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  • 1
    Online Resource
    Online Resource
    A novel streptococcal cell–cell communication peptide promotes pneumococcal virulence and biofilm formation
    Wiley ; 2017
    In:  Molecular Microbiology Vol. 105, No. 4 ( 2017-08), p. 554-571
    Details
    In: Molecular Microbiology, Wiley, Vol. 105, No. 4 ( 2017-08), p. 554-571
    Abstract: Streptococcus pneumoniae (pneumococcus) is a major human pathogen. It is a common colonizer of the human respiratory track, where it utilizes cell–cell communication systems to coordinate population‐level behaviors. We reasoned that secreted peptides that are highly expressed during infection are pivotal for virulence. Thus, we used in silico pattern searches to define a pneumococcal secretome and analyzed the transcriptome of the clinically important PMEN1 lineage to identify which peptide‐encoding genes are highly expressed in vivo . In this study, we characterized virulence peptide 1 ( vp1 ), a highly expressed Gly–Gly peptide‐encoding gene in chinchilla middle ear effusions. The vp1 gene is widely distributed across pneumococcus as well as encoded in related species. Studies in the chinchilla model of middle ear infection demonstrated that VP1 is a virulence determinant. The vp1 gene is positively regulated by a transcription factor from the Rgg family and its cognate SHP (short hydrophobic peptide). In vitro data indicated that VP1 promotes increased thickness and biomass for biofilms grown on chinchilla middle ear epithelial cells. Furthermore, the wild‐type biofilm is restored with the exogenous addition of synthetic VP1. We conclude that VP1 is a novel streptococcal regulatory peptide that controls biofilm development and pneumococcal pathogenesis.
    Type of Medium: Online Resource
    ISSN: 0950-382X , 1365-2958
    URL: Issue
    URL: Article
    DOI: 10.1111/mmi.2017.105.issue-4
    DOI: 10.1111/mmi.13721
    Language: English
    Publisher: Wiley
    Publication Date: 2017
    detail.hit.zdb_id: 1501537-3
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  • 2
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    Physical and Functional Interaction between the Dopamine Transporter and the Synaptic Vesicle Protein Synaptogyrin-3
    Society for Neuroscience ; 2009
    In:  The Journal of Neuroscience Vol. 29, No. 14 ( 2009-04-08), p. 4592-4604
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 29, No. 14 ( 2009-04-08), p. 4592-4604
    Abstract: Uptake through the dopamine transporter (DAT) represents the primary mechanism used to terminate dopaminergic transmission in brain. Although it is well known that dopamine (DA) taken up by the transporter is used to replenish synaptic vesicle stores for subsequent release, the molecular details of this mechanism are not completely understood. Here, we identified the synaptic vesicle protein synaptogyrin-3 as a DAT interacting protein using the split ubiquitin system. This interaction was confirmed through coimmunoprecipitation experiments using heterologous cell lines and mouse brain. DAT and synaptogyrin-3 colocalized at presynaptic terminals from mouse striatum. Using fluorescence resonance energy transfer microscopy, we show that both proteins interact in live neurons. Pull-down assays with GST (glutathione S -transferase) proteins revealed that the cytoplasmic N termini of both DAT and synaptogyrin-3 are sufficient for this interaction. Furthermore, the N terminus of DAT is capable of binding purified synaptic vesicles from brain tissue. Functional assays revealed that synaptogyrin-3 expression correlated with DAT activity in PC12 and MN9D cells, but not in the non-neuronal HEK-293 cells. These changes were not attributed to changes in transporter cell surface levels or to direct effect of the protein–protein interaction. Instead, the synaptogyrin-3 effect on DAT activity was abolished in the presence of the vesicular monoamine transporter-2 (VMAT2) inhibitor reserpine, suggesting a dependence on the vesicular DA storage system. Finally, we provide evidence for a biochemical complex involving DAT, synaptogyrin-3, and VMAT2. Collectively, our data identify a novel interaction between DAT and synaptogyrin-3 and suggest a physical and functional link between DAT and the vesicular DA system.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.4559-08.2009
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2009
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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  • 3
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    Abstract MP08: Telomerase Reverse Transcriptase Mediates Osteogenesis In Calcific Aortic Valve Disease
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 41, No. Suppl_1 ( 2021-09)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 41, No. Suppl_1 ( 2021-09)
    Abstract: Calcific aortic valve disease (CAVD) is the leading heart valve disorder in the US. It is characterized by an active accumulation of calcium nodules on the aortic valve leaflets which lead to stiffening and remodeling of the valve leaflets causing valve dysfunction, cardiac failure and increased stroke risk. Inflammation and mechanical stresses contribute to CAVD pathogenesis. However, the mechanisms driving the fibrocalcific remodeling of the aortic valve are currently ill-defined. Multiple studies have revealed that the catalytic subunit of telomerase reverse transcriptase (TERT) can induce gene transcription and its overexpression primes mesenchymal stem cells to differentiate into osteoblasts, suggesting that TERT has a role in the activation of osteogenic transcriptional programs. We hypothesized that TERT contributes to early events leading to calcification of the valve leaflet. In human calcified valve tissue, we found that TERT protein is highly expressed in areas of calcification compared to control valve tissue, with no effect on telomere length. Alpha-SMA, a VIC activation marker, and RUNX2, a key transcription factor involved in the osteogenic differentiation of osteoblast, were also elevated in CAVD tissue. Under osteogenic differentiation conditions, human valve interstitial cells (VICs) upregulated TERT, RUNX2, and alpha-SMA protein levels and calcified, while CAVD VICs calcified de novo. Inflammatory stimuli intensified in vitro calcification, and induced TERT, RUNX2, and alpha-SMA protein expression. PLA and ChIP analysis showed that TERT interacts with interacted with Signal Transducer and Activator of Transcription 5A/B (STAT5) and together bind to RUNX2 promoter, respectively. shRNA-mediated TERT downregulation reduced expression of RUNX2 and alpha-SMA and genetic deletion of Tert in murine mesenchymal stem cells and vascular smooth muscle cells prevented calcification. These data provide evidence that TERT is required for calcification, regulates the transition of quiescent VICs into calcifying VICs, and that STAT5 functions as a TERT-interacting partner for DNA binding.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.41.suppl_1.MP08
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 1494427-3
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  • 4
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    Abstract 484: Telomerase Reverse Transcriptase And Signal Transducer And Activator Of Transcription 5a Mediates Osteogenesis In Calcific Aortic Valve Disease
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 42, No. Suppl_1 ( 2022-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 42, No. Suppl_1 ( 2022-05)
    Abstract: Cardiovascular calcification is a highly prevalent pathological process found in the vessels and valves in the elderly and patients with diabetes, hypertension, and renal disease. Calcific aortic valve disease (CAVD) stiffens and remodels the valve leaflets and leads to valve dysfunction, cardiac failure, and increased stroke risk. Vascular calcification can occur in the necrotic core of atherosclerotic plaques or in the medial layer of arteries. However, the initial steps dictating the onset of calcification remain ill-defined. Multiple studies have revealed that the protein telomerase reverse transcriptase (TERT), the catalytic subunit of the enzymatic complex required for telomere length maintenance, is a co-factor to stimulate gene transcription, and its overexpression primes mesenchymal stem cells to differentiate into osteoblasts. We determined that TERT is required for the calcification valve interstitial cells (VICs) and coronary smooth muscle cells (SMCs); TERT expression and protein are increased in calcified tissues and cell lines, independent of changes in telomere length. Genetic deletion of Tert in murine VICs and SMCs prevented calcification. Upon osteogenic stimulation, TERT binds to Signal Transducer and Activator of Transcription 5A/B (STAT5) to translocate into the nucleus where the complex binds to the RUNX2 promoter to induce expression. We found that VICs cultured under inflammatory conditions calcified and upregulated STAT5, suggesting that inflammatory signaling may promote calcification in VICs. Lastly, testing several STAT5 inhibitors, we determined that STAT5A is required for the calcification of VICs and SMCs. These findings are the first to suggest that TERT and STAT5 are involved in driving the osteogenic switch and calcification of vascular cells and constitute potential therapeutic targets for the treatment of CAVD.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.42.suppl_1.484
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 1494427-3
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  • 5
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    Online Resource
    Antiviral Activity of Human OASL Protein Is Mediated by Enhancing Signaling of the RIG-I RNA Sensor
    Elsevier BV ; 2014
    In:  Immunity Vol. 40, No. 6 ( 2014-06), p. 936-948
    Details
    In: Immunity, Elsevier BV, Vol. 40, No. 6 ( 2014-06), p. 936-948
    Type of Medium: Online Resource
    ISSN: 1074-7613
    URL: Article
    DOI: 10.1016/j.immuni.2014.05.007
    RVK:
    XA 48754.8
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2014
    detail.hit.zdb_id: 2001966-X
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  • 6
    Online Resource
    Online Resource
    Gene Acquisition by a Distinct Phyletic Group within Streptococcus pneumoniae Promotes Adhesion to the Ocular Epithelium
    American Society for Microbiology ; 2017
    In:  mSphere Vol. 2, No. 5 ( 2017-10-25)
    Details
    In: mSphere, American Society for Microbiology, Vol. 2, No. 5 ( 2017-10-25)
    Abstract: Streptococcus pneumoniae (pneumococcus) displays broad tissue tropism and infects multiple body sites in the human host. However, infections of the conjunctiva are limited to strains within a distinct phyletic group with multilocus sequence types ST448, ST344, ST1186, ST1270, and ST2315. In this study, we sequenced the genomes of six pneumococcal strains isolated from eye infections. The conjunctivitis isolates are grouped in a distinct phyletic group together with a subset of nasopharyngeal isolates. The keratitis (infection of the cornea) and endophthalmitis (infection of the vitreous body) isolates are grouped with the remainder of pneumococcal strains. Phenotypic characterization is consistent with morphological differences associated with the distinct phyletic group. Specifically, isolates from the distinct phyletic group form aggregates in planktonic cultures and chain-like structures in biofilms grown on abiotic surfaces. To begin to investigate the association between genotype and epidemiology, we focused on a predicted surface-exposed adhesin (SspB) encoded exclusively by this distinct phyletic group. Phylogenetic analysis of the gene encoding SspB in the context of a streptococcal species tree suggests that sspB was acquired by lateral gene transfer from Streptococcus suis . Furthermore, an sspB deletion mutant displays decreased adherence to cultured cells from the ocular epithelium compared to the isogenic wild-type and complemented strains. Together these findings suggest that acquisition of genes from outside the species has contributed to pneumococcal tissue tropism by enhancing the ability of a subset of strains to infect the ocular epithelium causing conjunctivitis. IMPORTANCE Changes in the gene content of pathogens can modify their ability to colonize and/or survive in different body sites in the human host. In this study, we investigate a gene acquisition event and its role in the pathogenesis of Streptococccus pneumoniae (pneumococcus). Our findings suggest that the gene encoding the predicted surface protein SspB has been transferred from Streptococcus suis (a distantly related streptococcal species) into a distinct set of pneumococcal strains. This group of strains distinguishes itself from the remainder of pneumococcal strains by extensive differences in genomic composition and by the ability to cause conjunctivitis. We find that the presence of sspB increases adherence of pneumococcus to the ocular epithelium. Thus, our data support the hypothesis that a subset of pneumococcal strains has gained genes from neighboring species that enhance their ability to colonize the epithelium of the eye, thus expanding into a new niche.
    Type of Medium: Online Resource
    ISSN: 2379-5042
    URL: Article
    DOI: 10.1128/mSphere.00213-17
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2017
    detail.hit.zdb_id: 2844248-9
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  • 7
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    Online Resource
    Introduction to the Aortic Valve Disease Review Series
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Circulation Research Vol. 128, No. 9 ( 2021-04-30), p. 1327-1329
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 128, No. 9 ( 2021-04-30), p. 1327-1329
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/CIRCRESAHA.121.319286
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 1467838-X
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  • 8
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    Ecto-5′-nucleotidase (Nt5e/CD73)-mediated adenosine signaling attenuates TGFβ-2 induced elastin and cellular contraction
    American Physiological Society ; 2023
    In:  American Journal of Physiology-Cell Physiology Vol. 324, No. 2 ( 2023-02-01), p. C327-C338
    Details
    In: American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 324, No. 2 ( 2023-02-01), p. C327-C338
    Abstract: Arterial calcification due to deficiency of CD73 (ACDC) is a rare genetic disease caused by a loss-of-function mutation in the NT5E gene encoding the ecto-5′-nucleotidase (cluster of differentiation 73, CD73) enzyme. Patients with ACDC develop vessel arteriomegaly, tortuosity, and vascular calcification in their lower extremity arteries. Histological analysis shows that patients with ACDC vessels exhibit fragmented elastin fibers similar to that seen in aneurysmal-like pathologies. It is known that alterations in transforming growth factor β (TGFβ) pathway signaling contribute to this elastin phenotype in several connective tissue diseases, as TGFβ regulates extracellular matrix (ECM) remodeling. Our study investigates whether CD73-derived adenosine modifies TGFβ signaling in vascular smooth muscle cells (SMCs). We show that Nt5e −/− SMCs have elevated contractile markers and elastin gene expression compared with Nt5e +/+ SMCs. Ecto-5′-nucleotidase ( Nt5e)-deficient SMCs exhibit increased TGFβ-2 and activation of small mothers against decapentaplegic (SMAD) signaling, elevated elastin transcript and protein, and potentiate SMC contraction. These effects were diminished when the A2b adenosine receptor was activated. Our results identify a novel link between adenosine and TGFβ signaling, where adenosine signaling via the A2b adenosine receptor attenuates TGFβ signaling to regulate SMC homeostasis. We discuss how disruption in adenosine signaling is implicated in ACDC vessel tortuosity and could potentially contribute to other aneurysmal pathogenesis.
    Type of Medium: Online Resource
    ISSN: 0363-6143 , 1522-1563
    URL: Article
    DOI: 10.1152/ajpcell.00054.2022
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2023
    detail.hit.zdb_id: 1477334-X
    SSG: 12
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  • 9
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    Isolation of Human Primary Valve Cells for In vitro Disease Modeling
    MyJove Corporation ; 2021
    In:  Journal of Visualized Experiments , No. 170 ( 2021-04-16)
    Details
    In: Journal of Visualized Experiments, MyJove Corporation, , No. 170 ( 2021-04-16)
    Type of Medium: Online Resource
    ISSN: 1940-087X
    URL: Article
    DOI: 10.3791/62439
    Language: English
    Publisher: MyJove Corporation
    Publication Date: 2021
    detail.hit.zdb_id: 2259946-0
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  • 10
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    Abstract 15843: A Novel Role for Telomerase in Calcific Aortic Valve Disease
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Circulation Vol. 142, No. Suppl_3 ( 2020-11-17)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 142, No. Suppl_3 ( 2020-11-17)
    Abstract: Introduction: Calcific aortic valve disease (CAVD) is a disorder characterized by the slow, but a progressive thickening of the aortic valve leaflet that develops into severe calcification. The only current therapy is aortic valve replacement. Telomerase is an enzymatic complex best known for its telomere-extending activities on the ends of chromosomes yet, the catalytic subunit (TERT) has been implicated in multiple non-canonical transcriptional and epigenetic activities, including priming of mesenchymal stem cells (MSCs) to differentiate into osteoblasts, and transcriptional regulation of inflammatory genes. Hypothesis: We hypothesize that non-canonical TERT activity contributes to the progression of CAVD. Methods: We performed biochemical assays to study the role of TERT in the calcification process using primary tissues and valve interstitial cells (VICs) from control and CAVD patients, smooth muscle cells (SMCs) from WT and Tert knockout mice, and mesenchymal stem cells (MSCs). Results: We found that TERT protein is highly expressed in calcified aortic valves and VICs isolated from patients with calcified valves, compared to healthy valves. VICs can be induced to calcify under osteogenic differentiation conditions, and we found that TERT accumulated after fourteen days in this culture, with no effect on either telomere length, proliferation, or senescence. We expanded the scope of our approach by evaluating TERT's influence on calcification of mice aortic smooth muscle cells (mSMCs). We found WT mSMCs readily calcified in vitro, but mSMCs from Tert knockout mice did not, and Tert deletion also reduced valve calcification in a Ldlr / Tert double knockout mice model compared to Ldlr knockout alone. In VICs, shRNA mediated TERT downregulation reduced expression of RUNX2 . Finally, we found that inflammatory signals intensify in vitro calcification, induce TERT expression, and we show evidence that TERT interacts with STAT5. Conclusion: Our data suggest that TERT is required for valve calcification by stimulating transcriptional pathways promoting the osteogenic transition of quiescent VICs into calcifying VICs in the aortic valve. These results indicate that TERT is an active contributor to the calcification process of valve tissues.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.142.suppl_3.15843
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
    detail.hit.zdb_id: 1466401-X
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