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  • 1
    In: Genes, MDPI AG, Vol. 14, No. 5 ( 2023-05-15), p. 1086-
    Abstract: CHARGE syndrome typically results from mutations in the gene encoding chromodomain helicase DNA-binding protein 7 (CHD7). CHD7 is involved in regulating neural crest development, which gives rise to tissues of the skull/face and the autonomic nervous system (ANS). Individuals with CHARGE syndrome are frequently born with anomalies requiring multiple surgeries and often experience adverse events post-anesthesia, including oxygen desaturations, decreased respiratory rates, and heart rate abnormalities. Central congenital hypoventilation syndrome (CCHS) affects ANS components that regulate breathing. Its hallmark feature is hypoventilation during sleep, clinically resembling observations in anesthetized CHARGE patients. Loss of PHOX2B (paired-like homeobox 2b) underlies CCHS. Employing a chd7-null zebrafish model, we investigated physiologic responses to anesthesia and compared these to loss of phox2b. Heart rates were lower in chd7 mutants compared to the wild-type. Exposure to tricaine, a zebrafish anesthetic/muscle relaxant, revealed that chd7 mutants took longer to become anesthetized, with higher respiratory rates during recovery. chd7 mutant larvae demonstrated unique phox2ba expression patterns. The knockdown of phox2ba reduced larval heart rates similar to chd7 mutants. chd7 mutant fish are a valuable preclinical model to investigate anesthesia in CHARGE syndrome and reveal a novel functional link between CHARGE syndrome and CCHS.
    Type of Medium: Online Resource
    ISSN: 2073-4425
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2527218-4
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  • 2
    Online Resource
    Online Resource
    American Society for Clinical Investigation ; 2023
    In:  Journal of Clinical Investigation Vol. 133, No. 10 ( 2023-5-15)
    In: Journal of Clinical Investigation, American Society for Clinical Investigation, Vol. 133, No. 10 ( 2023-5-15)
    Type of Medium: Online Resource
    ISSN: 1558-8238
    Language: English
    Publisher: American Society for Clinical Investigation
    Publication Date: 2023
    detail.hit.zdb_id: 2018375-6
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  • 3
    In: eLife, eLife Sciences Publications, Ltd, Vol. 9 ( 2020-07-28)
    Abstract: Dose-limiting toxicities for cisplatin administration, including ototoxicity and nephrotoxicity, impact the clinical utility of this effective chemotherapy agent and lead to lifelong complications, particularly in pediatric cancer survivors. Using a two-pronged drug screen employing the zebrafish lateral line as an in vivo readout for ototoxicity and kidney cell-based nephrotoxicity assay, we screened 1280 compounds and identified 22 that were both oto- and nephroprotective. Of these, dopamine and L-mimosine, a plant-based amino acid active in the dopamine pathway, were further investigated. Dopamine and L-mimosine protected the hair cells in the zebrafish otic vesicle from cisplatin-induced damage and preserved zebrafish larval glomerular filtration. Importantly, these compounds did not abrogate the cytotoxic effects of cisplatin on human cancer cells. This study provides insights into the mechanisms underlying cisplatin-induced oto- and nephrotoxicity and compelling preclinical evidence for the potential utility of dopamine and L-mimosine in the safer administration of cisplatin.
    Type of Medium: Online Resource
    ISSN: 2050-084X
    Language: English
    Publisher: eLife Sciences Publications, Ltd
    Publication Date: 2020
    detail.hit.zdb_id: 2687154-3
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  • 4
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 2013
    In:  BMC Plant Biology Vol. 13, No. 1 ( 2013-12)
    In: BMC Plant Biology, Springer Science and Business Media LLC, Vol. 13, No. 1 ( 2013-12)
    Type of Medium: Online Resource
    ISSN: 1471-2229
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2013
    detail.hit.zdb_id: 2059868-3
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 2011
    In:  BMC Plant Biology Vol. 11, No. 1 ( 2011-12)
    In: BMC Plant Biology, Springer Science and Business Media LLC, Vol. 11, No. 1 ( 2011-12)
    Abstract: Programmed cell death (PCD) is the regulated death of cells within an organism. The lace plant ( Aponogeton madagascariensis ) produces perforations in its leaves through PCD. The leaves of the plant consist of a latticework of longitudinal and transverse veins enclosing areoles. PCD occurs in the cells at the center of these areoles and progresses outwards, stopping approximately five cells from the vasculature. The role of mitochondria during PCD has been recognized in animals; however, it has been less studied during PCD in plants. Results The following paper elucidates the role of mitochondrial dynamics during developmentally regulated PCD in vivo in A. madagascariensis . A single areole within a window stage leaf (PCD is occurring) was divided into three areas based on the progression of PCD; cells that will not undergo PCD (NPCD), cells in early stages of PCD (EPCD), and cells in late stages of PCD (LPCD). Window stage leaves were stained with the mitochondrial dye MitoTracker Red CMXRos and examined. Mitochondrial dynamics were delineated into four categories (M1-M4) based on characteristics including distribution, motility, and membrane potential (ΔΨ m ). A TUNEL assay showed fragmented nDNA in a gradient over these mitochondrial stages. Chloroplasts and transvacuolar strands were also examined using live cell imaging. The possible importance of mitochondrial permeability transition pore (PTP) formation during PCD was indirectly examined via in vivo cyclosporine A (CsA) treatment. This treatment resulted in lace plant leaves with a significantly lower number of perforations compared to controls, and that displayed mitochondrial dynamics similar to that of non-PCD cells. Conclusions Results depicted mitochondrial dynamics in vivo as PCD progresses within the lace plant, and highlight the correlation of this organelle with other organelles during developmental PCD. To the best of our knowledge, this is the first report of mitochondria and chloroplasts moving on transvacuolar strands to form a ring structure surrounding the nucleus during developmental PCD. Also, for the first time, we have shown the feasibility for the use of CsA in a whole plant system. Overall, our findings implicate the mitochondria as playing a critical and early role in developmentally regulated PCD in the lace plant.
    Type of Medium: Online Resource
    ISSN: 1471-2229
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2011
    detail.hit.zdb_id: 2059868-3
    SSG: 12
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  • 6
    Online Resource
    Online Resource
    Future Medicine Ltd ; 2021
    In:  Future Oncology Vol. 17, No. 32 ( 2021-11), p. 4371-4387
    In: Future Oncology, Future Medicine Ltd, Vol. 17, No. 32 ( 2021-11), p. 4371-4387
    Abstract: Lay abstract The microbiome describes all of the microorganisms (including bacteria, viruses and fungi) that are normally present on and inside the human body. Some diseases, including cancer, can be caused or worsened by an ‘unbalanced’ or ‘unhealthy’ gut microbiome. Some drugs that are given to people who have cancer can change the microbiome. Importantly, components of the gut microbiome can also change how a cancer drug will work in someone. We can change the microbiome in certain ways, like by giving someone antibiotics. Understanding how the microbiome influences the way anticancer drugs work is important because it could help us understand how to make cancer treatment safer and more effective. This review article summarizes available research on the impact of the microbiome on cancer treatment.
    Type of Medium: Online Resource
    ISSN: 1479-6694 , 1744-8301
    Language: English
    Publisher: Future Medicine Ltd
    Publication Date: 2021
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  • 7
    In: Viruses, MDPI AG, Vol. 12, No. 1 ( 2019-12-20), p. 12-
    Abstract: Kaposi’s sarcoma associated-herpesvirus (KSHV, also known as human herpesvirus-8) is a gammaherpesvirus that establishes life-long infection in human B lymphocytes. KSHV infection is typically asymptomatic, but immunosuppression can predispose KSHV-infected individuals to primary effusion lymphoma (PEL); a malignancy driven by aberrant proliferation of latently infected B lymphocytes, and supported by pro-inflammatory cytokines and angiogenic factors produced by cells that succumb to lytic viral replication. Here, we report the development of the first in vivo model for a virally induced lymphoma in zebrafish, whereby KSHV-infected PEL tumor cells engraft and proliferate in the yolk sac of zebrafish larvae. Using a PEL cell line engineered to produce the viral lytic switch protein RTA in the presence of doxycycline, we demonstrate drug-inducible reactivation from KSHV latency in vivo, which enabled real-time observation and evaluation of latent and lytic phases of KSHV infection. In addition, we developed a sensitive droplet digital PCR method to monitor latent and lytic viral gene expression and host cell gene expression in xenografts. The zebrafish yolk sac is not well vascularized, and by using fluorogenic assays, we confirmed that this site provides a hypoxic environment that may mimic the microenvironment of some human tumors. We found that PEL cell proliferation in xenografts was dependent on the host hypoxia-dependent translation initiation factor, eukaryotic initiation factor 4E2 (eIF4E2). This demonstrates that the zebrafish yolk sac is a functionally hypoxic environment, and xenografted cells must switch to dedicated hypoxic gene expression machinery to survive and proliferate. The establishment of the PEL xenograft model enables future studies that exploit the innate advantages of the zebrafish as a model for genetic and pharmacologic screens.
    Type of Medium: Online Resource
    ISSN: 1999-4915
    Language: English
    Publisher: MDPI AG
    Publication Date: 2019
    detail.hit.zdb_id: 2516098-9
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  • 8
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 2012
    In:  BMC Plant Biology Vol. 12, No. 1 ( 2012-12)
    In: BMC Plant Biology, Springer Science and Business Media LLC, Vol. 12, No. 1 ( 2012-12)
    Abstract: Developmentally regulated programmed cell death (PCD) is the controlled death of cells that occurs throughout the life cycle of both plants and animals. The lace plant ( Aponogeton madagascariensis ) forms perforations between longitudinal and transverse veins in spaces known as areoles, via developmental PCD; cell death begins in the center of these areoles and develops towards the margin, creating a gradient of PCD. This gradient was examined using both long- and short-term live cell imaging, in addition to histochemical staining, in order to establish the order of cellular events that occur during PCD. Results The first visible change observed was the reduction in anthocyanin pigmentation, followed by initial chloroplast changes and the bundling of actin microfilaments. At this stage, an increased number of transvacuolar strands (TVS) was evident. Perhaps concurrently with this, increased numbers of vesicles, small mitochondrial aggregates, and perinuclear accumulation of both chloroplasts and mitochondria were observed. The invagination of the tonoplast membrane and the presence of vesicles, both containing organelle materials, suggested evidence for both micro- and macro-autophagy, respectively. Mitochondrial aggregates, as well as individual chloroplasts were subsequently seen undergoing Brownian motion in the vacuole. Following these changes, fragmentation of nuclear DNA, breakdown of actin microfilaments and early cell wall changes were detected. The vacuole then swelled, causing nuclear displacement towards the plasma membrane (PM) and tonoplast rupture followed closely, indicating mega-autophagy. Subsequent to tonoplast rupture, cessation of Brownian motion occurred, as well as the loss of mitochondrial membrane potential (ΔΨ m ), nuclear shrinkage and PM collapse. Timing from tonoplast rupture to PM collapse was approximately 20 minutes. The entire process from initial chlorophyll reduction to PM collapse took approximately 48 hours. Approximately six hours following PM collapse, cell wall disappearance began and was nearly complete within 24 hours. Conclusion Results showed that a consistent sequence of events occurred during the remodelling of lace plant leaves, which provides an excellent system to study developmental PCD in vivo . These findings can be used to compare and contrast with other developmental PCD examples in plants.
    Type of Medium: Online Resource
    ISSN: 1471-2229
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2012
    detail.hit.zdb_id: 2059868-3
    SSG: 12
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