Publications by authors named "A Webb"

2,024 Publications

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Untangling the pathophysiologic link between coronary microvascular dysfunction and heart failure with preserved ejection fraction.

Eur Heart J 2021 Sep 16. Epub 2021 Sep 16.

British Heart Foundation Centre of Excellence and National Institute for Health Research Biomedical Research Centre at the School of Cardiovascular Medicine and Sciences, King's College London, St. Thomas' Hospital, Westminster bridge road, London SE1 7EH, UK.

Coronary microvascular disease (CMD), characterized by impaired coronary flow reserve (CFR), is a common finding in patients with stable angina. Impaired CFR, in the absence of obstructive coronary artery disease, is also present in up to 75% of patients with heart failure with preserved ejection fraction (HFpEF). Heart failure with preserved ejection fraction is a heterogeneous syndrome comprising distinct endotypes and it has been hypothesized that CMD lies at the centre of the pathogenesis of one such entity: the CMD-HFpEF endotype. This article provides a contemporary review of the pathophysiology underlying CMD, with a focus on the mechanistic link between CMD and HFpEF. We discuss the central role played by subendocardial ischaemia and impaired lusitropy in the development of CMD-HFpEF, as well as the clinical and research implications of the CMD-HFpEF mechanistic link. Future prospective follow-up studies detailing outcomes in patients with CMD and HFpEF are much needed to enhance our understanding of the pathological processes driving these conditions, which may lead to the development of physiology-stratified therapy to improve the quality of life and prognosis in these patients.
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http://dx.doi.org/10.1093/eurheartj/ehab653DOI Listing
September 2021

Dynamic reconfiguration of pro-apoptotic BAK on membranes.

EMBO J 2021 Sep 15:e107237. Epub 2021 Sep 15.

The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic., Australia.

BAK and BAX, the effectors of intrinsic apoptosis, each undergo major reconfiguration to an activated conformer that self-associates to damage mitochondria and cause cell death. However, the dynamic structural mechanisms of this reconfiguration in the presence of a membrane have yet to be fully elucidated. To explore the metamorphosis of membrane-bound BAK, we employed hydrogen-deuterium exchange mass spectrometry (HDX-MS). The HDX-MS profile of BAK on liposomes comprising mitochondrial lipids was consistent with known solution structures of inactive BAK. Following activation, HDX-MS resolved major reconfigurations in BAK. Mutagenesis guided by our HDX-MS profiling revealed that the BCL-2 homology (BH) 4 domain maintains the inactive conformation of BAK, and disrupting this domain is sufficient for constitutive BAK activation. Moreover, the entire N-terminal region preceding the BAK oligomerisation domains became disordered post-activation and remained disordered in the activated oligomer. Removal of the disordered N-terminus did not impair, but rather slightly potentiated, BAK-mediated membrane permeabilisation of liposomes and mitochondria. Together, our HDX-MS analyses reveal new insights into the dynamic nature of BAK activation on a membrane, which may provide new opportunities for therapeutic targeting.
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http://dx.doi.org/10.15252/embj.2020107237DOI Listing
September 2021

In vivo T and T relaxation time maps of brain tissue, skeletal muscle, and lipid measured in healthy volunteers at 50 mT.

Magn Reson Med 2021 Sep 14. Epub 2021 Sep 14.

Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands.

Purpose: Low-field (B < 0.1 T) MRI has generated much interest as a means of increased accessibility via reduced cost and improved portability compared to conventional clinical systems (B ≥ 1.5 Tesla). Here we measure MR relaxation times at 50 mT and compare results with commonly used models based on both in vivo and ex vivo measurements.

Methods: Using 3D turbo spin echo readouts, T and T maps of the human brain and lower leg were acquired on a custom-built 50 mT MRI scanner using inversion-recovery and multi-echo-based sequences, respectively. Image segmentation was performed based on a histogram analysis of the relaxation times.

Results: The average T times of gray matter, white matter, and cerebrospinal fluid (CSF) were 327 ± 10 ms, 275 ± 5 ms, and 3695 ± 287 ms, respectively. Corresponding values of T were 102 ± 6 ms, 102 ± 6 ms, and 1584 ± 124 ms. T times in the calf muscle were measured to be 171 ± 11 ms and were 130 ± 5 ms in subcutaneous and bone marrow lipid. Corresponding T times were 39 ± 2 ms in muscle and 90 ± 13 ms in lipid.

Conclusions: For tissues except for CSF, the measured T times are much shorter than reported at higher fields and generally lie within the range of different models in the literature. As expected, T times are similar to those seen at typical clinical field strengths. Analysis of the relaxation maps indicates that segmentation of white and gray matter based purely on T or T will be quite challenging at low field given the relatively small difference in relaxation times.
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http://dx.doi.org/10.1002/mrm.29009DOI Listing
September 2021

Dose-response for change in 25-hydroxyvitamin D after UV exposure: outcome of a systematic review.

Endocr Connect 2021 Sep 1. Epub 2021 Sep 1.

L Rhodes, Centre for Dermatology Research, School of Biological Sciences, The University of Manchester, Manchester, United Kingdom of Great Britain and Northern Ireland.

A systematic review of publications addressing change in vitamin D status (25-hydroxyvitamin D; 25OHD) after exposure to ultraviolet (UV) radiation identified 2001 independent peer-reviewed publications. Of these, 21 used artificial sources of UV radiation, met all inclusion criteria and were quality assured; 13 publications used solar radiation and met sufficient inclusion criteria to be retained as supporting evidence; one further included publication used both solar and artificial sources. The review consistently identified that low dose, sub-erythemal doses are more effective for vitamin D synthesis than doses close to a minimum erythema dose; increasing skin area exposed increases the amount of vitamin D synthesised although not necessarily in a linear manner; constant dosing leads to a dose-dependent plateau in 25OHD, and dose-response is greatest at the start of a dosing regime; there is a large interpersonal variation in response to UV exposure. Fourteen of the studies using artificial sources of radiation were used to determine a dose-response relationship for change in 25OHD on whole-body exposure to repeated sub-erythemal doses of UV radiation, taking the form Δ25OHD (nmol/L) = A ln(SDD) + B. This helps quantify our understanding of UV as a source of vitamin D and enables exposure regimes for safe synthesis of vitamin D to be assessed. Specific studies of people with pigmented skin (Fitzpatrick skin types 5 and 6) were rare and this dose-response is only applicable to white-skinned individuals as skin type is a determinant of response to UV radiation. Findings provide information for vitamin D guidance updates.
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http://dx.doi.org/10.1530/EC-21-0308DOI Listing
September 2021

Big cohort studies offer insights into preventable risk factors.

Eur Heart J 2021 Sep 4. Epub 2021 Sep 4.

Wolfson Centre for Prevention of Stroke and Dementia, Nuffield Department of Clinical Neurosciences, University of Oxford, Wolfson Building, John Radcliffe Hospital, Oxford OX3 9DU, UK.

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http://dx.doi.org/10.1093/eurheartj/ehab566DOI Listing
September 2021
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