Rationale
Human coronaviruses (HCoVs) seriously affect human health by causing respiratory diseases ranging from common colds to severe acute respiratory diseases. Immunophilins, including ...peptidyl-prolyl isomerases of the FK506-binding protein (FKBP) and the cyclophilin family, are promising targets for pharmaceutical inhibition of coronavirus replication, but cell-type specific effects have not been elucidated. FKBPs and cyclophilins bind the immunosuppressive drugs FK506 and cyclosporine A (CsA), respectively.
Methods
Primary human bronchial epithelial cells (phBECs) were treated with CsA, Alisporivir (ALV), FK506, and FK506-derived non-immunosuppressive analogs and infected with HCoV-229E. RNA and protein were assessed by RT-qPCR and immunoblot analysis. Treatment with the same compounds was performed in hepatoma cells (Huh-7.5) infected with HCoV-229E expressing
Renilla
luciferase (HCoV-229E-RLuc) and the kidney cell line HEK293 transfected with a SARS-CoV-1 replicon expressing
Renilla
luciferase (SARS-CoV-1-RLuc), followed by quantification of luminescence as a measure of viral replication.
Results
Both CsA and ALV robustly inhibited viral replication in all models; both compounds decreased HCoV-229E RNA in phBECs and reduced luminescence in HCoV-229E-RLuc-infected Huh7.5 and SARS-CoV-1-RLuc replicon-transfected HEK293. In contrast, FK506 showed inconsistent and less pronounced effects in phBECs while strongly affecting coronavirus replication in Huh-7.5 and HEK293. Two non-immunosuppressive FK506 analogs had no antiviral effect in any infection model.
Conclusion
The immunophilin inhibitors CsA and ALV display robust anti-coronaviral properties in multiple infection models, including phBECs, reflecting a primary site of HCoV infection. In contrast, FK506 displayed cell-type specific effects, strongly affecting CoV replication in Huh7.5 and HEK293, but inconsistently and less pronounced in phBECs.
Background
Implantable cardioverter defibrillators (ICDs) offer effective therapy for the prevention of sudden cardiac death (SCD) due to ventricular arrhythmias. However, inappropriate shocks have ...detrimental effects on survival and quality of life. The addition of hemodynamic monitoring may be useful in discriminating clinically important ventricular arrhythmias.
Objective
In this study, we assess the ability of laser Doppler flowmetry to assess the hemodynamic effect of paced atrial and ventricular arrhythmias using mean arterial blood pressure as the reference.
Methods
In this acute human study in patients undergoing an elective electrophysiological study, laser Doppler flowmetry, arterial blood pressure, and surface ECG were acquired during high‐rate atrial and ventricular pacing to simulate supraventricular and ventricular tachycardias.
Results
Arterial blood pressure and laser Doppler flow signals correlated well during atrial and ventricular pacing (rho = 0.694, p < .001). The hemodynamic impairment detected by both methods was greater during ventricular pacing than atrial pacing (–1.0% vs. 19.0%, p < .001). Laser Doppler flowmetry performed better than rate alone to identify hemodynamic impairments.
Conclusion
In this acute study, laser Doppler flowmetry tissue perfusion served as a good surrogate measure for arterial pressure, which could be incorporated into future ICDs.
Navigating the clinical literature to determine the optimal clinical management for rare diseases presents significant challenges. We introduce the Medical Action Ontology (MAxO), an ontology ...specifically designed to organize medical procedures, therapies, and interventions.
MAxO incorporates logical structures that link MAxO terms to numerous other ontologies within the OBO Foundry. Term development involves a blend of manual and semi-automated processes. Additionally, we have generated annotations detailing diagnostic modalities for specific phenotypic abnormalities defined by the Human Phenotype Ontology (HPO). We introduce a web application, POET, that facilitates MAxO annotations for specific medical actions for diseases using the Mondo Disease Ontology.
MAxO encompasses 1,757 terms spanning a wide range of biomedical domains, from human anatomy and investigations to the chemical and protein entities involved in biological processes. These terms annotate phenotypic features associated with specific disease (using HPO and Mondo). Presently, there are over 16,000 MAxO diagnostic annotations that target HPO terms. Through POET, we have created 413 MAxO annotations specifying treatments for 189 rare diseases.
MAxO offers a computational representation of treatments and other actions taken for the clinical management of patients. Its development is closely coupled to Mondo and HPO, broadening the scope of our computational modeling of diseases and phenotypic features. We invite the community to contribute disease annotations using POET (https://poet.jax.org/). MAxO is available under the open-source CC-BY 4.0 license (https://github.com/monarch-initiative/MAxO).
NHGRI 1U24HG011449-01A1 and NHGRI 5RM1HG010860-04.
