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  • 1
    Online Resource
    Online Resource
    The Mechanism of Mitochondrial Injury in Alpha-1 Antitrypsin Deficiency Mediated Liver Disease
    MDPI AG ; 2021
    In:  International Journal of Molecular Sciences Vol. 22, No. 24 ( 2021-12-09), p. 13255-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 22, No. 24 ( 2021-12-09), p. 13255-
    Abstract: Alpha-1 antitrypsin deficiency (AATD) is caused by a single mutation in the SERPINA1 gene, which culminates in the accumulation of misfolded alpha-1 antitrypsin (ZAAT) within the endoplasmic reticulum (ER) of hepatocytes. AATD is associated with liver disease resulting from hepatocyte injury due to ZAAT-mediated toxic gain-of-function and ER stress. There is evidence of mitochondrial damage in AATD-mediated liver disease; however, the mechanism by which hepatocyte retention of aggregated ZAAT leads to mitochondrial injury is unknown. Previous studies have shown that ER stress is associated with both high concentrations of fatty acids and mitochondrial dysfunction in hepatocytes. Using a human AAT transgenic mouse model and hepatocyte cell lines, we show abnormal mitochondrial morphology and function, and dysregulated lipid metabolism, which are associated with hepatic expression and accumulation of ZAAT. We also describe a novel mechanism of ZAAT-mediated mitochondrial dysfunction. We provide evidence that misfolded ZAAT translocates to the mitochondria for degradation. Furthermore, inhibition of ZAAT expression restores the mitochondrial function in ZAAT-expressing hepatocytes. Altogether, our results show that ZAAT aggregation in hepatocytes leads to mitochondrial dysfunction. Our findings suggest a plausible model for AATD liver injury and the possibility of mechanism-based therapeutic interventions for AATD liver disease.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms222413255
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
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  • 2
    Online Resource
    Online Resource
    Bcl2 Flexible Loop Domain Positively and Negatively Regulates Survival Function through Direct Interaction with p53.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 2623-2623
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 2623-2623
    Abstract: p53 not only functions as a transcription factor but also has a direct extranuclear apoptogenic role at the mitochondria. We have discovered that DNA damage-induced p53/Bcl2 binding is associated with decreased Bcl2/Bax interaction and increased apoptotic cell death in a mechanism regulated by Bcl2’s flexible loop regulatory domain (FLD) in IL3-dependent myeloid NSF/N1.H7 cells. Purified p53 protein can disrupt the Bcl2/Bax complex by directly binding to a negative regulatory region of the FLD (aa32–68). Deletion of the negative regulatory region (aa32–68) abolishes Bcl2/ p53 binding and enhances its antiapoptotic function. Removal of aa69–87 of the FLD, which contains Bcl2’s phosphorylation site(s) (T69, S70 and S87), enhances Bcl2/p53 binding and abrogates Bcl2’s potent survival activity, indicating this is a positive regulatory region. Phosphorylation of Bcl2 in the FLD inhibits p53 binding since the phosphomimetic T69E/S70E/S87E (EEE) but not the nonphosphorylatable T69A/S70A/S87A (AAA) Bcl2 mutant displays a reduced capacity to bind p53 and more potently inhibits p53-induced cytochrome c release. A full-length Bcl2 loop-only protein (aa32–87) can directly bind p53 to impede Bcl2/p53 binding in vitro. Either DNA damage or expression of p53 targeted to mitochondria results in Bcl2/p53 binding followed by exposure of Bcl2’s BH3 domain and inactivation of Bcl2’s antiapoptotic function. Therefore, Bcl2’s FLD contains both a positive and negative regulatory regions which functionally regulate Bcl2’s antiapoptotic activity via differential binding of Bax and p53, respectively.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.2623.2623
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 3
    Online Resource
    Online Resource
    Protein Phosphatase 2A Inactivates Bcl2’s Antiapoptotic Function by Dephosphorylation and Up-Regulation of Bcl2-p53 Binding.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-16), p. 1436-1436
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 1436-1436
    Abstract: DNA damage-induced p53/Bcl2 interaction at the outer mitochondrial membranes results in a Bcl2 conformational change and loss of its antiapoptotic function. Our data now indicate that either treatment of cells with the protein phosphatase 2A (PP2A) inhibitor, okadaic acid (10 nM), or specific disruption of PP2A activity by the expression of SV40 small tumor antigen enhances Bcl2 phosphorylation and suppresses the cisplatin-stimulated Bcl2-p53 interaction in association with prolonged cell survival. By contrast, C2-ceramide, a potent PP2A activator, reduces Bcl2 phosphorylation and increases Bcl2-p53 binding and promotes apoptotic cell death, suggesting that PP2A may function as a physiological regulator of Bcl2 by, at least in part, affecting its association with p53. Overexpression of the PP2A catalytic subunit (PP2A/C) suppresses Bcl2 phosphorylation in association with increased p53-Bcl2 binding and apoptotic cell death. By contrast, specific depletion of PP2A/C by RNA interference enhances Bcl2 phosphorylation, suppresses p53-Bcl2 interaction and prolongs cell survival. Purified PP2A can directly enhance the formation of the p53-Bcl2 complex in vitro in an okadaic acid-sensitive manner, supporting a direct mechanism. Importantly, PP2A directly interacts with Bcl2 at its BH4 domain which may function as the PP2A ‘docking site’ to potentially ‘bridge’ PP2A to the flexible loop domain which contains the physiological serine 70 phosphorylation site. Thus, PP2A may provide a double whammy to Bcl2’s survival function by both dephosphorylating and enhancing p53-Bcl2 binding. Therapeutically stimulating Bcl2 dephosphorylation and/or increasing Bcl2/p53 binding by activating PP2A may represent an efficient and novel antineoplastic approach.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.1436.1436
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
    Online Resource
    Online Resource
    Bcl2's Flexible Loop Domain Regulates p53 Binding and Survival
    Informa UK Limited ; 2006
    In:  Molecular and Cellular Biology Vol. 26, No. 12 ( 2006-06-01), p. 4421-4434
    Details
    In: Molecular and Cellular Biology, Informa UK Limited, Vol. 26, No. 12 ( 2006-06-01), p. 4421-4434
    Type of Medium: Online Resource
    ISSN: 1098-5549
    URL: Article
    DOI: 10.1128/MCB.01647-05
    Language: English
    Publisher: Informa UK Limited
    Publication Date: 2006
    detail.hit.zdb_id: 1474919-1
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  • 5
    Online Resource
    Online Resource
    Association of Smoking, Alcohol Consumption, Blood Pressure, Body Mass Index, and Glycemic Risk Factors With Age-Related Macular Degeneration : A Mendelian Randomization Study
    American Medical Association (AMA) ; 2021
    In:  JAMA Ophthalmology Vol. 139, No. 12 ( 2021-12-01), p. 1299-
    Details
    In: JAMA Ophthalmology, American Medical Association (AMA), Vol. 139, No. 12 ( 2021-12-01), p. 1299-
    Type of Medium: Online Resource
    ISSN: 2168-6165
    URL: Article
    DOI: 10.1001/jamaophthalmol.2021.4601
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2021
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  • 6
    Online Resource
    Online Resource
    Accelerating advanced practice palliative care competencies: An educational research initiative
    Sciedu Press ; 2023
    In:  Journal of Nursing Education and Practice Vol. 13, No. 11 ( 2023-07-25), p. 31-
    Details
    In: Journal of Nursing Education and Practice, Sciedu Press, Vol. 13, No. 11 ( 2023-07-25), p. 31-
    Abstract: Objective: To describe the process and impact of integrating palliative care into the nursing curriculum to accelerate advanced practice palliative care competencies.Methods: Educational research was implemented at the Johns Hopkins University School of Nursing, Baltimore, MD to integrate palliative care knowledge and skills into the advanced practice nursing curriculum. Palliative care principles and skills were threaded through the curriculum and resources and contents were shared across graduate programs, faculty members, and students throughout the school. Additionally, palliative care workshops, symposium and conference were organized at the school to increase academic-practice partnerships and disseminate project progress. The initiative was evaluated using the Palliative Care Quiz for Nursing (PCQN) and Palliative-Care Self-efficacy Scale (PCSES) among faculty and students annually. Additional data on overall feedback on research activities were collected. Data were analyzed using descriptive statistics, t-tests, and analysis of variance.Results: In total 54 students, faculty, and clinicians participated in two workshops. The evaluation of workshops identified a significant improvement in confidence scores. In total, 620 faculty and students responded to the annual school-wide survey: 203 in 2019, 242 in 2020, and 175 in 2021. There were no significant changes in palliative care knowledge and confidence scores after integrating content within the curriculum. The participants agreed or strongly agreed with the overall positive feedback for the project events regarding expectation, pace, relevance, and objective.Conclusions: The academic-practice partnership could be one model for improving palliative care competencies. More educational initiatives are needed to identify the role of educational models with appropriate evaluation measures in preparing a competent palliative care workforce.
    Type of Medium: Online Resource
    ISSN: 1925-4059 , 1925-4040
    URL: Article
    DOI: 10.5430/jnep.v13n11p31
    Language: Unknown
    Publisher: Sciedu Press
    Publication Date: 2023
    detail.hit.zdb_id: 2648998-3
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  • 7
    Online Resource
    Online Resource
    A transcriptome-wide association study based on 27 tissues identifies 106 genes potentially relevant for disease pathology in age-related macular degeneration
    Springer Science and Business Media LLC ; 2020
    In:  Scientific Reports Vol. 10, No. 1 ( 2020-01-31)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 10, No. 1 ( 2020-01-31)
    Abstract: Genome-wide association studies (GWAS) for late stage age-related macular degeneration (AMD) have identified 52 independent genetic variants with genome-wide significance at 34 genomic loci. Typically, such an approach rarely results in the identification of functional variants implicating a defined gene in the disease process. We now performed a transcriptome-wide association study (TWAS) allowing the prediction of effects of AMD-associated genetic variants on gene expression. The TWAS was based on the genotypes of 16,144 late-stage AMD cases and 17,832 healthy controls, and gene expression was imputed for 27 different human tissues which were obtained from 134 to 421 individuals. A linear regression model including each individuals imputed gene expression data and the respective AMD status identified 106 genes significantly associated to AMD variants in at least one tissue (Q-value  〈  0.001). Gene enrichment analysis highlighted rather systemic than tissue- or cell-specific processes. Remarkably, 31 of the 106 genes overlapped with significant GWAS signals of other complex traits and diseases, such as neurological or autoimmune conditions. Taken together, our study highlights the fact that expression of genes associated with AMD is not restricted to retinal tissue as could be expected for an eye disease of the posterior pole, but instead is rather ubiquitous suggesting processes underlying AMD pathology to be of systemic nature.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-020-58510-9
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2615211-3
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  • 8
    Online Resource
    Online Resource
    A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants
    Springer Science and Business Media LLC ; 2016
    In:  Nature Genetics Vol. 48, No. 2 ( 2016-2), p. 134-143
    Details
    In: Nature Genetics, Springer Science and Business Media LLC, Vol. 48, No. 2 ( 2016-2), p. 134-143
    Type of Medium: Online Resource
    ISSN: 1061-4036 , 1546-1718
    URL: Article
    DOI: 10.1038/ng.3448
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2016
    detail.hit.zdb_id: 1494946-5
    SSG: 12
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  • 9
    Online Resource
    Online Resource
    Mono- and multisite phosphorylation enhances Bcl2's antiapoptotic function and inhibition of cell cycle entry functions
    Proceedings of the National Academy of Sciences ; 2004
    In:  Proceedings of the National Academy of Sciences Vol. 101, No. 1 ( 2004-01-06), p. 153-158
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 101, No. 1 ( 2004-01-06), p. 153-158
    Abstract: Bcl2 functions to suppress apoptosis and retard cell cycle entry. Single-site phosphorylation at serine 70 (S70) is required for Bcl2's antiapoptotic function, and multisite phosphorylation at threonine 69 (T69), S70, and S87 has been reported to inactivate Bcl2. To address this apparent conflict and identify the regulatory role for Bcl2 phosphorylation in cell death and cell cycle control, a series of serine/threonine (S/T) → glutamate/alanine (E/A) mutants including T69E/A, S70E/A, S87E/A, T69E/S70A/S87A (EAA), T69A/S70E/S87A (AEA), T69A/S70A/S87E (AAE), T69E/S70E/S87E (EEE), and T69A/S70A/S87A (AAA) was created to mimic or abrogate, respectively, either single-site or multisite phosphorylation. The survival and cell cycle status of cells expressing the phosphomimetic or nonphosphorylatable Bcl2 mutants were compared. Surprisingly, all of the E but not the A Bcl2 mutants potently enhance cell survival after stress and retard G 1 /S cell cycle transition. The EEE Bcl2 mutant is the most potent, indicating a possible cumulative advantage for multisite phosphorylation of Bcl2 in survival and retardation of G 1 /S transition functions. Because the E-containing Bcl2 mutants, but not the A-containing mutants, can more potently block cytochrome c release from mitochondria during apoptotic stress, even at times when steady-state expression levels are similar for all mutants, we conclude that phosphorylation at one or multiple sites within the flexible loop domain of Bcl2 not only stimulates antiapoptotic activity but also can regulate cell cycle entry.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2533920100
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2004
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 10
    Online Resource
    Online Resource
    Loss of Tnk1/Kos1 in Mice Is Associated with B-Lymphomas Specifically DLBCL.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 3972-3972
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 3972-3972
    Abstract: Abstract 3972 Poster Board III-908 The ubiquitously expressed nonreceptor tyrosine kinase (NRPTK) Tnk1/Kos1 (Thirty-eight negative kinase/Kinase of the embryonic stem cell) functions as a negative regulator of growth in both murine and human cells by suppressing the Ras-Raf1-MapK growth pathway. Since Tnk1 requires its intrinsic protein tyrosine kinase activity to suppress Ras activity and cell growth, the kinase domain is critical for its function and deletion by targeted homologous recombination leads to spontaneous tumor development in mice. To date, Tnk1/Kos1 is the only reported NRPTK that functions as a tumor suppressor in vivo, while other tyrosine kinases may be oncogenic when mutated or activated. While Tnk1 knockout mice may develop primary tumors in different tissues/organs, mainly B-cell lymphomas develop in Tnk1-/- (80%, 47 of 60) and Tnk1+/- (57%, 31 of 54) mice with similar characteristics of Diffuse Large B-Cell Lymphoma (DLBCL) and Burkitt Lymphoma types. Typically in lymphomas from Tnk1+/- mice the intact wild type allele is epigenetically modified and silenced by promoter methylation. Importantly, the absence of Tnk1 occurs only in the tumor tissue but not in the adjacent uninvolved tissue. Now we find allelic loss with associated reduced expression of Tnk1 transcripts and protein in a cohort of human DLBCL patients. These data underscore the potential clinical relevance of Tnk1 in human hematological malignancies. Furthermore, the B-cell lymphomas that develop in the Tnk1 knockout mice express aberrantly high Ras activity indicating that unmutated Ras is a likely necessary effector of B-cell lymphoma development and survival. We also recently determined that the aberrantly high levels Ras activity in lymphoma (but not paired uninvolved lymphoid tissue) from mice results from a novel mechanism involving stabilization of the Grb2-Sos1 complex to maintain activated Ras in these tissues. Therefore, the Tnk1 knockout mouse provides a unique opportunity to test whether and how Tnk1 is involved in the development and/or maintenance of the B-cell lymphomas that develop in the absence of Ras mutation which may have clinical significance for patients with lymphoma. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.3972.3972
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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