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  1. Article ; Online: Generation of human-induced pluripotent-stem-cell-derived cortical neurons for high-throughput imaging of neurite morphology and neuron maturation.

    Wali, Gautam / Li, Yan / Abu-Bonsrah, Dad / Kirik, Deniz / Parish, Clare L / Sue, Carolyn M

    STAR protocols

    2023  Volume 4, Issue 2, Page(s) 102325

    Abstract: High-throughput imaging allows in vitro assessment of neuron morphology for screening populations under developmental, homeostatic, and/or disease conditions. Here, we present a protocol to differentiate cryopreserved human cortical neuronal progenitors ... ...

    Abstract High-throughput imaging allows in vitro assessment of neuron morphology for screening populations under developmental, homeostatic, and/or disease conditions. Here, we present a protocol to differentiate cryopreserved human cortical neuronal progenitors into mature cortical neurons for high-throughput imaging analysis. We describe the use of a notch signaling inhibitor to generate homogeneous neuronal populations at densities amenable to individual neurite identification. We detail neurite morphology assessment via measuring multiple parameters including neurite length, branches, roots, segments and extremities, and neuron maturation.
    Language English
    Publishing date 2023-06-09
    Publishing country United States
    Document type Journal Article
    ISSN 2666-1667
    ISSN (online) 2666-1667
    DOI 10.1016/j.xpro.2023.102325
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Transserosal migration of enteric neural stem cells: Developing an avian colon model.

    Jurkowicz, Boaz / Abu-Bonsrah, Dad / Zhang, Dongcheng / Hutson, John / King, Sebastian / Newgreen, Don

    Journal of pediatric surgery

    2018  Volume 53, Issue 12, Page(s) 2435–2439

    Abstract: Background: Stem cell transplantation is a potential therapy for enteric neuropathies, including Hirschsprung disease. Proof-of-principle has been obtained using focal transplants into neonatal mouse colon. The challenge now is to deliver stem cells to ... ...

    Abstract Background: Stem cell transplantation is a potential therapy for enteric neuropathies, including Hirschsprung disease. Proof-of-principle has been obtained using focal transplants into neonatal mouse colon. The challenge now is to deliver stem cells to a large surface area to reconstruct an enteric nerve plexus. One proposed method is serosal application using a polymer membrane. However, transserosal migration of stem cells has not been demonstrated in mature colon. This study aimed to develop an avian model to demonstrate stem cell migration across the intact serosa of mature colon.
    Methods: Hindguts were obtained from E14 quail embryos, transplanted onto E8 chicken chorioallantoic membranes and harvested after 2 and 8 days. Tissues were assessed immunohistologically for apoptosis (caspase-3), maturity (α-SMA), preservation of mucosa (E-cadherin), and preservation of serosa (cytokeratin).
    Results: Transient necrosis of the central mucosa was observed over the first two days, followed by recovery. Twenty-three grafts were assessed immunohistologically at day 8. Nineteen grafts demonstrated progressive maturation and an intact mucosa. Circumferential serosal preservation was observed in 9 grafts. No apoptosis was seen.
    Conclusion: Avian colon may be successfully harvested with an intact serosa. Large chorioallantoic membrane grafts remain viable for at least 8 days, and the serosa can be preserved throughout. This provides an economical platform for assessing transserosal migration of stem cells in mature colon.
    MeSH term(s) Animals ; Cadherins/metabolism ; Caspase 3/metabolism ; Cell Movement/physiology ; Colon/metabolism ; Colon/transplantation ; Enteric Nervous System/cytology ; Fluorescent Antibody Technique ; Keratins/metabolism ; Neural Stem Cells/metabolism ; Serous Membrane/cytology ; Serous Membrane/metabolism ; Stem Cell Transplantation/methods
    Chemical Substances Cadherins ; Keratins (68238-35-7) ; Caspase 3 (EC 3.4.22.-)
    Language English
    Publishing date 2018-09-02
    Publishing country United States
    Document type Journal Article
    ZDB-ID 80165-3
    ISSN 1531-5037 ; 0022-3468
    ISSN (online) 1531-5037
    ISSN 0022-3468
    DOI 10.1016/j.jpedsurg.2018.08.017
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: GLA-modified RNA treatment lowers GB3 levels in iPSC-derived cardiomyocytes from Fabry-affected individuals.

    Ter Huurne, Menno / Parker, Benjamin L / Liu, Ning Qing / Qian, Elizabeth Ling / Vivien, Celine / Karavendzas, Kathy / Mills, Richard J / Saville, Jennifer T / Abu-Bonsrah, Dad / Wise, Andrea F / Hudson, James E / Talbot, Andrew S / Finn, Patrick F / Martini, Paolo G V / Fuller, Maria / Ricardo, Sharon D / Watt, Kevin I / Nicholls, Kathy M / Porrello, Enzo R /
    Elliott, David A

    American journal of human genetics

    2023  Volume 110, Issue 9, Page(s) 1600–1605

    Abstract: Recent studies in non-human model systems have shown therapeutic potential of nucleoside-modified messenger RNA (modRNA) treatments for lysosomal storage diseases. Here, we assessed the efficacy of a modRNA treatment to restore the expression of the ... ...

    Abstract Recent studies in non-human model systems have shown therapeutic potential of nucleoside-modified messenger RNA (modRNA) treatments for lysosomal storage diseases. Here, we assessed the efficacy of a modRNA treatment to restore the expression of the galactosidase alpha (GLA), which codes for α-Galactosidase A (α-GAL) enzyme, in a human cardiac model generated from induced pluripotent stem cells (iPSCs) derived from two individuals with Fabry disease. Consistent with the clinical phenotype, cardiomyocytes from iPSCs derived from Fabry-affected individuals showed accumulation of the glycosphingolipid Globotriaosylceramide (GB3), which is an α-galactosidase substrate. Furthermore, the Fabry cardiomyocytes displayed significant upregulation of lysosomal-associated proteins. Upon GLA modRNA treatment, a subset of lysosomal proteins were partially restored to wild-type levels, implying the rescue of the molecular phenotype associated with the Fabry genotype. Importantly, a significant reduction of GB3 levels was observed in GLA modRNA-treated cardiomyocytes, demonstrating that α-GAL enzymatic activity was restored. Together, our results validate the utility of iPSC-derived cardiomyocytes from affected individuals as a model to study disease processes in Fabry disease and the therapeutic potential of GLA modRNA treatment to reduce GB3 accumulation in the heart.
    MeSH term(s) Humans ; Myocytes, Cardiac ; RNA ; Induced Pluripotent Stem Cells ; Fabry Disease/genetics ; Fabry Disease/therapy ; RNA, Messenger
    Chemical Substances RNA (63231-63-0) ; RNA, Messenger
    Language English
    Publishing date 2023-08-21
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 219384-x
    ISSN 1537-6605 ; 0002-9297
    ISSN (online) 1537-6605
    ISSN 0002-9297
    DOI 10.1016/j.ajhg.2023.07.013
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  4. Article ; Online: Parallel use of human stem cell lung and heart models provide insights for SARS-CoV-2 treatment.

    Rudraraju, Rajeev / Gartner, Matthew J / Neil, Jessica A / Stout, Elizabeth S / Chen, Joseph / Needham, Elise J / See, Michael / Mackenzie-Kludas, Charley / Yang Lee, Leo Yi / Wang, Mingyang / Pointer, Hayley / Karavendzas, Kathy / Abu-Bonsrah, Dad / Drew, Damien / Yang Sun, Yu Bo / Tan, Jia Ping / Sun, Guizhi / Salavaty, Adrian / Charitakis, Natalie /
    Nim, Hieu T / Currie, Peter D / Tham, Wai-Hong / Porrello, Enzo / Polo, Jose M / Humphrey, Sean J / Ramialison, Mirana / Elliott, David A / Subbarao, Kanta

    Stem cell reports

    2023  Volume 18, Issue 6, Page(s) 1308–1324

    Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily infects the respiratory tract, but pulmonary and cardiac complications occur in severe coronavirus disease 2019 (COVID-19). To elucidate molecular mechanisms in the lung and heart, we ...

    Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily infects the respiratory tract, but pulmonary and cardiac complications occur in severe coronavirus disease 2019 (COVID-19). To elucidate molecular mechanisms in the lung and heart, we conducted paired experiments in human stem cell-derived lung alveolar type II (AT2) epithelial cell and cardiac cultures infected with SARS-CoV-2. With CRISPR-Cas9-mediated knockout of ACE2, we demonstrated that angiotensin-converting enzyme 2 (ACE2) was essential for SARS-CoV-2 infection of both cell types but that further processing in lung cells required TMPRSS2, while cardiac cells required the endosomal pathway. Host responses were significantly different; transcriptome profiling and phosphoproteomics responses depended strongly on the cell type. We identified several antiviral compounds with distinct antiviral and toxicity profiles in lung AT2 and cardiac cells, highlighting the importance of using several relevant cell types for evaluation of antiviral drugs. Our data provide new insights into rational drug combinations for effective treatment of a virus that affects multiple organ systems.
    MeSH term(s) Humans ; SARS-CoV-2 ; Angiotensin-Converting Enzyme 2 ; COVID-19 ; Stem Cells ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; Lung
    Chemical Substances Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Antiviral Agents
    Language English
    Publishing date 2023-06-14
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2720528-9
    ISSN 2213-6711 ; 2213-6711
    ISSN (online) 2213-6711
    ISSN 2213-6711
    DOI 10.1016/j.stemcr.2023.05.007
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Parallel use of pluripotent human stem cell lung and heart models provide new insights for treatment of SARS-CoV-2.

    Rudraraju, Rajeev / Gartner, Matthew J / Neil, Jessica A / Stout, Elizabeth S / Chen, Joseph / Needham, Elise J / See, Michael / Mackenzie-Kludas, Charley / Yang Lee, Leo Yi / Wang, Mingyang / Pointer, Hayley / Karavendzas, Kathy / Abu-Bonsrah, Dad / Drew, Damien / Sun, Yu Bo Yang / Tan, Jia Ping / Sun, Guizhi / Salavaty, Abbas / Charitakis, Natalie /
    Nim, Hieu T / Currie, Peter D / Tham, Wai-Hong / Porrello, Enzo / Polo, Jose / Humphrey, Sean J / Ramialison, Mirana / Elliott, David A / Subbarao, Kanta

    bioRxiv : the preprint server for biology

    2022  

    Abstract: SARS-CoV-2 primarily infects the respiratory tract, but pulmonary and cardiac complications occur in severe COVID-19. To elucidate molecular mechanisms in the lung and heart, we conducted paired experiments in human stem cell-derived lung alveolar type ... ...

    Abstract SARS-CoV-2 primarily infects the respiratory tract, but pulmonary and cardiac complications occur in severe COVID-19. To elucidate molecular mechanisms in the lung and heart, we conducted paired experiments in human stem cell-derived lung alveolar type II (AT2) epithelial cell and cardiac cultures infected with SARS-CoV-2. With CRISPR- Cas9 mediated knock-out of ACE2, we demonstrated that angiotensin converting enzyme 2 (ACE2) was essential for SARS-CoV-2 infection of both cell types but further processing in lung cells required TMPRSS2 while cardiac cells required the endosomal pathway. Host responses were significantly different; transcriptome profiling and phosphoproteomics responses depended strongly on the cell type. We identified several antiviral compounds with distinct antiviral and toxicity profiles in lung AT2 and cardiac cells, highlighting the importance of using several relevant cell types for evaluation of antiviral drugs. Our data provide new insights into rational drug combinations for effective treatment of a virus that affects multiple organ systems.
    One-sentence summary: Rational treatment strategies for SARS-CoV-2 derived from human PSC models.
    Language English
    Publishing date 2022-09-21
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2022.09.20.508614
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Parallel use of pluripotent human stem cell lung and heart models provide new insights for treatment of SARS-CoV-2

    Rudraraju, Rajeev / Gartner, Matthew J / Neil, Jessica A / Stout, Elizabeth S / Chen, Joseph / Needham, Elise J / See, Michael / Mackenzie-Kludas, Charley / Yang, Leo Yi / Wang, Mingyang / Pointer, Hayley / Karavendzas, Kathy / Abu-Bonsrah, Dad / Drew, Damien / Sun, Yu Bo Yang / Tan, Jia Ping / Sun, Guizhi / Salavaty, Abbas / Charitakis, Natalie /
    Nim, Hieu T / Currie, Peter D / Tham, Wai-Hong / Porrello, Enzo / Polo, Jose / Humphrey, Sean J / Ramialison, Mirana / Elliott, David A / Subbarao, Kanta

    bioRxiv

    Abstract: SARS-CoV-2 primarily infects the respiratory tract, but pulmonary and cardiac complications occur in severe COVID-19. To elucidate molecular mechanisms in the lung and heart, we conducted paired experiments in human stem cell-derived lung alveolar type ... ...

    Abstract SARS-CoV-2 primarily infects the respiratory tract, but pulmonary and cardiac complications occur in severe COVID-19. To elucidate molecular mechanisms in the lung and heart, we conducted paired experiments in human stem cell-derived lung alveolar type II (AT2) epithelial cell and cardiac cultures infected with SARS-CoV-2. With CRISPR-Cas9 mediated knock-out of ACE2, we demonstrated that angiotensin converting enzyme 2 (ACE2) was essential for SARS-CoV-2 infection of both cell types but further processing in lung cells required TMPRSS2 while cardiac cells required the endosomal pathway. Host responses were significantly different; transcriptome profiling and phosphoproteomics responses depended strongly on the cell type. We identified several antiviral compounds with distinct antiviral and toxicity profiles in lung AT2 and cardiac cells, highlighting the importance of using several relevant cell types for evaluation of antiviral drugs. Our data provide new insights into rational drug combinations for effective treatment of a virus that affects multiple organ systems.
    Keywords covid19
    Language English
    Publishing date 2022-09-21
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2022.09.20.508614
    Database COVID19

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  7. Article ; Online: Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy.

    Lopes, Luis R / Garcia-Hernández, Soledad / Lorenzini, Massimiliano / Futema, Marta / Chumakova, Olga / Zateyshchikov, Dmitry / Isidoro-Garcia, Maria / Villacorta, Eduardo / Escobar-Lopez, Luis / Garcia-Pavia, Pablo / Bilbao, Raquel / Dobarro, David / Sandin-Fuentes, Maria / Catalli, Claudio / Gener Querol, Blanca / Mezcua, Ainhoa / Garcia Pinilla, Jose / Bloch Rasmussen, Torsten / Ferreira-Aguar, Ana /
    Revilla-Martí, Pablo / Basurte Elorz, Maria Teresa / Bautista Paves, Alicia / Ramon Gimeno, Juan / Figueroa, Ana Virginia / Franco-Gutierrez, Raul / Fuentes-Cañamero, Maria Eugenia / Martinez Moreno, Marina / Ortiz-Genga, Martin / Piqueras-Flores, Jesus / Analia Ramos, Karina / Rudzitis, Ainars / Ruiz-Guerrero, Luis / Stein, Ricardo / Triguero-Bocharán, Mayte / de la Higuera, Luis / Ochoa, Juan Pablo / Abu-Bonsrah, Dad / Kwok, Cecilia Y T / Smith, Jacob B / Porrello, Enzo R / Akhtar, Mohammed M / Jager, Joanna / Ashworth, Michael / Syrris, Petros / Elliott, David A / Monserrat, Lorenzo / Elliott, Perry M

    European heart journal

    2021  Volume 42, Issue 32, Page(s) 3063–3073

    Abstract: Aims: The aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co- ... ...

    Abstract Aims: The aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies.
    Methods and results: In a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv [odds ratio(OR) 16.11, 95% confidence interval (CI) 7.94-30.02, P = 8.05e-11] compared to the Genome Aggregation Database (gnomAD) population. In a validation cohort of 2047 HCM probands, 32 (1.56%) carried heterozygous ALPK3tv (OR 16.17, 95% CI 10.31-24.87, P < 2.2e-16, compared to gnomAD). Combined logarithm of odds score in seven families with ALPK3tv was 2.99. In comparison with a cohort of genotyped patients with HCM (n = 1679) with and without pathogenic sarcomere gene variants (SP+ and SP-), ALPK3tv carriers had a higher prevalence of apical/concentric patterns of hypertrophy (60%, P < 0.001) and of a short PR interval (10%, P = 0.009). Age at diagnosis and maximum left ventricular wall thickness were similar to SP- and left ventricular systolic impairment (6%) and non-sustained ventricular tachycardia (31%) at baseline similar to SP+. After 5.3 ± 5.7 years, 4 (9%) patients with ALPK3tv died of heart failure or had cardiac transplantation (log-rank P = 0.012 vs. SP- and P = 0.425 vs. SP+). Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation.
    Conclusions: Heterozygous ALPK3tv are pathogenic and segregate with a characteristic HCM phenotype.
    MeSH term(s) Cardiomyopathy, Hypertrophic/genetics ; Heterozygote ; Humans ; Muscle Proteins/genetics ; Mutation ; Protein Kinases/genetics ; Sarcomeres
    Chemical Substances Alpk3 protein human ; Muscle Proteins ; Protein Kinases (EC 2.7.-)
    Language English
    Publishing date 2021-07-13
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 603098-1
    ISSN 1522-9645 ; 0195-668X
    ISSN (online) 1522-9645
    ISSN 0195-668X
    DOI 10.1093/eurheartj/ehab424
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: BET inhibition blocks inflammation-induced cardiac dysfunction and SARS-CoV-2 infection.

    Mills, Richard J / Humphrey, Sean J / Fortuna, Patrick R J / Lor, Mary / Foster, Simon R / Quaife-Ryan, Gregory A / Johnston, Rebecca L / Dumenil, Troy / Bishop, Cameron / Rudraraju, Rajeev / Rawle, Daniel J / Le, Thuy / Zhao, Wei / Lee, Leo / Mackenzie-Kludas, Charley / Mehdiabadi, Neda R / Halliday, Christopher / Gilham, Dean / Fu, Li /
    Nicholls, Stephen J / Johansson, Jan / Sweeney, Michael / Wong, Norman C W / Kulikowski, Ewelina / Sokolowski, Kamil A / Tse, Brian W C / Devilée, Lynn / Voges, Holly K / Reynolds, Liam T / Krumeich, Sophie / Mathieson, Ellen / Abu-Bonsrah, Dad / Karavendzas, Kathy / Griffen, Brendan / Titmarsh, Drew / Elliott, David A / McMahon, James / Suhrbier, Andreas / Subbarao, Kanta / Porrello, Enzo R / Smyth, Mark J / Engwerda, Christian R / MacDonald, Kelli P A / Bald, Tobias / James, David E / Hudson, James E

    Cell

    2021  Volume 184, Issue 8, Page(s) 2167–2182.e22

    Abstract: Cardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined but could be through direct cardiac infection and/or inflammation-induced dysfunction. To identify mechanisms and cardio-protective drugs, ...

    Abstract Cardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined but could be through direct cardiac infection and/or inflammation-induced dysfunction. To identify mechanisms and cardio-protective drugs, we use a state-of-the-art pipeline combining human cardiac organoids with phosphoproteomics and single nuclei RNA sequencing. We identify an inflammatory "cytokine-storm", a cocktail of interferon gamma, interleukin 1β, and poly(I:C), induced diastolic dysfunction. Bromodomain-containing protein 4 is activated along with a viral response that is consistent in both human cardiac organoids (hCOs) and hearts of SARS-CoV-2-infected K18-hACE2 mice. Bromodomain and extraterminal family inhibitors (BETi) recover dysfunction in hCOs and completely prevent cardiac dysfunction and death in a mouse cytokine-storm model. Additionally, BETi decreases transcription of genes in the viral response, decreases ACE2 expression, and reduces SARS-CoV-2 infection of cardiomyocytes. Together, BETi, including the Food and Drug Administration (FDA) breakthrough designated drug, apabetalone, are promising candidates to prevent COVID-19 mediated cardiac damage.
    MeSH term(s) Angiotensin-Converting Enzyme 2/metabolism ; Animals ; COVID-19/complications ; Cardiotonic Agents/therapeutic use ; Cell Cycle Proteins/antagonists & inhibitors ; Cell Cycle Proteins/metabolism ; Cell Line ; Cytokines/metabolism ; Female ; Heart Diseases/drug therapy ; Heart Diseases/etiology ; Human Embryonic Stem Cells ; Humans ; Inflammation/complications ; Inflammation/drug therapy ; Mice ; Mice, Inbred C57BL ; Quinazolinones/therapeutic use ; Transcription Factors/antagonists & inhibitors ; Transcription Factors/metabolism ; COVID-19 Drug Treatment
    Chemical Substances BRD4 protein, human ; Cardiotonic Agents ; Cell Cycle Proteins ; Cytokines ; Quinazolinones ; Transcription Factors ; apabetalone (8R4A7GDZ1D) ; ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
    Language English
    Publishing date 2021-03-16
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 187009-9
    ISSN 1097-4172 ; 0092-8674
    ISSN (online) 1097-4172
    ISSN 0092-8674
    DOI 10.1016/j.cell.2021.03.026
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  9. Article ; Online: Bromodomain Inhibition Blocks Inflammation-Induced Cardiac Dysfunction and SARS-CoV2 Infection in Pre-Clinical Models

    Mills, Richard J / Humphrey, Sean J / Fortuna, Patrick RJ / Quaife-Ryan, Gregory A / Lor, Mary / Ruraraju, Rajeev / Rawle, Daniel J / Le, Thuy / Zhao, Wei / Lee, Leo / Mackenzie-Kludas, Charley / Mehdiabadi, Neda R / Devilée, Lynn / Voges, Holly K / Reynolds, Liam T / Krumeich, Sophie / Mathieson, Ellen / Abu-Bonsrah, Dad / Karavendzas, Kathy /
    Griffen, Brendan / Titmarsh, Drew / Elliott, David A / McMahon, James / Suhrbier, Andreas / Subbarao, Kanta / Porrello, Enzo R / Smyth, Mark J / Engwerda, Christian R / MacDonald, Kelli PA / Bald, Tobias / James, David E / Hudson, James E

    bioRxiv

    Abstract: Cardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined, but could be through direct cardiac infection and/or ‘cytokine-storm’ induced dysfunction. To identify mechanisms and discover cardio- ... ...

    Abstract Cardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined, but could be through direct cardiac infection and/or ‘cytokine-storm’ induced dysfunction. To identify mechanisms and discover cardio-protective therapeutics, we use a state-of-the-art pipeline combining human cardiac organoids with high throughput phosphoproteomics and single nuclei RNA sequencing. We identify that ‘cytokine-storm’ induced diastolic dysfunction can be caused by a cocktail of interferon gamma, interleukin 1β and poly(I:C) and also human serum from COVID-19 patients. Bromodomain protein 4 (BRD4) is activated along with pathology driving fibrotic and induced nitric oxide synthase genes. BRD inhibitors fully recover function in hCO and completely prevent death in a cytokine-storm mouse model. BRD inhibition decreases transcription of multiple genes, including fibrotic, induced nitric oxide synthase and ACE2, and reduces cardiac infection from SARS-CoV2. Thus, BRD inhibitors are promising candidates to prevent COVID-19 mediated cardiac damage.
    Keywords covid19
    Publisher BioRxiv; WHO
    Document type Article ; Online
    DOI 10.1101/2020.08.23.258574
    Database COVID19

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  10. Article ; Online: Bromodomain Inhibition Blocks Inflammation-Induced Cardiac Dysfunction and SARS-CoV2 Infection

    Mills, Richard J. / Humphrey, Sean / Fortuna, Patrick RJ / Quaife-Ryan, Gregory / Lor, Mary / Ruraraju, Rajeev / Rawle, Daniel / Le, Thuy / Zhao, Wei / Lee, Leo / Mackenzie-Kludas, Charley / Mehdiabadi, Neda / Foster, Simon R. / Devilee, Lynn / Voges, Holly / Reynolds, Liam / Krumeich, Sophie / Mathieson, Ellen / Abu-Bonsrah, Dad /
    Karavendzas, Kathy / Griffen, Brendan / Titmarsh, Drew / Elliott, David / McMahon, James / Suhrbier, Andreas / Subbarao, Kanta / Porrello, Enzo / Smyth, Mark John / Engwerda, Christian / MacDonald, Kelli / Bald, Tobias / James, David E. / Hudson, James Edward

    SSRN Electronic Journal ; ISSN 1556-5068

    2020  

    Keywords covid19
    Language English
    Publisher Elsevier BV
    Publishing country us
    Document type Article ; Online
    DOI 10.2139/ssrn.3726271
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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