The man of the renaissance interpreted through the life and plays of Christopher Marlowe

Thesis (M.A.)--Boston University This item was digitized by the Internet Archive

Hemodynamic-mediated endocardial signaling controls in vivo myocardial reprogramming

Lower vertebrate and neonatal mammalian hearts exhibit the remarkable capacity to regenerate through the reprogramming of pre-existing cardiomyocytes. However, how cardiac injury initiates signaling pathways controlling this regenerative reprogramming remains to be defined. Here, we utilize in vivo biophysical and genetic fate mapping zebrafish studies to reveal that altered hemodynamic forces due to cardiac injury activate a sequential endocardial-myocardial signaling cascade to direct cardiomyocyte reprogramming and heart regeneration. Specifically, these altered forces are sensed by the endocardium through the mechanosensitive channel Trpv4 to control Klf2a transcription factor expression. Consequently, Klf2a then activates endocardial Notch signaling which results in the non-cell autonomous initiation of myocardial Erbb2 and BMP signaling to promote cardiomyocyte reprogramming and heart regeneration. Overall, these findings not only reveal how the heart senses and adaptively responds to environmental changes due to cardiac injury, but also provide insight into how flow-mediated mechanisms may regulate cardiomyocyte reprogramming and heart regeneration

Immune response to intravenous immunoglobulin in patients with Kawasaki disease and MIS-C

BACKGROUNDMultisystem inflammatory syndrome in children (MIS-C) is a rare but potentially severe illness that follows exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Kawasaki disease (KD) shares several clinical features with MIS-C, which prompted the use of intravenous immunoglobulin (IVIG), a mainstay therapy for KD. Both diseases share a robust activation of the innate immune system, including the IL-1 signaling pathway, and IL-1 blockade has been used for the treatment of both MIS-C and KD. The mechanism of action of IVIG in these 2 diseases and the cellular source of IL-1β have not been defined.METHODSThe effects of IVIG on peripheral blood leukocyte populations from patients with MIS-C and KD were examined using flow cytometry and mass cytometry (CyTOF) and live-cell imaging.RESULTSCirculating neutrophils were highly activated in patients with KD and MIS-C and were a major source of IL-1β. Following IVIG treatment, activated IL-1β+ neutrophils were reduced in the circulation. In vitro, IVIG was a potent activator of neutrophil cell death via PI3K and NADPH oxidase, but independently of caspase activation.CONCLUSIONSActivated neutrophils expressing IL-1β can be targeted by IVIG, supporting its use in both KD and MIS-C to ameliorate inflammation.FUNDINGPatient Centered Outcomes Research Institute; NIH; American Asthma Foundation; American Heart Association; Novo Nordisk Foundation; NIGMS; American Academy of Allergy, Asthma and Immunology Foundation