Recent Submissions

  • Investigating the Effects of Small Molecules on the Proliferation of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

    Yang, Jack; Fuller, Daniela; Chun, Young Wook; Williams, Charles H. (Charles Houston); Hong, Charles C., 1967- (2022)
    Congenital dilated cardiomyopathy (cDCM) is a rare condition in which infants suffer heart failure in the absence of obvious causes such as toxins, infection/inflammation, global metabolic derangements, or gross structural defects. While the pathophysiology of cDCM is unclear, genetic etiologies have been suspected. The Hong Lab has found that mutations in the gene RTTN encoding the centrosome protein Rotatin causes poor contractile function in an induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) model. Interestingly, this mutation also causes centrosome defects and aberrant CM proliferation. We hypothesize that the iPSC-CM model can be implemented to discover new therapeutic strategies for cDCM and other heart diseases. Previously, we found that certain small molecules (SMs) that modulate Hippo signaling pathways can reverse the cDCM phenotype in the iPSC-CMs model. In an independent set of experiments, the Hong lab and collaborators found that a novel small molecule Wnt inhibitor LRN11 inhibits proliferation and may promote maturation of CMs, while another novel small molecule, named LRN9, promotes proliferation in wild-type CMs. To confirm these findings and to observe their effects on proliferation at different stages of CM differentiation, we treated human iPSC-CMs with the small molecules after 13, 23, 33, and 43 days of differentiation. The results somewhat replicated the earlier finding for LRN9 and LRN11 on CM proliferation, but they are not conclusive. To assess the effects of LRN9 and LRN11 on proliferation in non-CMs, we tested LRN9 and LRN11 on several cancer cell lines. Our initial results indicate that the small molecules either do not affect the proliferation of these non-CMs or affect them in a way that we cannot explain. Based on these promising preliminary results, we hypothesize that compounds such as LRN11 may be therapeutic for cDCM while LRN9 may be therapeutic as a regenerative therapy to replace heart tissue lost to heart attacks without promoting cancer formation.
  • Examining The Role of Ventral Pallidal Inputs In Stress-induced Social Avoidance

    Martinez, Daisy; Campbell, Rianne; Lobo, Mary Kay (2022-07-29)
  • Examining the Association Between Pandemic-related Changes in Caregiver Mental Health and Child Weight Status Over Time

    Pimentel-Soler, Tatiana; Black, Maureen M.; Parker, Elizabeth A., Ph.D., R.D.; Arbaiza, Raquel; Wang, Yan Dr.Ph.; Hager, Erin (2022)
  • Differential Dendritic Cell Recruitment Induced by the Gut Microbiota in Cardiac Transplantation

    Lee, Zachariah L.; Iyyathurai, Jegan; Lakhan, Ram; Saxena, Vikas; Gavzy, Samuel J.; Bromberg, Jonathan Scott (2022-08)
  • The Impact of Sleep Duration on Functional Brain Networks and Pubertal Hormone Levels in Young Adolescents

    Turan, Ozerk; Isaiah, Amal; Ernst, Thomas Ph.D.; Garner, Jonathan; Chang, Linda M.D. (2022-07-29)
  • Cleavage of PC1 is not Required for Embryonic Vasculature Development

    Basquin, Denis; Outeda, Patricia; Qian, Feng; Watnick, Terry (2022-07)
  • Site-specific immune responses of tissue resident memory T cells following live attenuated oral typhoid vaccine Ty21a in humans

    Booth, Jayaum S.; Goldberg, Eric; Patil, Seema A.; Barnes, Robin S.; Greenwald, Bruce D.; Sztein, Marcelo B. (2022-07)
  • Pyronaridine is an antiviral and anti-inflammatory drug active against multiple highly pathogenic Coronaviruses (2)

    Ardanuy, Jeremy; Johnson, Robert M.; Dillen, Carly; Hammond, Holly; Weston, Stuart M.; Frieman, Matthew B. (2022-07-16)
    There is a major need for antiviral drugs that are efficacious and usable for treatment of SARS-CoV-2, SARS-CoV-1, and MERS-CoV infections. One drug with strong potential to join this limited subset of efficacious in vivo oral antivirals, is Pyronaridine tetraphosphate. It has now been shown to have both in vitro and in vivo efficacy in A549 cells and K18 mice respectively by functioning as a protease inhibitor of PLpro. In our studies, Pyronaridine treatment showed significant reductions in lung inflammatory pathology, pro inflammatory cytokine and chemokine levels, and weight loss seen in the mouse model associated with severity of disease in three highly pathogenic coronavirus models. Additionally, we found that when Pyronaridine treatment was combined with Molvupiravir and Nirmatrelvir in a SARS-CoV-2 in vivo model there was evidence of a synergistic effect that further dropped viral titers, inflammatory lung pathology, and inflammatory cytokine and chemokine levels. These results indicate that Pyronaridine represents a strong potential therapeutic candidate for COVID-19 treatment individually, or in combination with other approved antivirals as well as a potential therapeutic option for treatment of other pathogenic coronaviruses such as SARS1 and MERS.
  • Determining the Unique Cellular Targets of Enterovirus-D68 Proteases 3C and 2A

    Pollack, Noah A.; Wagner, Michael; Jackson, William T. (2022)
  • BECC Adjuvanted Vaccine Provides Protection from Homologous and Heterologous Infuenza A Infections

    Baracco, Lauren; Haupt, Robert E.; Harberts, Erin; Krammer, Florian; Ernst, Robert K.; Frieman, Matthew B. (2022-07)
    Influenza A virus (IAV) is a leading cause of mild to severe respiratory disease worldwide with significant infections resulting in hospitalization or death, especially in older people, young children and people with comorbidities. Influenza virus is characterized for its high rate of mutation causing an antigen drift in its glycoprotein that allows the virus to evade the host immune system with new emerging variants. Vaccine production changes annually in order to match circulating strains but predicting these new variants can become challenging. MF59, a squalene oil emulsion, is currently the only approved Influenza vaccine. Adjuvant is used to cause an enhanced immune response with the vaccination, however is still limited to people aged 65 years and older. Using formulations of oil emulsion or aluminum hydroxide (alum) creates adjuvants that allows for an activation of a Th2 response. Alternatively, the adjuvant monophosphoryl lipid A, activates aTh1 response leading to a proinflammatory response. New technology has led to a novel creation of adjuvants by the use of Bacterial Enzymatic Combinatorial Chemistry (BECC) system that produces TLR4 immunostimulatory molecules. These molecules drive a balanced Th1/Th2 response and enhanced immunogenicity in combination with a HA IAV vaccine. These BECC/HA vaccines display superior protection compared to standard adjuvants when challenged with a homologous IAV strain (NL/09), heterologous IAV strain (Sing/15) in a BALB/c mouse model. Formulating with HA/BECC requires less antigen, and works with only a single vaccination. The BECC adjuvant may allow for improved efficacy and broader protection utilizing current Influenza vaccines and potentially other in the future.
  • Pyronaridine is an antiviral and anti-inflammatory drug active against multiple highly pathogenic Coronaviruses

    Ardanuy, Jeremy; Johnson, Robert M.; Dillen, Carly; Hammond, Holly; Weston, Stuart M.; Frieman, Matthew B. (2022-07-16)
    There is a major need for antiviral drugs that are efficacious and usable for treatment of SARS-CoV-2, SARS-CoV-1, and MERS-CoV infections. One drug with strong potential to join this limited subset of efficacious in vivo oral antivirals, is Pyronaridine tetraphosphate. It has now been shown to have both in vitro and in vivo efficacy in A549 cells and K18 mice respectively by functioning as a protease inhibitor of PLpro. In our studies, Pyronaridine treatment showed significant reductions in lung inflammatory pathology, pro inflammatory cytokine and chemokine levels, and weight loss seen in the mouse model associated with severity of disease in three highly pathogenic coronavirus models. Additionally, we found that when Pyronaridine treatment was combined with Molvupiravir and Nirmatrelvir in a SARS-CoV-2 in vivo model there was evidence of a synergistic effect that further dropped viral titers, inflammatory lung pathology, and inflammatory cytokine and chemokine levels. These results indicate that Pyronaridine represents a strong potential therapeutic candidate for COVID-19 treatment individually, or in combination with other approved antivirals as well as a potential therapeutic option for treatment of other pathogenic coronaviruses such as SARS1 and MERS.
  • Immunogenicity and in vivo protection of a variant nanoparticle vaccine that confers broad protection against emerging SARS-CoV-2 variants

    Logue, James; Johnson, Robert M.; Patel, Nita; Zhou, Bin; Maciejewski, Sonia; Zhou, Haixia; Portnoff, Alyse D.; Tian, Jing-Hui; McGrath, Marisa E.; Haupt, Robert E.; et al. (2022-07-18)
    The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continues to spread globally. As SARS-CoV-2 has transmitted from person to person, variant viruses have emerged with elevated transmission rates and higher risk of infection for vaccinees. We present data showing that the Novavax® recombinant prefusionstabilized Spike (rS) protein based on the B.1.351 sequence (rSB.1.351) was highly immunogenic in mice and produced neutralizing antibodies against SARS-CoV-2/WA1, B.1.1.7, and B.1.351. Mice vaccinated with the Novavax® prototype vaccine NVX-CoV2373 (rSWU1) or rS-B.1.351 alone, in combination, or as a heterologous prime boost, were protected when challenged with live SARS-CoV-2/B.1.1.7 or SARS-CoV-2/B.1.351. Virus titer was reduced to undetectable levels in the lungs post-challenge in all vaccinated mice, and Th1-skewed cellular responses were observed. A strong anamnestic response was demonstrated in baboons boosted with rS-B.1.351 approximately one year after immunization with NVX-CoV2373 (rS-WU1). An rS-B.1.351 vaccine alone or in combination with prototype rS-WU1 induced protective antibody- and cell-mediated responses that were protective against challenge with SARS-CoV-2 variant viruses.
  • Extracellular vesicles coordinate stress-dependent mitochondrial programming

    Moon, Nickole; Chan, Jennifer; Morgan, Christopher; Bale, Tracy, 1969- (2022-07)
  • Microtubule disruption reduces tumor cell migration and invasion while microtubule stabilizers increase metastasis phenotypes (2)

    Thompson, Keyata N.; Campbell, Riyan N.; Ju, Julia A.; Annis, David A.; Chang, Katarina T.; Mull, Makenzy L.; Stemberger, Megan; Vitolo, Michele I.; Martin, Stuart S. (2022-06)
  • Pharmacometabolomics of clopidogrel: Determining the genetic and metabolic contributors to clopidogrel response

    Bromberek, Sarah Katherine; Beitelshees, Amber L. (2021)
    Clopidogrel is a commonly prescribed antiplatelet drug and there is considerable variability in response. The PAPI study was conducted in 687 individuals to determine the genetic predictors of clopidogrel response. Targeted metabolomic profiling of 42 amines was performed in a subset of 198 PAPI subjects with genetics data available. We identified the metabolic signature of clopidogrel and determined metabolites associated with clopidogrel-induced changes in platelet reactivity. We found tyrosine was most significantly changed after exposure to clopidogrel, and BCAAs baseline levels were associated with clopidogrel-induced changes in platelet aggregation. Gaining insights into factors that influence variability in antiplatelet response is important for identifying novel antiplatelet mechanisms or biomarkers for predicting response. These findings can have long-term implications toward advancing precision medicine in antiplatelet therapy.

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