David J. Beech
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View article: Ex Vivo Human Liver Hyperperfusion Model: Study Protocol to Understand the Pathophysiology and Identify Strategies for Reduction of Small-for-Size Syndrome
Ex Vivo Human Liver Hyperperfusion Model: Study Protocol to Understand the Pathophysiology and Identify Strategies for Reduction of Small-for-Size Syndrome Open
Introduction Liver has the unique ability to regenerate following surgical resection or partial liver transplantation. This underpins the surgical practice of cancer surgery and Living donor liver transplantation. A rate limiting factor fo…
View article: Contribution of endothelial Piezo1 in mechanically induced muscle hypertrophy
Contribution of endothelial Piezo1 in mechanically induced muscle hypertrophy Open
Piezo1 proteins form nonselective cation channels with key roles in endothelial responses to mechanical forces. Here we reveal that endothelial Piezo1 regulates skeletal muscle hypertrophy following mechanical overload. Using a conditional…
View article: PIEZO Force Sensing in Vascular Biology: An Explosion of New Knowledge, Concepts and Opportunity
PIEZO Force Sensing in Vascular Biology: An Explosion of New Knowledge, Concepts and Opportunity Open
The discovery of PIEZO1 channels as robust, rapidly activating, electrically transducing mechanical force sensors of endothelial biology led to intense research efforts that have transformed the appreciation and understanding of pivotal re…
View article: NAADP-mediated calcium release promotes angiopoietin 2 secretion by regulating Rab46-dependent Weibel-Palade body trafficking
NAADP-mediated calcium release promotes angiopoietin 2 secretion by regulating Rab46-dependent Weibel-Palade body trafficking Open
Angiopoietin2 (Ang2), a regulator of angiogenesis, is stored with other pro-inflammatory and pro-thrombotic mediators, in endothelial-specific vesicles called Weibel-Palade bodies (WPBs). Acute stimulation of endothelial cells with histami…
View article: PIEZO Force Sensors and the Heart
PIEZO Force Sensors and the Heart Open
The PIEZO1 and PIEZO2 membrane proteins form uniquely structured calcium permeable nonselective cation channels dedicated to mechanical force sensing in eukaryotic cells. In this review of the scientific literature, we address PIEZOs in th…
View article: PIEZO1 mechanical insensitivity in generalized lymphatic dysplasia with the potential for pharmacological rescue
PIEZO1 mechanical insensitivity in generalized lymphatic dysplasia with the potential for pharmacological rescue Open
PIEZO1 variants have been associated with generalized lymphatic dysplasia (GLD) through mechanisms involving reduced PIEZO1 expression. Here, we report variants where the mechanism involves reduced channel mechanical sensitivity. Two of th…
View article: (-)-Englerin A binds a conserved lipid site of TRPC5 and exposes a Met-aromatic motif in channel activation
(-)-Englerin A binds a conserved lipid site of TRPC5 and exposes a Met-aromatic motif in channel activation Open
TRPC4/5 cation channels are polymodal cellular sensors that play key roles in signal transduction/integration and have been implicated in various human pathologies, including anxiety, pain and cardiometabolic disease 1–3 . The plant natura…
View article: <i>PIEZO1</i> variant implications for biological understanding and human health
<i>PIEZO1</i> variant implications for biological understanding and human health Open
The large membrane protein PIEZO1 assembles as trimers to form exceptional mechanical force-sensing ion channels of eukaryotes. When these channels are activated by force, cell membrane permeability to calcium ions and other ions increases…
View article: Regulation of PIEZO1 channel force sensitivity by interblade handshaking
Regulation of PIEZO1 channel force sensitivity by interblade handshaking Open
PIEZOs form trimeric calcium-permeable nonselective cationic channels that serve mechanical sensing needs across eukaryotic biology. Forces act on the channels by causing their curved blades to flatten and decompact, leading to an activate…
View article: Endothelial insulin-like growth factor-1 signalling regulates vascular barrier function and atherogenesis
Endothelial insulin-like growth factor-1 signalling regulates vascular barrier function and atherogenesis Open
Aims Progressive deposition of cholesterol in the arterial wall characterizes atherosclerosis, which underpins most cases of myocardial infarction and stroke. Insulin-like growth factor-1 (IGF-1) is a hormone that regulates systemic growth…
View article: Two-pore channel protein 2-mediated calcium release promotes angiopoietin 2 secretion by regulating Rab46-dependent Weibel-Palade body trafficking
Two-pore channel protein 2-mediated calcium release promotes angiopoietin 2 secretion by regulating Rab46-dependent Weibel-Palade body trafficking Open
Angiopoietin2 (Ang2), a regulator of angiogenesis, is stored with other pro-inflammatory and pro-thrombotic mediators, in endothelial-specific vesicles called Weibel-Palade bodies (WPBs). The WPB secretagogue, histamine, delays Ang2 secret…
View article: Small molecule modulation of insulin receptor-insulin like growth factor-1 receptor heterodimers in human endothelial cells
Small molecule modulation of insulin receptor-insulin like growth factor-1 receptor heterodimers in human endothelial cells Open
We identified a small molecule that decreases the formation of IR: IGF-1R hybrid receptors in human endothelial cells, without significant impact on the overall expression of IR or IGF-1R. In HUVECs, reduction of IR: IGF-1R hybrid receptor…
View article: Pharmacology of PIEZO1 channels
Pharmacology of PIEZO1 channels Open
PIEZO1 is a eukaryotic membrane protein that assembles as trimers to form calcium‐permeable, non‐selective cation channels with exquisite capabilities for mechanical force sensing and transduction of force into effect in diverse cell types…
View article: Myocardial remodelling in bicuspid aortic valve associated severe aortic stenosis and reverse remodelling after aortic valve replacement
Myocardial remodelling in bicuspid aortic valve associated severe aortic stenosis and reverse remodelling after aortic valve replacement Open
Background Bicuspid aortic valve (BAV) is a common congenital heart disease and a major risk factor for aortic stenosis (AS). Myocardial remodelling response to AS plays an important prognostic role1. Cardiovascular magnetic resonance (CMR…
View article: Endothelial force sensing signals to parenchymal cells to regulate bile and plasma lipids
Endothelial force sensing signals to parenchymal cells to regulate bile and plasma lipids Open
How cardiovascular activity interacts with lipid homeostasis is incompletely understood. We postulated a role for blood flow acting at endothelium in lipid regulatory organs. Transcriptome analysis was performed on livers from mice enginee…
View article: Thomas (Tom) B. Bolton – a major force in smooth muscle research
Thomas (Tom) B. Bolton – a major force in smooth muscle research Open
International audience
View article: 9 Myocardial remodelling patterns in severe aortic stenosis with bicuspid and tricuspid valve disease, and reverse remodelling after aortic valve replacement
9 Myocardial remodelling patterns in severe aortic stenosis with bicuspid and tricuspid valve disease, and reverse remodelling after aortic valve replacement Open
Background Bicuspid aortic valve (BAV) is a common congenital heart disease and a major risk factor for aortic stenosis (AS). Myocardial remodelling response to AS plays an important prognostic role1. Cardiovascular magnetic resonance (CMR…
View article: A rare ORAI1 missense variant associates with risk of vascular diseases in White British adults
A rare ORAI1 missense variant associates with risk of vascular diseases in White British adults Open
Background Pathological remodelling of native vascular smooth muscle cells (VSMC) within the arterial wall is a key contributor to vascular disease. A driver of this remodelling is platelet-derived growth factor BB (PDGF-BB) and its signal…
View article: Small molecule modulation of insulin receptor-insulin like growth factor-1 receptor heterodimers in human endothelial cells
Small molecule modulation of insulin receptor-insulin like growth factor-1 receptor heterodimers in human endothelial cells Open
Objectives The insulin receptor (IR) and insulin like growth factor-1 receptor (IGF-1R) are heterodimers consisting of two extracellular α-subunits and two transmembrane β -subunits. Insulin αβ and insulin like growth factor-1 αβ hemi-rece…
View article: Side-by-side comparison of published small molecule inhibitors against thapsigargin-induced store-operated Ca2+ entry in HEK293 cells
Side-by-side comparison of published small molecule inhibitors against thapsigargin-induced store-operated Ca2+ entry in HEK293 cells Open
Calcium (Ca 2+ ) is a key second messenger in eukaryotes, with store-operated Ca 2+ entry (SOCE) being the main source of Ca 2+ influx into non-excitable cells. ORAI1 is a highly Ca 2+ -selective plasma membrane channel that encodes SOCE. …
View article: Pico145 inhibits TRPC4-mediated mICAT and postprandial small intestinal motility
Pico145 inhibits TRPC4-mediated mICAT and postprandial small intestinal motility Open
In intestinal smooth muscle cells, receptor-operated TRPC4 are responsible for the majority of muscarinic receptor cation current (mICAT), which initiates cholinergic excitation-contraction coupling. Our aim was to examine the effects of t…
View article: A high-throughput electrophysiology assay to study the response of PIEZO1 to mechanical stimulation
A high-throughput electrophysiology assay to study the response of PIEZO1 to mechanical stimulation Open
PIEZO1 channels are mechanically activated cation channels that play a pivotal role in sensing mechanical forces in various cell types. Their dysfunction has been associated with numerous pathophysiological states, including generalized ly…
View article: Association Between Type 2 Diabetes and Changes in Myocardial Structure, Contractile Function, Energetics, and Blood Flow Before and After Aortic Valve Replacement in Patients With Severe Aortic Stenosis
Association Between Type 2 Diabetes and Changes in Myocardial Structure, Contractile Function, Energetics, and Blood Flow Before and After Aortic Valve Replacement in Patients With Severe Aortic Stenosis Open
BACKGROUND: Type 2 diabetes (T2D) is associated with an increased risk of left ventricular dysfunction after aortic valve replacement (AVR) in patients with severe aortic stenosis (AS). Persistent impairments in myocardial energetics and m…