A5003567567- Neurogenetic and Muscular Disorders Research
- RNA modifications and cancer
- Ion Channels and Receptors
- Erythrocyte Function and Pathophysiology
- Ion channel regulation and function
- Hepatitis C virus research
- Neurobiology and Insect Physiology Research
- Blood properties and coagulation
- Tumors and Oncological Cases
- Computational Drug Discovery Methods
- Congenital Anomalies and Fetal Surgery
- Influenza Virus Research Studies
- Protein Structure and Dynamics
- Phytochemicals and Antioxidant Activities
- RNA Research and Splicing
- Synthesis of heterocyclic compounds
- Mosquito-borne diseases and control
- Cardiovascular, Neuropeptides, and Oxidative Stress Research
- Hepatitis B Virus Studies
- Energy Harvesting in Wireless Networks
- Alzheimer's disease research and treatments
- Pancreatic function and diabetes
- Parvovirus B19 Infection Studies
- Nicotinic Acetylcholine Receptors Study
- Synthesis and Catalytic Reactions
University of Leeds
2016-2025
Institute of Structural and Molecular Biology
2015-2024
Biogen (United Kingdom)
2019-2024
Physical Sciences (United States)
2024
Universidade Federal do Rio de Janeiro
2023-2024
Fudan University
2023-2024
Kitasato University
2022
North West Regional Hospital
2021
St James's University Hospital
2015-2020
Biogen (United States)
2017-2020
Nusinersen is an antisense oligonucleotide drug that modulates pre–messenger RNA splicing of the survival motor neuron 2 (SMN2) gene. It has been developed for treatment spinal muscular atrophy (SMA).
Abstract Mammalian biology adapts to physical activity but the molecular mechanisms sensing remain enigmatic. Recent studies have revealed how Piezo1 protein senses mechanical force enable vascular development. Here, we address in adult endothelium, major control site activity. Mice without endothelial lack obvious phenotype close inspection reveals a specific effect on endothelium-dependent relaxation mesenteric resistance artery. Strikingly, is required for elevated blood pressure during...
Kidney failure is frequently observed during and after COVID-19, but it remains elusive whether this a direct effect of the virus. Here, we report that SARS-CoV-2 directly infects kidney cells associated with increased tubule-interstitial fibrosis in patient autopsy samples. To study effects virus on independent systemic infected human-induced pluripotent stem-cell-derived organoids SARS-CoV-2. Single-cell RNA sequencing indicated injury dedifferentiation activation profibrotic signaling...
We report the results of COVID Moonshot, a fully open-science, crowdsourced, and structure-enabled drug discovery campaign targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease. discovered noncovalent, nonpeptidic inhibitor scaffold with lead-like properties that is differentiated from current protease inhibitors. Our approach leveraged crowdsourcing, machine learning, exascale molecular simulations, high-throughput structural biology chemistry. generated...
Abstract Introduction/Aims NURTURE (NCT02386553) is an open‐label study of nusinersen in children (two SMN2 copies, n = 15; three 10) who initiated treatment the presymptomatic stage spinal muscular atrophy (SMA). A prior analysis after ~3 y showed benefits on survival, respiratory outcomes, motor milestone achievement, and a favorable safety profile. An additional 2 follow‐up (data cut: February 15, 2021) are reported. Methods The primary endpoint time to death or intervention (≥6 h/day...
Orai1 and the associated calcium release-activated (CRAC) channel were discovered in immune system. Existence also endothelial cells has been suggested, but relevance to biology is mostly unknown.The aim of this study was investigate CRAC channels vascular growth factor (VEGF) tube formation.In human umbilical vein cells, disruption by short-interfering RNA or dominant-negative mutant inhibited (store-operated) entry, VEGF-evoked cell migration, vitro formation. Expression exogenous...
The mechanosensitive Piezo1 channel has important roles in vascular physiology and disease. Yoda1 is a small-molecule agonist, but the pharmacology of these channels otherwise limited.Yoda1 analogues were generated by synthetic chemistry. Intracellular Ca2+ Tl+ measurements made HEK 293 or CHO cell lines overexpressing subunits HUVECs, which natively express Piezo1. Isometric tension recordings from rings mouse thoracic aorta.Modification pyrazine ring yielded an analogue, lacked agonist...
Piezo1 is a mechanosensitive cation channel with widespread physiological importance; however, its role in the heart poorly understood. Cardiac fibroblasts help preserve myocardial integrity and play key regulating repair remodeling following stress or injury. Here we investigated expression function cultured human mouse cardiac fibroblasts. RT-PCR experiments confirmed that mRNA expressed at levels similar to those endothelial cells. The results of Fura-2 intracellular Ca2+ assay validated...
ABSTRACT High-risk human papillomavirus type 16 (HPV16) is the primary causative agent of cervical cancer and therefore responsible for significant morbidity mortality worldwide. Cellular transformation mediated directly by expression viral oncogenes, least characterized which, E5, subverts cellular proliferation immune recognition processes. Despite a growing catalogue E5-specific host interactions, little understood regarding molecular basis its function. Here we describe novel function...
Treatment with nusinersen has demonstrated significant and clinically meaningful benefits in clinical trials infants children spinal muscular atrophy (SMA). The objective of this analysis was to characterize the safety across trial program symptomatic SMA. An integrated evaluated end study data from seven completed that enrolled SMA who were treated intrathecal or underwent sham procedures. Two studies conducted infantile-onset (most likely develop type I II) remaining five adolescents...
Abstract Introduction Ambulatory individuals with spinal muscular atrophy (SMA) experience muscle weakness, gait impairments, and fatigue that affect their walking ability. Improvements have been observed in motor function children treated nusinersen, but its impact on has not studied. Methods Post hoc analyses were used to examine changes 6‐minute walk test (6MWT) distance adolescents SMA type II III who received first dose of nusinersen the phase Ib/IIa, open‐label CS2 study ambulatory...
Human islet amyloid polypeptide (hIAPP) self-assembles into fibrils which deposit in pancreatic islets of type 2 diabetes (T2D) patients. Here, we applied chemical kinetics to study the mechanism assembly wild-type hIAPP and its more amyloidogenic natural variant S20G. We show that aggregation both peptides involves primary nucleation, secondary nucleation elongation. also report discovery two structurally distinct small-molecule modulators assembly, one delaying wt hIAPP, but not S20G;...
Background: Pulmonary arterial hypertension (PAH) is characterized by progressive distal pulmonary artery (PA) obstruction, leading to right ventricular hypertrophy and failure. Exacerbated intracellular calcium (Ca 2+ ) signaling contributes abnormalities in PA smooth muscle cells (PASMCs), including aberrant proliferation, apoptosis resistance, exacerbated migration, contractility. Store-operated Ca entry involved homeostasis PASMCs, but its properties PAH are unclear. Methods: Using a...
Apelin peptide analogues displaying bias towards G protein signalling pathways have beneficial cardiovascular actions compared with the native in humans vivo. Our aim was to determine whether small molecule agonists could retain bias. We identified a biased molecule, CMF-019, and characterised it vitro In competition radioligand binding experiments heart homogenates, CMF-019 bound human, rat mouse apelin receptor high affinity (pKi=8.58±0.04, 8.49±0.04 8.71±0.06 respectively). cell-based...
Kallikrein (PKa), generated by activation of its precursor prekallikrein (PK), plays a role in the contact phase coagulation and functions kallikrein-kinin system to generate bradykinin. The general dogma has been that contribution PKa cascade is dependent on action FXII. Recently this challenged studies human plasma showing thrombin generation due activity FIX also murine formation FIXa-antithrombin complexes FXI deficient mice. In study, we demonstrate high-affinity binding interactions...
Abstract: The hepatitis C virus (HCV) p7 ion channel plays a critical role during infectious production and represents an important new therapeutic target. Its activity is blocked by structurally distinct classes of small molecules, with sensitivity varying between isolate sequences. Although this indicative specific protein–drug interactions, lack high-resolution structural information has precluded the identification inhibitor binding sites, their modes action remain undefined....
Current interferon-based therapy for hepatitis C virus (HCV) infection is inadequate, prompting a shift toward combinations of direct-acting antivirals (DAA) with the first protease-targeted drugs licensed in 2012. Many compounds are pipeline yet primarily target only three viral proteins, namely, NS3/4A protease, NS5B polymerase, and NS5A. With concerns growing over resistance, broadening repertoire DAA targets major priority. Here we describe complete structure HCV p7 protein as monomeric...
Electrospray ionisation-ion mobility spectrometry-mass spectrometry (ESI-IMS-MS) is a powerful method for the study of conformational changes in protein complexes, including oligomeric species populated during self-aggregation into amyloid fibrils. Information on mass, stability, cross-sectional area and ligand binding capability each transiently intermediate, present heterogeneous mixture assembling species, can be determined individually single experiment real-time. Determining structural...
Wireless sensor networks have become incredibly popular due to the Internet of Things' (IoT) rapid development.IoT routing is basis for efficient operation perception-layer network.As a type machine learning, reinforcement learning techniques gained significant attention their successful application in field network communication.In traditional Routing Protocol lowpower and Lossy Networks (RPL) protocol, solve fairness control message transmission between IoT terminals, fair broadcast...