Publications by authors named "Jourdan K Ewoldt"

6 Publications

  • Page 1 of 1

Probing the subcellular nanostructure of engineered human cardiomyocytes in 3D tissue.

Microsyst Nanoeng 2021 27;7:10. Epub 2021 Jan 27.

Department of Mechanical Engineering, Boston University, Boston, MA 02215 USA.

The structural and functional maturation of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) is essential for pharmaceutical testing, disease modeling, and ultimately therapeutic use. Multicellular 3D-tissue platforms have improved the functional maturation of hiPSC-CMs, but probing cardiac contractile properties in a 3D environment remains challenging, especially at depth and in live tissues. Using small-angle X-ray scattering (SAXS) imaging, we show that hiPSC-CMs matured and examined in a 3D environment exhibit a periodic spatial arrangement of the myofilament lattice, which has not been previously detected in hiPSC-CMs. The contractile force is found to correlate with both the scattering intensity (  = 0.44) and lattice spacing (  = 0.46). The scattering intensity also correlates with lattice spacing (  = 0.81), suggestive of lower noise in our structural measurement than in the functional measurement. Notably, we observed decreased myofilament ordering in tissues with a myofilament mutation known to lead to hypertrophic cardiomyopathy (HCM). Our results highlight the progress of human cardiac tissue engineering and enable unprecedented study of structural maturation in hiPSC-CMs.
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http://dx.doi.org/10.1038/s41378-020-00234-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8433147PMC
January 2021

Filamin C Cardiomyopathy Variants Cause Protein and Lysosome Accumulation.

Circ Res 2021 09 18;129(7):751-766. Epub 2021 Aug 18.

Department of Genetics (R.A., C.N.T., Q.Z., J.G., S.R.D., C.E.S., J.G.S.), Harvard Medical School, Boston, MA.

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http://dx.doi.org/10.1161/CIRCRESAHA.120.317076DOI Listing
September 2021

SARS-CoV-2 Disrupts Proximal Elements in the JAK-STAT Pathway.

J Virol 2021 09 9;95(19):e0086221. Epub 2021 Sep 9.

Department of Biochemistry, Boston Universitygrid.189504.1 School of Medicine, Boston, Massachusetts, USA.

SARS-CoV-2 can infect multiple organs, including lung, intestine, kidney, heart, liver, and brain. The molecular details of how the virus navigates through diverse cellular environments and establishes replication are poorly defined. Here, we generated a panel of phenotypically diverse, SARS-CoV-2-infectible human cell lines representing different body organs and performed longitudinal survey of cellular proteins and pathways broadly affected by the virus. This revealed universal inhibition of interferon signaling across cell types following SARS-CoV-2 infection. We performed systematic analyses of the JAK-STAT pathway in a broad range of cellular systems, including immortalized cells and primary-like cardiomyocytes, and found that SARS-CoV-2 targeted the proximal pathway components, including Janus kinase 1 (JAK1), tyrosine kinase 2 (Tyk2), and the interferon receptor subunit 1 (IFNAR1), resulting in cellular desensitization to type I IFN. Detailed mechanistic investigation of IFNAR1 showed that the protein underwent ubiquitination upon SARS-CoV-2 infection. Furthermore, chemical inhibition of JAK kinases enhanced infection of stem cell-derived cultures, indicating that the virus benefits from inhibiting the JAK-STAT pathway. These findings suggest that the suppression of interferon signaling is a mechanism widely used by the virus to evade antiviral innate immunity, and that targeting the viral mediators of immune evasion may help block virus replication in patients with COVID-19. SARS-CoV-2 can infect various organs in the human body, but the molecular interface between the virus and these organs remains unexplored. In this study, we generated a panel of highly infectible human cell lines originating from various body organs and employed these cells to identify cellular processes commonly or distinctly disrupted by SARS-CoV-2 in different cell types. One among the universally impaired processes was interferon signaling. Systematic analysis of this pathway in diverse culture systems showed that SARS-CoV-2 targets the proximal JAK-STAT pathway components, destabilizes the type I interferon receptor though ubiquitination, and consequently renders the infected cells resistant to type I interferon. These findings illuminate how SARS-CoV-2 can continue to propagate in different tissues even in the presence of a disseminated innate immune response.
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http://dx.doi.org/10.1128/JVI.00862-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428404PMC
September 2021

SARS-CoV-2 desensitizes host cells to interferon through inhibition of the JAK-STAT pathway.

bioRxiv 2020 Oct 28. Epub 2020 Oct 28.

SARS-CoV-2 can infect multiple organs, including lung, intestine, kidney, heart, liver, and brain. The molecular details of how the virus navigates through diverse cellular environments and establishes replication are poorly defined. Here, we performed global proteomic analysis of the virus-host interface in a newly established panel of phenotypically diverse, SARS-CoV-2-infectable human cell lines representing different body organs. This revealed universal inhibition of interferon signaling across cell types following SARS-CoV-2 infection. We performed systematic analyses of the JAK-STAT pathway in a broad range of cellular systems, including immortalized cell lines and primary-like cardiomyocytes, and found that several pathway components were targeted by SARS-CoV-2 leading to cellular desensitization to interferon. These findings indicate that the suppression of interferon signaling is a mechanism widely used by SARS-CoV-2 in diverse tissues to evade antiviral innate immunity, and that targeting the viral mediators of immune evasion may help block virus replication in patients with COVID-19.
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http://dx.doi.org/10.1101/2020.10.27.358259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605551PMC
October 2020

Quantification of a single score (1+) in the Modified Ashworth Scale (MAS), a clinical assessment of spasticity.

Annu Int Conf IEEE Eng Med Biol Soc 2016 Aug;2016:1737-1740

The Modified Ashworth Scale (MAS) is an assessment that is often used by clinicians to grade spasticity in the affected limbs of stroke survivors. The MAS is a function of the angle at which the clinician perceives a resistance to stretch and/or a `catch' during a passive joint rotation. The qualitative nature of the assessment in combination with the low resolution of the scale could result in varied grouping of spastic patients, even for a single score. The objective of this pilot study was to develop a method for the quantification of the MAS, which could provide greater resolution and could eventually guide better informed therapeutic interventions. The MAS assessment at the elbow joint for four stroke survivors with the same clinical MAS score of 1+ was performed by a clinician and quantified using signals from surface electromyography (EMG) and an electrogoniometer. The subjects were tested on both the affected and contralateral upper limbs. The findings from this study show a varied set of signal outputs across four stroke survivors, all graded at 1+. The quantification provides insight as to the mechanisms underlying the passive resistance.
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http://dx.doi.org/10.1109/EMBC.2016.7591052DOI Listing
August 2016
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