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Genetic fuzzy system predicting contractile reactivity patterns of small arteries.

ABSTRACT: Monitoring of physiological surrogate end points in drug development generates dynamic time-domain data reflecting the state of the biological system. Conventional data analysis often reduces the information in these data by extracting specific data points, thereby discarding potentially useful information. We developed a genetic fuzzy system (GFS) algorithm that is capable of learning all information in time-domain physiological data. Data on isometric force development of isolated small arteries were used as a framework for developing and optimizing a GFS. GFS performance was improved by several strategies. Results show that optimized fuzzy systems (OFSs) predict contractile reactivity of arteries accurately. In addition, OFSs identified significant differences that were undetectable using conventional analysis in the responses of arteries between groups. We concluded that OFSs may be used in clustering or classification tasks as aids in the objective identification or prediction of dynamic physiological behavior.

SUBMITTER: Tang J

PROVIDER: S-EPMC4011165 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Genetic fuzzy system predicting contractile reactivity patterns of small arteries.

Tang J J Sheykhzade M M Clausen B F BF Boonen H C M HC

CPT: pharmacometrics & systems pharmacology 20140402

Monitoring of physiological surrogate end points in drug development generates dynamic time-domain data reflecting the state of the biological system. Conventional data analysis often reduces the information in these data by extracting specific data points, thereby discarding potentially useful information. We developed a genetic fuzzy system (GFS) algorithm that is capable of learning all information in time-domain physiological data. Data on isometric force development of isolated small arteri ...[more]

PMID: 24695357

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Project description:Disruptions in stress response system development have been posited as mechanisms linking child maltreatment (CM) to psychopathology. Existing theories predict elevated sympathetic nervous system reactivity after CM, but evidence for this is inconsistent. We present a novel framework for conceptualizing stress reactivity after CM that uses the biopsychosocial model of challenge and threat. We predicted that in the context of a social-evaluative stressor, maltreated adolescents would exhibit a threat pattern of reactivity, involving sympathetic nervous system activation paired with elevated vascular resistance and blunted cardiac output (CO) reactivity.A sample of 168 adolescents (mean age =14.9 years) participated. Recruitment targeted maltreated adolescents; 38.2% were maltreated. Electrocardiogram, impedance cardiography, and blood pressure were acquired at rest and during an evaluated social stressor (Trier Social Stress Test). Pre-ejection period (PEP), CO, and total peripheral resistance reactivity were computed during task preparation, speech delivery, and verbal mental arithmetic. Internalizing and externalizing symptoms were assessed.Maltreatment was unrelated to PEP reactivity during preparation or speech, but maltreated adolescents had reduced PEP reactivity during math. Maltreatment exposure (F(1,145) = 3.8-9.4, p = .053-<.001) and severity (? = -0.10-0.12, p = .030-.007) were associated with significantly reduced CO reactivity during all components of the stress task and marginally associated with elevated total peripheral resistance reactivity (F(1,145) = 3.8-9.4; p = .053-<.001 [? = 0.07-0.11] and p = .11-.009, respectively). Threat reactivity was positively associated with externalizing symptoms.CM is associated with a dysregulated pattern of physiological reactivity consistent with theoretical conceptualizations of threat but not previously examined in relation to maltreatment, suggesting a more nuanced pattern of stress reactivity than predicted by current theoretical models.

Project description:New findingsWhat is the central question of this study? DAPK3 contributes to the Ca2+ -sensitization of vascular smooth muscle contraction: does this protein kinase participate in the myogenic response of cerebral arteries? What is the main finding and its importance? Small molecule inhibitors of DAPK3 effectively block the myogenic responses of cerebral arteries. HS38-dependent changes to vessel constriction occur independent of LC20 phosphorylation, and therefore DAPK3 appears to operate via the actin cytoskeleton. A role for DAPK3 in the myogenic response was not previously reported, and the results support a potential new therapeutic target in the cerebrovascular system.AbstractThe vascular smooth muscle (VSM) of resistance blood vessels is a target of intrinsic autoregulatory responses to increased intraluminal pressure, the myogenic response. In the brain, the myogenic reactivity of cerebral arteries is critical to homeostatic blood flow regulation. Here we provide the first evidence to link the death-associated protein kinase 3 (DAPK3) to the myogenic response of rat and human cerebral arteries. DAPK3 is a Ser/Thr kinase involved in Ca2+ -sensitization mechanisms of smooth muscle contraction. Ex vivo administration of a specific DAPK3 inhibitor (i.e., HS38) could attenuate vessel constrictions invoked by serotonin as well as intraluminal pressure elevation. The HS38-dependent dilatation was not associated with any change in myosin light chain (LC20) phosphorylation. The results suggest that DAPK3 does not regulate Ca2+ sensitization pathways during the myogenic response of cerebral vessels but rather operates to control the actin cytoskeleton. A slow return of myogenic tone was observed during the sustained ex vivo exposure of cerebral arteries to HS38. Recovery of tone was associated with greater LC20 phosphorylation that suggests intrinsic signalling compensation in response to attenuation of DAPK3 activity. Additional experiments with VSM cells revealed HS38- and siDAPK-dependent effects on the actin cytoskeleton and focal adhesion kinase phosphorylation status. The translational importance of DAPK3 to the human cerebral vasculature was noted, with robust expression of the protein kinase and significant HS38-dependent attenuation of myogenic reactivity found for human pial vessels.

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Genetic fuzzy system predicting contractile reactivity patterns of small arteries.

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Genetic fuzzy system predicting contractile reactivity patterns of small arteries.

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