Biology subjects

Morgan, B. P.

Publications and source records attributed to Morgan, B. P..

8 recordsLinked to original sources

bioRxiv2026

Ulacamten: A Novel, RLC-Targeting Cardiac Myosin Inhibitor for Potential Treatment of Cardiac Hypercontractility, Including HFpEF

BackgroundCardiac myosin inhibitors (CMIs) demonstrate advantages over other guideline-directed therapy for patients with obstructive hypertrophic cardiomyopathy (oHCM). By reducing hypercontractility, CMIs abrogate excessive systolic function and improve diastolic function; diminish hypertrophy of the left ventricle (LV); and improve exercise capacity, functional class, and symptoms. Whether CMIs are therapeutic in heart failure with preserved ejection fraction (HFpEF) is of interest because a significant subset of these patients demonstrate supranormal ejection fractions and abnormal LV structure, characteristics in common with HCM, where CMIs have proved effective. ObjectivesOur goal was to characterize the mechanism of myosin inhibition for ulacamten and determine its efficacy in a rodent model of HFpEF. MethodsUlacamten was characterized using biophysical and biochemical approaches, cardiomyocytes from humans and the ZSF1 obese rat model of HFpEF, hypercontractile human-engineered heart tissues, and echocardiography in the ZSF1 rat model. ResultsUnlike the other CMIs, aficamten and mavacamten, ulacamten binds outside the S1 domain of myosin and requires the regulatory light chain domain to bind and inhibit the activity of 2-headed myosin. Ulacamten only partially inhibits the myosin ATPase activity in both myofibrillar and protein systems, but inhibition of contractility was nearly complete in cardiomyocytes. Improvement in relaxation was demonstrated in hypercontractile-engineered heart tissues, and chronic treatment of ZSF1 obese rats showed benefits in both cardiac structure and function. ConclusionsUlacamten inhibits myosin in a manner distinct from aficamten and mavacamten, potentially broadening the mechanistic properties of CMIs available for treatment of hypercontractile cardiac dysfunction. CONDENSED ABSTRACTCardiac myosin inhibitors (CMIs) abrogate excessive systolic function and improve diastolic function, diminish cardiac hypertrophy, and improve exercise capacity in humans with obstructive hypertrophic cardiomyopathy (oHCM). Supranormal ejection fraction underlies heart failure with preserved ejection fraction (HFpEF) in some patients. We describe a new CMI, ulacamten, with binding and inhibitory properties distinct from two other FDA-approved CMIs, aficamten and mavacamten. Specifically, ulacamten requires 2-headed myosin to inhibit activity, whereas aficamten and mavacamten inhibit single-headed myosin. Ulacamten inhibits contractility in primary myocytes isolated from control human and hypercontractile ZSF1 obese rat hearts, as well as engineered heart tissues created with induced pluripotent stem cell cardiomyocytes bearing an HCM mutation. Chronic treatment of ZSF1 obese rats as a preclinical model of HFpEF improves diastolic function and reduces hypertrophy and fibrosis, broadening the potential mechanistic landscape of CMIs. Visual abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=96 SRC="FIGDIR/small/701387v2_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@11f9cecorg.highwire.dtl.DTLVardef@776847org.highwire.dtl.DTLVardef@15f19ddorg.highwire.dtl.DTLVardef@9b20c6_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2025

Platelets Link Coagulation and Complement in Regulating Placental Vascular Development

During early pregnancy, maternal blood surrounds the embryo before the placenta is fully developed, requiring tight regulation of maternal blood flow into the placental vasculature. We identify placental microthrombi (PMTs) as essential structures guiding this process. PMTs contain platelets, coagulation factors, and complement proteins, and their formation depends on maternal platelet activation by thrombin through the protease-activated receptor PAR4. Deficiency of PAR4 abolished PMTs and caused excessive bleeding at the implantation site. C3 deficiency also led to increased bleeding events, indicating that complement activation contributes to thrombosis in the placental circulation. Conversely, dysregulated complement activation in CMP-sialic acid synthase-deficient (Cmas-/-) mice led to widespread thrombosis and failed placental development. Strikingly, platelet activation via PAR4 was necessary to localize complement activation to trophoblast surfaces, thereby coupling coagulation and complement in PMT formation. Depletion of maternal platelets mitigated complement-driven thromboinflammation in Cmas-/- pregnancies, restoring placental growth. These findings uncover a critical cooperation between platelets, coagulation, and complement in establishing maternal blood flow to the placenta. Successful pregnancy therefore requires not only activation but also tight regulation of these systems to balance necessary PMT formation with the prevention of pathological thrombosis. Graphical abstract(Created in BioRender. Tiede, A. (2025) https://BioRender.com/l6zeezr) O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=137 SRC="FIGDIR/small/675525v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@c04354org.highwire.dtl.DTLVardef@844863org.highwire.dtl.DTLVardef@ac7ba5org.highwire.dtl.DTLVardef@1e9be32_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Complement biosynthesis in human brain: Insights from single-nucleus transcriptomics of hippocampus.

Complement is a key contributor to neuroinflammation, driving pathology in neurodegenerative diseases (NDDs); however, little is known about the source of complement in brain. Effective targeting of complement in NDDs requires understanding of its source; in particular, which brain cells express complement genes, how expression is regulated and how expression changes in disease. To address this knowledge gap, we identified and integrated single-nucleus RNA sequencing (snRNA-seq) datasets from 398,097 nuclei across 48 hippocampal samples from non-demented brains to create a comprehensive transcriptomic atlas of complement gene expression ("complementome") in healthy brain. Expression levels of genes encoding complement components, receptors, and regulators were analysed across different brain cell types and the impact of sex and age on complement gene expression tested. To test impact of disease, we generated a further atlas from datasets comprising 11 non-demented and 12 Alzheimers disease (AD) patient hippocampi to assess changes in complement gene expression in AD. All glial cells in the non-demented hippocampus expressed complement genes. C1Q A/B/C genes were exclusively expressed in microglia, while C3 was highly expressed in microglia and astrocytes. Notably, C3 expression defined a subset of pro-inflammatory microglia. Complement receptor encoding genes (C3AR1, C5AR2, ITGAM, ITGAX, ITGB2, VSIG4) were predominantly expressed in microglia, while neurons expressed a set of brain-specific putative receptors (NPTX 1/2, NPTXR, NRP1). Endothelial cells abundantly expressed key regulators (CD46, CD55, CD59, CFH), while neurons and OPCs expressed a set of putative regulators (CSMD 1/2/3, and SUSD4). Astrocytes abundantly expressed CLU. Cell type-specific gender differences included higher expression of C1Q A/B/C, C1R, C1S in female microglia and higher expression of ITGAM and ITGAX in male microglia. Generally higher complement gene expression was seen in older donors. Compared to controls, AD microglia showed higher expression of C1QB and C3, and AD astrocytes showed higher C1S and C3 expression. Expression of ITGAX was elevated in AD microglia compared to controls, while many AD cell types demonstrated reduced expression of brain-specific putative receptors. Defining the complementome in non-demented hippocampus provides a baseline for exploration of brain complement expression. Complement expression is upregulated in AD, likely contributing to neuroinflammation and highlighting its potential as a therapeutic target. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=183 SRC="FIGDIR/small/652374v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@100fbc1org.highwire.dtl.DTLVardef@1905402org.highwire.dtl.DTLVardef@7b8573org.highwire.dtl.DTLVardef@176424a_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2021

Complement Regulator Factor H is a Cofactor for Thrombin in both Pro- and Anticoagulant Roles

BackgroundComplement FH (FH) is a key regulator of complement activity whereas thrombin (FIIa) is central to hemostasis with both pro- and anticoagulant functions. Both have separately been shown to have auxiliary activities across the two systems. The purpose of this study was to determine the effect of FH on pro- and anti-coagulant functions and investigate the interaction between FH and thrombin. MethodsTail bleeding time and hemolysis were measured in FH-deficient mice (CFH-/-). Activated partial thromboplastin time (aPTT) was determined in FH-depleted human plasma. FH effect on fibrin clot generation was investigated in turbidity assays and on activated protein C (APC) generation. Binding affinity of thrombin with FH was determined using surface plasmon resonance (SPR). ResultsTail bleeding time in CFH-/- mice was significantly prolonged compared to wild type mice. The aPTT in FH-depleted human plasma was elevated compared to normal plasma and restored by adding back FH to depleted plasma. Accordingly, FH enhanced thrombin-mediated fibrin clot generation by shortening lag time, increasing rate of clot formation and maximum turbidity, and affected clot structure. Despite this, FH also increased the rate of thrombin-mediated protein C (PC) activation, both in the presence and absence of soluble recombinant thrombomodulin (TM). Nanomolar affinity binding of FH with thrombin, but not prothrombin, was confirmed. ConclusionComplement FH binds thrombin with strong affinity and acts as a novel cofactor that enhances both pro- and anticoagulant actions of thrombin. These data highlight an important role for FH in hemostasis. Key pointsO_LIAbsence of FH prolongs tail bleeding time in CFH-/- mice and activated partial thromboplastin time (aPTT) is elevated in human FH-depleted plasma. C_LIO_LIFH acts a cofactor for thrombin by enhancing fibrin generation, altering fibrin clot structure and enhancing TM-thrombin mediated protein C activation C_LI

immunology↗

bioRxiv2021

ADNKA overcomes SARS-CoV2-mediated NK cell inhibition through non-spike antibodies

The outcome of infection is dependent on the ability of viruses to manipulate the infected cell to evade immunity, and the ability of the immune response to overcome this evasion. Understanding this process is key to understanding pathogenesis, genetic risk factors, and both natural and vaccine-induced immunity. SARS-CoV-2 antagonises the innate interferon response, but whether it manipulates innate cellular immunity is unclear. An unbiased proteomic analysis determined how cell surface protein expression is altered on SARS-CoV-2-infected lung epithelial cells, showing downregulation of activating NK ligands B7-H6, MICA, ULBP2, and Nectin1, with minimal effects on MHC-I. This correlated with a reduction in NK cell activation, identifying a novel mechanism by which SARS-CoV2 antagonises innate immunity. Later in the disease process, strong antibody-dependent NK cell activation (ADNKA) developed. These responses were sustained for at least 6 months in most patients, and led to high levels of pro-inflammatory cytokine production. Depletion of spike-specific antibodies confirmed their dominant role in neutralisation, but these antibodies played only a minor role in ADNKA compared to antibodies to other proteins, including ORF3a, Membrane, and Nucleocapsid. In contrast, ADNKA induced following vaccination was focussed solely on spike, was weaker than ADNKA following natural infection, and was not boosted by the second dose. These insights have important implications for understanding disease progression, vaccine efficacy, and vaccine design.

immunology↗

bioRxiv2021

Abi3 regulates microglial ramification and dynamic tissue surveillance in vivo.

A rare coding variant of Abelson-interactor gene family member 3 (Abi3) is associated with increased risk of late-onset Alzheimers Disease (AD). Although Abi3 is recognised as a core microglial gene, its role in microglia is largely unknown. Here we demonstrate that Abi3 is crucial for normal microglial morphology, distribution, and homeostatic tissue surveillance activity in vivo.

neuroscience↗

bioRxiv2019

Complement C3 and C3aR differentially impact on learned fear and innate anxiety

Complement is a key component of the immune system with roles in inflammation and host-defence. Here we reveal novel functions of complement pathways impacting on emotional reactivity of potential relevance to the emerging links between complement and risk for psychiatric disorder. We used mouse models to assess the effects of manipulating components of the complement system on emotionality. Mice lacking the complement C3a Receptor (C3aR-/-) demonstrated a selective increase in unconditioned (innate) anxiety whilst mice deficient in the central complement component C3 (C3-/-) showed a selective increase in conditioned (learned) fear. The dissociable behavioural phenotypes were linked to different signalling mechanisms. Effects on innate anxiety were independent of C3a, the canonical ligand for C3aR, consistent with the existence of an alternative ligand mediating innate anxiety, whereas effects on learned fear were due to loss of iC3b/CR3 signalling. Our findings show that specific elements of the complement system and associated signalling pathways contribute differentially to heightened states of anxiety and fear commonly seen in psychopathology.

neuroscience↗

bioRxiv2018

CryoEM reveals how the complement membrane attack complex ruptures lipid bilayers

The membrane attack complex (MAC) is one of the immune systems first responders. Complement proteins assemble on target membranes to form pores that lyse pathogens and impact tissue homeostasis of self-cells. How MAC disrupts the membrane barrier remains unclear. Here we use electron cryo-microscopy and flicker spectroscopy to show that MAC interacts with lipid bilayers in two distinct ways. Whereas C6 and C7 associate with the outer leaflet and reduce the energy for membrane bending, C8 and C9 traverse the bilayer increasing membrane rigidity. CryoEM reconstructions reveal plasticity of the MAC pore and demonstrate how C5b6 acts as a platform, directing assembly of a giant {beta}-barrel whose structure is supported by a glycan scaffold. Our work provides a structural basis for understanding how {beta}-pore forming proteins breach the membrane and reveals a mechanism for how MAC kills pathogens and regulates cell functions.

biophysics↗