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  1. Article ; Online: Disease of mRNA Regulation: Relevance for Ischemic Brain Injury.

    DeGracia, Donald J

    Translational stroke research

    2017  Volume 9, Issue 3, Page(s) 251–257

    Abstract: In this mini-review we give an overview of the role of mRNA-binding proteins and their associated messenger ribonucleoprotein complexes (mRNPs) in several disease states, and bring this information to bear on the pathophysiology of brain ischemia. One ... ...

    Abstract In this mini-review we give an overview of the role of mRNA-binding proteins and their associated messenger ribonucleoprotein complexes (mRNPs) in several disease states, and bring this information to bear on the pathophysiology of brain ischemia. One conclusion reached is that mRNPs may play a causal role in proteotoxicity instead of being merely passive targets. Ischemia therapies targeting mRNPs have advantages over targeting single pathways, but the behavior of mRNPs needs to be considered in the design of therapies.
    MeSH term(s) Animals ; Brain Injuries, Traumatic/metabolism ; Brain Ischemia/metabolism ; Humans ; Neurodegenerative Diseases/metabolism ; RNA-Binding Proteins/metabolism
    Chemical Substances RNA-Binding Proteins
    Language English
    Publishing date 2017-11-10
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 2541897-X
    ISSN 1868-601X ; 1868-4483
    ISSN (online) 1868-601X
    ISSN 1868-4483
    DOI 10.1007/s12975-017-0586-7
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  2. Article ; Online: Regulation of mRNA following brain ischemia and reperfusion.

    DeGracia, Donald J

    Wiley interdisciplinary reviews. RNA

    2017  Volume 8, Issue 4

    Abstract: There is growing appreciation that mRNA regulation plays important roles in disease and injury. mRNA regulation and ribonomics occur in brain ischemia and reperfusion (I/R) following stroke and cardiac arrest and resuscitation. It was recognized over 40 ... ...

    Abstract There is growing appreciation that mRNA regulation plays important roles in disease and injury. mRNA regulation and ribonomics occur in brain ischemia and reperfusion (I/R) following stroke and cardiac arrest and resuscitation. It was recognized over 40 years ago that translation arrest (TA) accompanies brain I/R and is now recognized as part of the intrinsic stress responses triggered in neurons. However, neuron death correlates to a prolonged TA in cells fated to undergo delayed neuronal death (DND). Dysfunction of mRNA regulatory processes in cells fated to DND prevents them from translating stress-induced mRNAs such as heat shock proteins. The morphological and biochemical studies of mRNA regulation in postischemic neurons are discussed in the context of the large variety of molecular damage induced by ischemic injury. Open issues and areas of future investigation are highlighted. A sober look at the molecular complexity of ischemia-induced neuronal injury suggests that a network framework will assist in making sense of this complexity. The ribonomic network sits between the gene network and the various protein and metabolic networks. Thus, targeting the ribonomic network may prove more effective at neuroprotection than targeting specific molecular pathways, for which all efforts have failed to the present time to stop DND in stroke and after cardiac arrest. WIREs RNA 2017, 8:e1415. doi: 10.1002/wrna.1415 For further resources related to this article, please visit the WIREs website.
    MeSH term(s) Animals ; Brain Ischemia/genetics ; Brain Ischemia/metabolism ; Gene Expression Regulation ; Humans ; Neurons/metabolism ; Neurons/pathology ; Protein Biosynthesis/genetics ; RNA, Messenger/genetics ; RNA, Messenger/metabolism
    Chemical Substances RNA, Messenger
    Language English
    Publishing date 2017-01-17
    Publishing country United States
    Document type Journal Article ; Review ; Research Support, N.I.H., Extramural
    ZDB-ID 2634714-3
    ISSN 1757-7012 ; 1757-7004
    ISSN (online) 1757-7012
    ISSN 1757-7004
    DOI 10.1002/wrna.1415
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6953: Show issues Location:
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  3. Article: Towards a dynamical network view of brain ischemia and reperfusion. Part IV: additional considerations.

    Degracia, Donald J

    Journal of experimental stroke & translational medicine

    2011  Volume 3, Issue 1, Page(s) 104–114

    Abstract: The general failure of neuroprotectants in clinical trials of ischemic stroke points to the possibility of a fundamental blind spot in the current conception of ischemic brain injury, the "ischemic cascade". This is the fourth in a series of four papers ... ...

    Abstract The general failure of neuroprotectants in clinical trials of ischemic stroke points to the possibility of a fundamental blind spot in the current conception of ischemic brain injury, the "ischemic cascade". This is the fourth in a series of four papers whose purpose is to work towards a revision of the concept of brain ischemia by applying network concepts to develop a bistable model of brain ischemia. Here we consider additional issues to round out and close out this initial presentation of the bistable network view of brain ischemia. Initial considerations of the network architecture underlying the post-ischemic state space are discussed. Network and differential equation models of brain ischemia are compared. We offer a first look at applying the bistable model to focal cerebral ischemia. The limitations of the present formulation of the bistable model are discussed. This work concludes with a series of questions by which to direct future efforts.
    Language English
    Publishing date 2011-02-23
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2605730-X
    ISSN 1939-067X
    ISSN 1939-067X
    DOI 10.6030/1939-067x-3.1.104
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  4. Article: Towards a dynamical network view of brain ischemia and reperfusion. Part I: background and preliminaries.

    Degracia, Donald J

    Journal of experimental stroke & translational medicine

    2011  Volume 3, Issue 1, Page(s) 59–71

    Abstract: The general failure of neuroprotectants in clinical trials of ischemic stroke points to the possibility of a fundamental blind spot in the current conception of ischemic brain injury, the "ischemic cascade". This is the first in a series of four papers ... ...

    Abstract The general failure of neuroprotectants in clinical trials of ischemic stroke points to the possibility of a fundamental blind spot in the current conception of ischemic brain injury, the "ischemic cascade". This is the first in a series of four papers whose purpose is to work towards a revision of the concept of brain ischemia by applying network concepts to develop a bistable model of brain ischemia. This first paper sets the stage for developing the bistable model of brain ischemia. Necessary background in network theory is introduced using examples from developmental biology which, perhaps surprisingly, can be adapted to brain ischemia with only minor modification. Then, to move towards a network model, we extract two core generalizations about brain ischemia from the mass of empirical data. First, we conclude that all changes induced in the brain by ischemia can be classified as either damage mechanisms that contribute to cell death, or stress responses that contribute to cell survival. Second, we move towards formalizing the idea of the "amount of ischemia", I, as a continuous, nonnegative, monotonically increasing quantity. These two generalizations are necessary precursors to reformulating brain ischemia as a bistable network.
    Language English
    Publishing date 2011-02-23
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2605730-X
    ISSN 1939-067X
    ISSN 1939-067X
    DOI 10.6030/1939-067x-3.1.59
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  5. Article: A program for solving the brain ischemia problem.

    DeGracia, Donald J

    Brain sciences

    2013  Volume 3, Issue 2, Page(s) 460–503

    Abstract: Our recently described nonlinear dynamical model of cell injury is here applied to the problems of brain ischemia and neuroprotection. We discuss measurement of global brain ischemia injury dynamics by time course analysis. Solutions to proposed ... ...

    Abstract Our recently described nonlinear dynamical model of cell injury is here applied to the problems of brain ischemia and neuroprotection. We discuss measurement of global brain ischemia injury dynamics by time course analysis. Solutions to proposed experiments are simulated using hypothetical values for the model parameters. The solutions solve the global brain ischemia problem in terms of "master bifurcation diagrams" that show all possible outcomes for arbitrary durations of all lethal cerebral blood flow (CBF) decrements. The global ischemia master bifurcation diagrams: (1) can map to a single focal ischemia insult, and (2) reveal all CBF decrements susceptible to neuroprotection. We simulate measuring a neuroprotectant by time course analysis, which revealed emergent nonlinear effects that set dynamical limits on neuroprotection. Using over-simplified stroke geometry, we calculate a theoretical maximum protection of approximately 50% recovery. We also calculate what is likely to be obtained in practice and obtain 38% recovery; a number close to that often reported in the literature. The hypothetical examples studied here illustrate the use of the nonlinear cell injury model as a fresh avenue of approach that has the potential, not only to solve the brain ischemia problem, but also to advance the technology of neuroprotection.
    Language English
    Publishing date 2013-04-08
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2651993-8
    ISSN 2076-3425
    ISSN 2076-3425
    DOI 10.3390/brainsci3020460
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  6. Article: Towards a dynamical network view of brain ischemia and reperfusion. Part III: therapeutic implications.

    Degracia, Donald J

    Journal of experimental stroke & translational medicine

    2010  Volume 3, Issue 1, Page(s) 90–103

    Abstract: The general failure of neuroprotectants in clinical trials of ischemic stroke points to the possibility of a fundamental blind spot in the current conception of ischemic brain injury, the "ischemic cascade". This is the third in a series of four papers ... ...

    Abstract The general failure of neuroprotectants in clinical trials of ischemic stroke points to the possibility of a fundamental blind spot in the current conception of ischemic brain injury, the "ischemic cascade". This is the third in a series of four papers whose purpose is to work towards a revision of the concept of brain ischemia by applying network concepts to develop a bistable model of brain ischemia. Here the bistable model of brain ischemia is compared to the ischemic cascade concept. The core weakness of the ischemic cascade concept is revealed to be its assumption of superposition, or that the elements of the ischemic cascade can be summed as linearly independent events. This assumption leads to a concept of neuroprotection as a subtraction of ostensibly independent damage events. The bistable model offers a different concept of neuroprotection where the role of individual molecular pathways decreases in relevance with respect to the efficacy of outcome. Network thinking provides a framework for critical assessment of widely-used preclinical experimental approaches. The importance of allometric scaling is also discussed. We illustrate that the bistable model provides a viable alternative to the ischemic cascade as an explanatory framework and as a guide for therapeutic development.
    Language English
    Publishing date 2010-11-19
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2605730-X
    ISSN 1939-067X
    ISSN 1939-067X
    DOI 10.6030/1939-067x-3.1.90
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  7. Article: Towards a dynamical network view of brain ischemia and reperfusion. Part II: a post-ischemic neuronal state space.

    Degracia, Donald J

    Journal of experimental stroke & translational medicine

    2010  Volume 3, Issue 1, Page(s) 72–89

    Abstract: The general failure of neuroprotectants in clinical trials of ischemic stroke points to the possibility of a fundamental blind spot in the current conception of ischemic brain injury, the "ischemic cascade". This is the second in a series of four papers ... ...

    Abstract The general failure of neuroprotectants in clinical trials of ischemic stroke points to the possibility of a fundamental blind spot in the current conception of ischemic brain injury, the "ischemic cascade". This is the second in a series of four papers whose purpose is to work towards a revision of the concept of brain ischemia by applying network concepts to develop a bistable model of brain ischemia. We here build the bistable network model of brain ischemia. The central concept is that of a post-ischemic state space. Ischemia, as a quantitative perturbation, is envisioned to push the brain through a series of four phenotypes as a function of the amount of ischemia: the homeostatic, preconditioned, delayed neuronal death and necrotic phenotypes. The phenotypes are meta-stable attractors in the landscape of the post-ischemic state space. The sequence of the phenotypes derives from the mutual antagonism between damage mechanisms and stress responses, each conceived as aggregate ensemble variables. The competition between damage mechanisms and stress responses is posited to have the form of a bistability. Application of bistability to brain ischemia is grounded in the incontrovertible fact that post-ischemic neurons face the mutually exclusive decision to either live or die.
    Language English
    Publishing date 2010-12-19
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2605730-X
    ISSN 1939-067X
    ISSN 1939-067X
    DOI 10.6030/1939-067x-3.1.72
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  8. Article ; Online: 'Functional histology' in brain ischemia studies.

    DeGracia, Donald J

    Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

    2011  Volume 31, Issue 8, Page(s) 1661–1662

    MeSH term(s) Animals ; Cerebral Cortex/pathology ; Endoplasmic Reticulum/pathology ; Heart Arrest/pathology ; Neurons/ultrastructure
    Language English
    Publishing date 2011-03-30
    Publishing country United States
    Document type Journal Article ; Comment
    ZDB-ID 604628-9
    ISSN 1559-7016 ; 0271-678X
    ISSN (online) 1559-7016
    ISSN 0271-678X
    DOI 10.1038/jcbfm.2011.40
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1663: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  9. Article ; Online: Nonautonomous dynamics of acute cell injury.

    DeGracia, Donald J / Taha, Doaa / Anggraini, Fika Tri / Huang, Zhi-Feng

    Physical review. E

    2019  Volume 100, Issue 5-1, Page(s) 52407

    Abstract: Medical conditions due to acute cell injury, such as stroke and heart attack, are of tremendous impact and have attracted huge amounts of research effort. The biomedical research that seeks cures for these conditions has been dominated by a qualitative, ... ...

    Abstract Medical conditions due to acute cell injury, such as stroke and heart attack, are of tremendous impact and have attracted huge amounts of research effort. The biomedical research that seeks cures for these conditions has been dominated by a qualitative, inductive mind-set. Although the inductive approach has not been effective in developing medical treatments, it has amassed enough information to allow construction of quantitative, deductive models of acute cell injury. In this work we develop a modeling approach by extending an autonomous nonlinear dynamic theory of acute cell injury that offered new ways to conceptualize cell injury but possessed limitations that decrease its effectiveness. Here we study the global dynamics of the cell injury theory using a nonautonomous formulation. Different from the standard scenario in nonlinear dynamics that is determined by the steady state and fixed points of the model equations, in this nonautonomous model with a trivial fixed point, the system property is dominated by the transient states and the corresponding dynamic processes. The model gives rise to four qualitative types of dynamical patterns that can be mapped to the behavior of cells after clinical acute injuries. The nonautonomous theory predicts the existence of a latent stress response capacity (LSRC) possessed by injured cells. The LSRC provides a theoretical explanation of how therapies, such as hypothermia, can prevent cell death after lethal injuries. The nonautonomous theory of acute cell injury provides an improved quantitative framework for understanding cell death and recovery and lays a foundation for developing effective therapeutics for acute injury.
    MeSH term(s) Adaptation, Physiological ; Cell Death ; Cells/pathology ; Models, Biological ; Nonlinear Dynamics ; Stress, Physiological
    Language English
    Publishing date 2019-12-24
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2844562-4
    ISSN 2470-0053 ; 2470-0045
    ISSN (online) 2470-0053
    ISSN 2470-0045
    DOI 10.1103/PhysRevE.100.052407
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  10. Article ; Online: A Program for Solving the Brain Ischemia Problem

    Donald J. DeGracia

    Brain Sciences, Vol 3, Iss 2, Pp 460-

    2013  Volume 503

    Abstract: Our recently described nonlinear dynamical model of cell injury is here applied to the problems of brain ischemia and neuroprotection. We discuss measurement of global brain ischemia injury dynamics by time course analysis. Solutions to proposed ... ...

    Abstract Our recently described nonlinear dynamical model of cell injury is here applied to the problems of brain ischemia and neuroprotection. We discuss measurement of global brain ischemia injury dynamics by time course analysis. Solutions to proposed experiments are simulated using hypothetical values for the model parameters. The solutions solve the global brain ischemia problem in terms of “master bifurcation diagrams” that show all possible outcomes for arbitrary durations of all lethal cerebral blood flow (CBF) decrements. The global ischemia master bifurcation diagrams: (1) can map to a single focal ischemia insult, and (2) reveal all CBF decrements susceptible to neuroprotection. We simulate measuring a neuroprotectant by time course analysis, which revealed emergent nonlinear effects that set dynamical limits on neuroprotection. Using over-simplified stroke geometry, we calculate a theoretical maximum protection of approximately 50% recovery. We also calculate what is likely to be obtained in practice and obtain 38% recovery; a number close to that often reported in the literature. The hypothetical examples studied here illustrate the use of the nonlinear cell injury model as a fresh avenue of approach that has the potential, not only to solve the brain ischemia problem, but also to advance the technology of neuroprotection.
    Keywords brain ischemia ; neuroprotection ; nonlinear dynamics ; bistability ; cell injury ; Neurosciences. Biological psychiatry. Neuropsychiatry ; RC321-571 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Neurology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
    Subject code 612
    Language English
    Publishing date 2013-04-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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