54.2 (11.9) years, FEV1 65.1 (20.5) % predicted, 58% female. 37% completing the MARS reported sub-optimal adherence, and 43% with urinary corticosteroid data did not have detectable prednisolone or metabolites in their urine. Good adherence by both methods was detected in 35% participants who had both performed; adherence detection did not match between methods in 53%. Self-reported high-adherers had better asthma control and quality of life, whereas directly-measured high-adherers had lower blood eosinophils. INTERPRETATION Low adherence is a common problem in severe asthma, whether measured directly or self-reported. We report poor agreement between the two methods suggesting some disassociation between self-assessment of medication adherence and regular oral corticosteroid use, which suggests that each approach may provide complementary information in clinical practice.

Midkine and chronic kidney disease-associated multisystem organ dysfunctions

Nephrology Dialysis Transplantation, 2020

Chronic kidney disease (CKD) is a progressive multisystem condition with yet undefined mechanisti... more Chronic kidney disease (CKD) is a progressive multisystem condition with yet undefined mechanistic drivers and multiple implicated soluble factors. If identified, these factors could be targeted for therapeutic intervention for a disease that currently lacks specific treatment. There is increasing preclinical evidence that the heparin/endothelial glycocalyx-binding molecule midkine (MK) has a pathological role in multiple CKD-related, organ-specific disease processes, including CKD progression, hypertension, vascular and cardiac disease, bone disease and CKD-related cancers. Concurrent with this are studies documenting increases in circulating and urine MK proportional to glomerular filtration rate (GFR) loss in CKD patients and evidence that administering soluble MK reverses the protective effects of MK deficiency in experimental kidney disease. This review summarizes the growing body of evidence supporting MK’s potential role in driving CKD-related multisystem disease, including M...

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Respiratory Medicine, 2020

Background: Asthma prevalence is 339 million globally. 'Severe asthma' (SA) comprises subjects wi... more Background: Asthma prevalence is 339 million globally. 'Severe asthma' (SA) comprises subjects with uncontrolled asthma despite proper management. Objectives: To compare asthma from diverse ethnicities and environments. Methods: A cross-sectional analysis of two adult cohorts, a Brazilian (ProAR) and a European (U-BIOPRED). U-BIOPRED comprised of 311 non-smoking with Severe Asthma (SAn), 110 smokers or ex-smokers with SA (SAs) and 88 mild to moderate asthmatics (MMA) while ProAR included 544 SA and 452 MMA. Although these projects were independent, there were similarities in objectives and methodology, with ProAR adopting operating procedures of U-BIOPRED. Results: Among SA subjects, age, weight, proportion of former smokers and FEV 1 pre-bronchodilator were similar. The proportion of SA with a positive skin prick tests (SPT) to aeroallergens, the scores of sino-nasal symptoms and quality of life were comparable. In addition, blood eosinophil counts (EOS) and the % of subjects with EOS > 300 cells/μl were not different. The Europeans with SA however, were more severe with a greater proportion of continuous oral corticosteroids (OCS), worse symptoms and more frequent exacerbations. FEV 1 /FVC pre-and post-bronchodilator were lower among the Europeans. The MMA cohorts were less comparable in control and treatment, but similar in the proportion of allergic rhinitis, gastroesophageal reflux disease and EOS >3%. Conclusions: ProAR and U-BIOPRED cohorts, with varying severity, ethnicity and environment have similarities, which provide the basis for global external validation of asthma phenotypes. This should stimulate collaboration between asthma consortia with the aim of understanding SA, which will lead to better management.

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IL-17–high asthma with features of a psoriasis immunophenotype

Journal of Allergy and Clinical Immunology, 2019

IL-17 High Clinical phenotype Nasal polyps Smoking Antibiotic use Epithelial Gene Expression Prof... more IL-17 High Clinical phenotype Nasal polyps Smoking Antibiotic use Epithelial Gene Expression Profile Clinical phenotype FeNO Exacerbations Gene expression shared with psoriasis IDO1 IL1B DEFB4B S100A8, S100A9 PI3 CXCL3, CXCL8 CXCL10, CCL20 Gene signature SERPINB2 POSTN CLCA1 IL-13 High T cell infiltration Neutrophilia Eosinophilia IL-17-high asthma with features of a psoriasis immunophenotype

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Stratification of asthma phenotypes by airway proteomic signatures

Journal of Allergy and Clinical Immunology, 2019

Background: Stratification by eosinophil and neutrophil counts increases our understanding of ast... more Background: Stratification by eosinophil and neutrophil counts increases our understanding of asthma and helps target therapy, but there is room for improvement in our accuracy in prediction of treatment responses and a need for better understanding of the underlying mechanisms. Objective: We sought to identify molecular subphenotypes of asthma defined by proteomic signatures for improved stratification. Methods: Unbiased label-free quantitative mass spectrometry and topological data analysis were used to analyze the proteomes of sputum supernatants from 246 participants (206 asthmatic patients) as a novel means of asthma stratification. Microarray analysis of sputum cells provided transcriptomics data additionally to inform on underlying mechanisms. Results: Analysis of the sputum proteome resulted in 10 clusters (ie, proteotypes) based on similarity in proteomic features, representing discrete molecular subphenotypes of asthma. Overlaying granulocyte counts onto the 10 clusters as metadata further defined 3 of these as highly eosinophilic, 3 as highly neutrophilic, and 2 as highly atopic with relatively low granulocytic inflammation. For each of these 3 phenotypes, logistic regression analysis identified candidate protein biomarkers, and matched transcriptomic data pointed to differentially activated underlying mechanisms.

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Sputum proteomic signature of gastro-oesophageal reflux in patients with severe asthma

Respiratory Medicine, 2019

Gastro-oesophageal reflux disease (GORD) has long been associated with poor asthma control withou... more Gastro-oesophageal reflux disease (GORD) has long been associated with poor asthma control without an established cause-effect relationship. 610 asthmatics (421 severe/88 mild-moderate) and 101 healthy controls were assessed clinically and a subset of 154 severe asthmatics underwent proteomic analysis of induced sputum using untargeted mass spectrometry, LC-IMS-MS E. Univariate and multiple logistic regression analyses (MLR) were conducted to identify proteins associated with GORD in this cohort. When compared to mild/moderate asthmatics and healthy individuals, respectively, GORD was three-and tenfold more prevalent in severe asthmatics and was associated with increased asthma symptoms and oral corticosteroid use, poorer quality of life, depression/anxiety, obesity and symptoms of sino-nasal disease. Comparison of sputum proteomes in severe asthmatics with and without active GORD showed five differentially abundant proteins with described roles in antimicrobial defences, systemic inflammation and epithelial integrity. Three of these were associated with active GORD by multiple linear regression analysis: Ig lambda variable 1-47 (p=0•017) and plasma protease C1 inhibitor (p=0•043), both in lower concentrations, and lipocalin-1 (p=0•034) in higher concentrations in active GORD. This study provides evidence which suggests that reflux can cause subtle perturbation of proteins detectable in the airways lining fluid and that severe asthmatics with GORD may represent a distinct phenotype of asthma.

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Large-Scale Label-Free Quantitative Mapping of the Sputum Proteome

Journal of proteome research, 2018

Analysis of induced sputum supernatant is a minimally invasive approach to study the epithelial l... more Analysis of induced sputum supernatant is a minimally invasive approach to study the epithelial lining fluid and, thereby, provide insight into normal lung biology and the pathobiology of lung diseases. We present here a novel proteomics approach to sputum analysis developed within the U-BIOPRED (unbiased biomarkers predictive of respiratory disease outcomes) international project. We present practical and analytical techniques to optimize the detection of robust biomarkers in proteomic studies. The normal sputum proteome was derived using data-independent HDMS applied to 40 healthy nonsmoking participants, which provides an essential baseline from which to compare modulation of protein expression in respiratory diseases. The "core" sputum proteome (proteins detected in ≥40% of participants) was composed of 284 proteins, and the extended proteome (proteins detected in ≥3 participants) contained 1666 proteins. Quality control procedures were developed to optimize the accura...

format_quoteAtopic individuals showed higher serum IgE and LDH levels, revealing unexpected associations in allergy-related biomarkers (p<0.001).format_quote

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Urine and serum midkine levels in an Australian chronic kidney disease clinic population: an observational study

BMJ open, Jan 27, 2017

The cytokine midkine (MK) is pathologically implicated in progressive chronic kidney disease (CKD... more The cytokine midkine (MK) is pathologically implicated in progressive chronic kidney disease (CKD) and its systemic consequences and has potential as both a biomarker and therapeutic target. To date, there are no published data on MK levels in patients with different stages of CKD. This study aims to quantify MK levels in patients with CKD and to identify any correlation with CKD stage, cause, progression, comorbid disease or prescribed medication. In this observational, single-centre study, demographic data were collected, and serum and urine assayed from 197 patients with CKD and 19 healthy volunteers in an outpatient setting. The median serum and urine MK level in volunteers was 754 pg/mL (IQR: 554-1025) and 239 pg/mL (IQR: 154-568), respectively. Compared with serum MK in stage 1 CKD (660 pg/mL, IQR: 417-893), serum MK increased in stage 3 (1878 pg/mL, IQR: 1188-2756; p<0.001), 4 (2768 pg/mL, IQR: 2065-4735; p<0.001) and 5 (4816 pg/mL, IQ: 37477807; p<0.001). Urine MK l...

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Promotion of anagen, increased hair density and reduction of hair fall in a clinical setting following identification of FGF5-inhibiting compounds via a novel 2-stage process

Clinical, cosmetic and investigational dermatology, 2017

There are very few effective, scientifically validated treatments with known mechanisms of action... more There are very few effective, scientifically validated treatments with known mechanisms of action for treatment of hair loss in both men and women. Fibroblast growth factor 5 (FGF5) is an important factor in the irreversible transition from anagen to catagen, and inhibition of FGF5 prolongs anagen phase and reduces hair loss. We aimed to screen botanically derived molecules for FGF5 inhibitory activity in vitro and assess efficacy in a clinical setting. We screened for FGF5 inhibitory efficacy via a novel 2-step in vitro pipeline consisting of an engineered FGF5 responsive cell line, followed by an activated dermal papillae (DP) cell method. Efficacy in a clinical setting was assessed in a randomized, single-blind, placebo-controlled trial against early- to mid-stage pattern hair loss in men and women. We observed FGF5 inhibitory activity for a number of compounds from the monoterpenoid family, many showing greater inhibitory efficacy than our previously reported crude plant extract...

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Proteome fingerprints define groups with distinct clinico-pathological phenotypes in the U-BIOPRED asthma study

European Respiratory Journal, 2016

Background: Severe asthma is not a single disease and likely consists of several subtypes (phenot... more Background: Severe asthma is not a single disease and likely consists of several subtypes (phenotypes) but the molecular basis for this diversity is poorly understood. Aims: The pan-European U-BIOPRED consortium utilized state of the art omics technologies to characterise the molecular biology of severe asthma sub-phenotypes as 9omic fingerprints and combined 9omic handprints by systems biology. Methods: 250 induced sputum samples from 169 severe asthmatics (49 smokers), 40 mild to moderate asthmatics and 41 healthy control participants were analysed by label-free quantitative data independent mass spectrometry. Abundance profiles of proteins between participants was analysed by topological data analysis (TDA) supported by standard statistics. Topological graphs of the proteomic data allowed us to identify groups of participants defined by their similarity in sputum proteome profiles (fingerprints); their clinico-pathological characteristics were defined and comparisons were made between groups. Results: In asthmatic participants, 10 groups were identified with distinct proteome fingerprints (proteomic phenotypes) and similarly diverse clinico-pathological phenotypes and were associated with different granulocyte counts: 4 neutrophilic, 3 eosinophilic, 2 paucigranulocytic and 1 mixed granulocytic. Machine learning further identified biomarkers predictive of each of the 10 fingerprints. Conclusions: Characterisation of the proteome fingerprints of asthma phenotypes, and the identification of phenotype-specific biomarkers represents a step towards stratified medicine and personalised treatment of asthmatics.

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