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  • 1
    Online Resource
    Online Resource
    Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer
    Elsevier BV ; 2022
    In:  Annals of Oncology Vol. 33, No. 12 ( 2022-12), p. 1250-1268
    Details
    In: Annals of Oncology, Elsevier BV, Vol. 33, No. 12 ( 2022-12), p. 1250-1268
    Type of Medium: Online Resource
    ISSN: 0923-7534
    URL: Article
    DOI: 10.1016/j.annonc.2022.09.159
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
    detail.hit.zdb_id: 2003498-2
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  • 2
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    Online Resource
    Data_Sheet_1.pdf
    Frontiers Media SA ; 2021
    In:  Frontiers in Neurology Vol. 12 ( 2021-3-4)
    Details
    In: Frontiers in Neurology, Frontiers Media SA, Vol. 12 ( 2021-3-4)
    Abstract: There is mounting evidence linking the cumulative effects of repetitive head impacts to neuro-degenerative conditions. Robust clinical assessment tools to identify mild traumatic brain injuries are needed to assist with timely diagnosis for return-to-field decisions and appropriately guide rehabilitation. The focus of the present study is to investigate the potential for oculomotor features to complement existing diagnostic tools, such as measurements of Optic Nerve Sheath Diameter (ONSD) and Immediate Post-concussion Assessment and Cognitive Testing (ImPACT). Thirty-one high school American football and soccer athletes were tracked through the course of a sports season. Given the high risk of repetitive head impacts associated with both soccer and football, our hypotheses were that (1) ONSD and ImPACT scores would worsen through the season and (2) oculomotor features would effectively capture both neurophysiological changes reflected by ONSD and neuro-functional status assessed via ImPACT. Oculomotor features were used as input to Linear Mixed-Effects Regression models to predict ONSD and ImPACT scores as outcomes. Prediction accuracy was evaluated to identify explicit relationships between eye movements, ONSD, and ImPACT scores. Significant Pearson correlations were observed between predicted and actual outcomes for ONSD (Raw = 0.70; Normalized = 0.45) and for ImPACT (Raw = 0.86; Normalized = 0.71), demonstrating the capability of oculomotor features to capture neurological changes detected by both ONSD and ImPACT. The most predictive features were found to relate to motor control and visual-motor processing. In future work, oculomotor models, linking neural structures to oculomotor function, can be built to gain extended mechanistic insights into neurophysiological changes observed through seasons of participation in contact sports.
    Type of Medium: Online Resource
    ISSN: 1664-2295
    URL: Article
    URL: Article
    DOI: 10.3389/fneur.2021.584684
    DOI: 10.3389/fneur.2021.584684.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2564214-5
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  • 3
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    Online Resource
    Using Dynamics of Eye Movements, Speech Articulation and Brain Activity to Predict and Track mTBI Screening Outcomes
    Frontiers Media SA ; 2021
    In:  Frontiers in Neurology Vol. 12 ( 2021-7-6)
    Details
    In: Frontiers in Neurology, Frontiers Media SA, Vol. 12 ( 2021-7-6)
    Abstract: Repeated subconcussive blows to the head during sports or other contact activities may have a cumulative and long lasting effect on cognitive functioning. Unobtrusive measurement and tracking of cognitive functioning is needed to enable preventative interventions for people at elevated risk of concussive injury. The focus of the present study is to investigate the potential for using passive measurements of fine motor movements (smooth pursuit eye tracking and read speech) and resting state brain activity (measured using fMRI) to complement existing diagnostic tools, such as the Immediate Post-concussion Assessment and Cognitive Testing (ImPACT), that are used for this purpose. Thirty-one high school American football and soccer athletes were tracked through the course of a sports season. Hypotheses were that (1) measures of complexity of fine motor coordination and of resting state brain activity are predictive of cognitive functioning measured by the ImPACT test, and (2) within-subject changes in these measures over the course of a sports season are predictive of changes in ImPACT scores. The first principal component of the six ImPACT composite scores was used as a latent factor that represents cognitive functioning. This latent factor was positively correlated with four of the ImPACT composites: verbal memory, visual memory, visual motor speed and reaction speed. Strong correlations, ranging between r = 0.26 and r = 0.49, were found between this latent factor and complexity features derived from each sensor modality. Based on a regression model, the complexity features were combined across sensor modalities and used to predict the latent factor on out-of-sample subjects. The predictions correlated with the true latent factor with r = 0.71. Within-subject changes over time were predicted with r = 0.34. These results indicate the potential to predict cognitive performance from passive monitoring of fine motor movements and brain activity, offering initial support for future application in detection of performance deficits associated with subconcussive events.
    Type of Medium: Online Resource
    ISSN: 1664-2295
    URL: Article
    DOI: 10.3389/fneur.2021.665338
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2564214-5
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  • 4
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    Online Resource
    Inhibition of the Super Elongation Complex Suppresses Herpes Simplex Virus Immediate Early Gene Expression, Lytic Infection, and Reactivation from Latency
    American Society for Microbiology ; 2020
    In:  mBio Vol. 11, No. 3 ( 2020-06-30)
    Details
    In: mBio, American Society for Microbiology, Vol. 11, No. 3 ( 2020-06-30)
    Abstract: Induction of herpes simplex virus (HSV) immediate early (IE) gene transcription promotes the initiation of lytic infection and reactivation from latency in sensory neurons. IE genes are transcribed by the cellular RNA polymerase II (RNAPII) and regulated by multiple transcription factors and coactivators. The HCF-1 cellular coactivator plays a central role in driving IE expression at multiple stages through interactions with transcription factors, chromatin modulation complexes, and transcription elongation components, including the active s uper e longation c omplex/P-TEFb (SEC-P-TEFb). Here, we demonstrate that the SEC occupies the promoters of HSV IE genes during the initiation of lytic infection and during reactivation from latency. Specific inhibitors of the SEC suppress viral IE expression and block the spread of HSV infection. Significantly, these inhibitors also block the initiation of viral reactivation from latency in sensory ganglia. The potent suppression of IE gene expression by SEC inhibitors indicates that transcriptional elongation represents a determining rate-limiting stage in HSV IE gene transcription and that the SEC plays a critical role in driving productive elongation during both phases of the viral life cycle. Most importantly, this supports the model that signal-mediated induction of SEC-P-TEFb levels can promote reactivation of a population of poised latent genomes. IMPORTANCE HSV infections can cause pathologies ranging from recurrent lesions to significant ocular disease. Initiation of lytic infection and reactivation from latency in sensory neurons are dependent on the induced expression of the viral immediate early genes. Transcription of these genes is controlled at multiple levels, including modulation of the chromatin state of the viral genome and appropriate recruitment of transcription factors and coactivators. Following initiation of transcription, IE genes are subject to a key regulatory stage in which transcriptional elongation rates are controlled by the activity of the super elongation complex. Inhibition of the SEC blocks both lytic infection and reactivation from latency in sensory neurons. In addition to providing insights into the mechanisms controlling viral infection and reactivation, inhibitors of critical components such as the SEC may represent novel antivirals.
    Type of Medium: Online Resource
    ISSN: 2161-2129 , 2150-7511
    URL: Article
    DOI: 10.1128/mBio.01216-20
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2020
    detail.hit.zdb_id: 2557172-2
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  • 5
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    Online Resource
    A Single Amino Acid Switch in the Adenoviral DNA Binding Protein Abrogates Replication Center Formation and Productive Viral Infection
    American Society for Microbiology ; 2022
    In:  mBio Vol. 13, No. 2 ( 2022-04-26)
    Details
    In: mBio, American Society for Microbiology, Vol. 13, No. 2 ( 2022-04-26)
    Abstract: Adenoviruses are very efficient high-capacity vaccine vectors and are common gene delivery systems. Despite their extensive use in preclinical models and clinical trials over the past decades, adenoviral vectors still require optimization. To achieve that, more thorough characterizations of adenoviral genes and gene products, as well as pathogen-host interactions, are indispensable. The adenoviral DNA binding protein (DBP) is a key regulatory protein involved in various cellular and viral processes. Here, we show that single amino acid exchange mutations in human adenovirus C5 (HAdV-C5) DBP strongly influence adenoviral replication by altering interaction with the cellular ubiquitination machinery. Specifically, phenotypic analyses of DBP mutants demonstrate that single amino acid substitutions can regulate interactions with the cellular USP7 deubiquitinase, impede viral DNA synthesis, and completely abolish viral late protein expression and progeny production. Importantly, cells infected with the DBP mutant UBM5 consistently lack DBP-positive replication centers (RCs), which are usually formed during the transition from the early to the late phase of infection. Our findings demonstrate that DBP regulates a key step at the onset of the late phase of infection and that this activity is unambiguously linked to the formation and integrity of viral RCs. These data provide the experimental basis for future work that targets DBP and its interference with the formation of viral RCs during productive infection. Consequently, this work will have immediate impact on DNA virus and adenovirus research in general and, potentially, also on safety optimization of existing and development of novel adenoviral vectors and anti-adenoviral compounds. IMPORTANCE To further understand the biology of human adenoviruses (HAdVs) and to optimize HAdVs for use in prophylactic and therapeutic therapies, a thorough understanding of key viral proteins is paramount. As one of the essential HAdV proteins, the DNA binding protein DBP plays important roles in various steps of the viral replication cycle. In this work, we aimed at deciphering the role of single amino acid exchange mutations in the HAdV-C5 DBP on interaction with the cellular deubiquitinase USP7 and regulation of viral replication. We identify interaction with USP7, viral replication center formation, and viral progeny production as potently regulated steps of the viral life cycle that are affected by these few and distinct mutations in DBP.
    Type of Medium: Online Resource
    ISSN: 2150-7511
    URL: Article
    DOI: 10.1128/mbio.00144-22
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2022
    detail.hit.zdb_id: 2557172-2
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  • 6
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    Online Resource
    Longitudinal Changes in Health-Related Quality of Life in Primary Glomerular Disease: Results From the CureGN Study
    Elsevier BV ; 2020
    In:  Kidney International Reports Vol. 5, No. 10 ( 2020-10), p. 1679-1689
    Details
    In: Kidney International Reports, Elsevier BV, Vol. 5, No. 10 ( 2020-10), p. 1679-1689
    Type of Medium: Online Resource
    ISSN: 2468-0249
    URL: Article
    DOI: 10.1016/j.ekir.2020.06.041
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
    detail.hit.zdb_id: 2887223-X
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  • 7
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    Online Resource
    Mus musculus papillomavirus 1 E8^E2 represses expression of late protein E4 in basal-like keratinocytes via NCoR/SMRT-HDAC3 co-repressor complexes to enable wart formation in vivo
    American Society for Microbiology ; 2023
    In:  mBio
    Details
    In: mBio, American Society for Microbiology
    Abstract: Human papillomaviruses (PVs) initiate productive replication, which is characterized by genome amplification and expression of E4 protein strictly within suprabasal, differentiated keratinocytes. Mus musculus PV1 mutants that disrupt splicing of the E8^E2 transcript or abolish the interaction of E8^E2 with cellular NCoR/SMRT-HDAC3 co-repressor complexes display increased gene expression in tissue culture but are unable to form warts in vivo . This confirms that the repressor activity of E8^E2 is required for tumor formation and genetically defines a conserved E8 interaction domain. E8^E2 prevents expression of E4 protein in basal-like, undifferentiated keratinocytes and thereby their arrest in G2 phase. Since binding of E8^E2 to NCoR/SMRT-HDAC3 co-repressor is required to enable expansion of infected cells in the basal layer and wart formation in vivo , this interaction represents a novel, conserved, and potentially druggable target.
    Type of Medium: Online Resource
    ISSN: 2150-7511
    URL: Article
    DOI: 10.1128/mbio.00696-23
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2023
    detail.hit.zdb_id: 2557172-2
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  • 8
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    Online Resource
    Viral DNA Binding Protein SUMOylation Promotes PML Nuclear Body Localization Next to Viral Replication Centers
    American Society for Microbiology ; 2020
    In:  mBio Vol. 11, No. 2 ( 2020-04-28)
    Details
    In: mBio, American Society for Microbiology, Vol. 11, No. 2 ( 2020-04-28)
    Abstract: Human adenoviruses (HAdVs) have developed mechanisms to manipulate cellular antiviral measures to ensure proper DNA replication, with detailed processes far from being understood. Host cells repress incoming viral genomes through a network of transcriptional regulators that normally control cellular homeostasis. The nuclear domains involved are promyelocytic leukemia protein nuclear bodies (PML-NBs), interferon-inducible, dot-like nuclear structures and hot spots of SUMO posttranslational modification (PTM). In HAdV-infected cells, such SUMO factories are found in close proximity to newly established viral replication centers (RCs) marked by the adenoviral DNA binding protein (DBP) E2A. Here, we show that E2A is a novel target of host SUMOylation, leading to PTMs supporting E2A function in promoting productive infection. Our data show that SUMOylated E2A interacts with PML. Decreasing SUMO-E2A protein levels by generating HAdV variants mutated in the three main SUMO conjugation motifs (SCMs) led to lower numbers of viral RCs and PML-NBs, and these two structures were no longer next to each other. Our data further indicate that SUMOylated E2A binds the host transcription factor Sp100A, promoting HAdV gene expression, and represents the molecular bridge between PML tracks and adjacent viral RCs. Consequently, E2A SCM mutations repressed late viral gene expression and progeny production. These data highlight a novel mechanism used by the virus to benefit from host antiviral responses by exploiting the cellular SUMO conjugation machinery. IMPORTANCE PML nuclear bodies (PML-NBs) are implicated in general antiviral defense based on recruiting host restriction factors; however, it is not understood so far why viruses would establish viral replication centers (RCs) juxtaposed to such “antiviral” compartments. To understand this enigma, we investigate the cross talk between PML-NB components and viral RCs to find the missing link connecting both compartments to promote efficient viral replication and gene expression. Taken together, the current concept is more intricate than originally believed, since viruses apparently take advantage of several specific PML-NB-associated proteins to promote productive infection. Simultaneously, they efficiently inhibit antiviral measures to maintain the viral infectious program. Our data provide evidence that SUMOylation of the viral RC marker protein E2A represents the basis of this virus-host interface and regulates various downstream events to support HAdV productive infection. These results are the basis of our current attempts to generate and screen for specific E2A SUMOylation inhibitors to constitute novel therapeutic approaches to limit and prevent HAdV-mediated diseases and mortality of immunosuppressed patients.
    Type of Medium: Online Resource
    ISSN: 2161-2129 , 2150-7511
    URL: Article
    DOI: 10.1128/mBio.00049-20
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2020
    detail.hit.zdb_id: 2557172-2
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  • 9
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    Online Resource
    Human Cytomegalovirus Uses a Host Stress Response To Balance the Elongation of Saturated/Monounsaturated and Polyunsaturated Very-Long-Chain Fatty Acids
    American Society for Microbiology ; 2021
    In:  mBio Vol. 12, No. 3 ( 2021-06-29)
    Details
    In: mBio, American Society for Microbiology, Vol. 12, No. 3 ( 2021-06-29)
    Abstract: Stress and virus infection regulate lipid metabolism. Human cytomegalovirus (HCMV) infection induces fatty acid (FA) elongation and increases the abundance of lipids with very-long-chain FA (VLCFA) tails. While reprogramming of metabolism can be stress related, the role of stress in HCMV reprogramming of lipid metabolism is poorly understood. In this study, we engineered cells to knock out protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) in the ER stress pathway and measured lipid changes using lipidomics to determine if PERK is needed for lipid changes associated with HCMV infection. In HCMV-infected cells, PERK promotes increases in the levels of phospholipids with saturated FA (SFA) and monounsaturated FA (MUFA) VLCFA tails. Further, PERK enhances FA elongase 7 (ELOVL7) protein levels, which elongates SFA and MUFA VLCFAs. Additionally, we found that increases in the elongation of polyunsaturated fatty acids (PUFAs) associated with HCMV infection were independent of PERK and that lipids with PUFA tails accumulated in HCMV-infected PERK knockout cells. Additionally, the protein levels of ELOVL5, which elongates PUFAs, are increased by HCMV infection through a PERK-independent mechanism. These observations show that PERK differentially regulates ELOVL7 and ELOVL5, creating a balance between the synthesis of lipids with SFA/MUFA tails and PUFA tails. Additionally, we found that PERK was necessary for virus replication and the infectivity of released viral progeny. Overall, our findings indicate that PERK—and, more broadly, ER stress—may be necessary for the membrane biogenesis needed to generate infectious HCMV virions. IMPORTANCE HCMV is a common herpesvirus that establishes lifelong persistent infections. While infection is asymptomatic in most people, HCMV causes life-threatening illnesses in immunocompromised people, including transplant recipients and cancer patients. Additionally, HCMV infection is a leading cause of congenital disabilities. HCMV replication relies on lipid synthesis. Here, we demonstrated that the ER stress mediator PERK controls FA elongation and the cellular abundance of several types of lipids following HCMV infection. Specifically, PERK promotes FA elongase 7 synthesis and phospholipids with saturated/monounsaturated very-long-chain FA tails. Overall, our study shows that PERK is an essential host factor that supports HCMV replication and promotes lipidome changes caused by HCMV infection.
    Type of Medium: Online Resource
    ISSN: 2150-7511
    URL: Article
    DOI: 10.1128/mBio.00167-21
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2021
    detail.hit.zdb_id: 2557172-2
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  • 10
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    Online Resource
    The US21 viroporin of human cytomegalovirus stimulates cell migration and adhesion
    American Society for Microbiology ; 2023
    In:  mBio
    Details
    In: mBio, American Society for Microbiology
    Abstract: Human cytomegalovirus (HCMV) is an opportunistic pathogen that owes part of its success to the capture, duplication, and tuning of cellular genes to generate modern viral proteins which promote infection and persistence in the host by interfering with many cell biochemical and physiological pathways. The US21 viral protein provides an example of this evolutionary strategy: it is a cellular-derived calcium channel that manipulates intracellular calcium homeostasis to confer edges to HCMV replication. Here, we report on the characterization of a novel function of the US21 protein as a viral regulator of cell migration and adhesion through mechanisms involving its calcium channel activity. Characterization of HCMV multifunctional regulatory proteins, like US21, supports the better understanding of viral pathogenesis and may open avenues for the design of new antiviral strategies that exploit their functions.
    Type of Medium: Online Resource
    ISSN: 2150-7511
    URL: Article
    DOI: 10.1128/mbio.00749-23
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2023
    detail.hit.zdb_id: 2557172-2
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