Neural stem/progenitor cells (NSCs) in the hippocampus produce new neurons throughout adult life. NSCs are maintained in a state of reversible quiescence and the failure to maintain the quiescent ...state can result in the premature depletion of the stem cell pool. The epigenetic mechanisms that maintain this quiescent state have not been identified. Using an inducible knockout mouse model, we show that the chromatin remodeling factor chromodomain–helicase‐DNA‐binding protein 7 (CHD7) is essential for maintaining NSC quiescence. CHD7 inactivation in adult NSCs results in a loss of stem cell quiescence in the hippocampus, a transient increase in cell divisions, followed by a significant decline in neurogenesis. This loss of NSC quiescence is associated with the premature loss of NSCs in middle‐aged mice. We find that CHD7 represses the transcription of several positive regulators of cell cycle progression and is required for full induction of the Notch target gene Hes5 in quiescent NSCs. These findings directly link CHD7 to pathways involved in NSC quiescence and identify the first chromatin‐remodeling factor with a role in NSC quiescence and maintenance. As CHD7 haplo‐insufficiency is associated with a range of cognitive disabilities in CHARGE syndrome, our observations may have implications for understanding the basis of these deficits. Stem Cells 2015;33:196–210
Oxidative/inflammatory stresses due to cardiopulmonary bypass (CPB) cause prolonged microglia activation and cortical dysmaturation, thereby contributing to neurodevelopmental impairments in children ...with congenital heart disease (CHD). This study found that delivery of mesenchymal stromal cells (MSCs) via CPB minimizes microglial activation and neuronal apoptosis, with subsequent improvement of cortical dysmaturation and behavioral alteration after neonatal cardiac surgery. Furthermore, transcriptomic analyses suggest that exosome-derived miRNAs may be the key drivers of suppressed apoptosis and STAT3-mediated microglial activation. Our findings demonstrate that MSC treatment during cardiac surgery has significant translational potential for improving cortical dysmaturation and neurological impairment in children with CHD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Sonic Hedgehog (SHH) medulloblastomas are brain tumours that arise in the posterior fossa. Cancer-propagating cells (CPCs) provide a reservoir of cells capable of tumour regeneration and relapse ...post-treatment. Understanding and targeting the mechanisms by which CPCs are maintained and expanded in SHH medulloblastoma could present novel therapeutic opportunities. We identified the aryl hydrocarbon receptor (AHR) pathway as a potent tumour suppressor in a SHH medulloblastoma mouse model. Ahr-deficient tumours and CPCs grown in vitro, showed elevated activation of the TGFβ mediator, SMAD3. Pharmacological inhibition of the TGFβ/SMAD3 signalling axis was sufficient to inhibit the proliferation and promote the differentiation of Ahr-deficient CPCs. Human SHH medulloblastomas with high expression of the AHR repressor (AHRR) exhibited a significantly worse prognosis compared to AHRR
tumours in two independent patient cohorts. Together, these findings suggest that reduced AHR pathway activity promotes SHH medulloblastoma progression, consistent with a tumour suppressive role for AHR. We propose that TGFβ/SMAD3 inhibition may represent an actionable therapeutic approach for a subset of aggressive SHH medulloblastomas characterised by reduced AHR pathway activity.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Apoptosis, classically initiated by caspase pathway activation, plays a prominent role during normal brain development as well as in neurodegeneration. The non-canonical, non-lethal arm of the ...caspase pathway is evolutionarily conserved and has also been implicated in both processes, yet is relatively understudied. Dysregulated pathway activation during critical periods of neurodevelopment due to environmental neurotoxins or exposure to compounds such as anesthetics can have detrimental consequences for brain maturation and long-term effects on behavior. In this review, we discuss key molecular characteristics and roles of the non-canonical caspase pathway and how its dysregulation may adversely affect brain development. We highlight both genetic and environmental factors that regulate apoptotic and sub-lethal caspase responses, and discuss potential interventions that target the non-canonical caspase pathway for developmental brain injuries.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Apoptosis, classically initiated by caspase pathway activation, plays a prominent role during normal brain development as well as in neurodegeneration. The noncanonical, nonlethal arm of the caspase ...pathway is evolutionarily conserved and has also been implicated in both processes, yet is relatively understudied. Dysregulated pathway activation during critical periods of neurodevelopment due to environmental neurotoxins or exposure to compounds such as anesthetics can have detrimental consequences for brain maturation and long-term effects on behavior. In this review, we discuss key molecular characteristics and roles of the noncanonical caspase pathway and how its dysregulation may adversely affect brain development. We highlight both genetic and environmental factors that regulate apoptotic and sublethal caspase responses and discuss potential interventions that target the noncanonical caspase pathway for developmental brain injuries.
Caspase activity is necessary for normal neuronal development and maturation. Studies are increasingly showing important caspase roles in axonal pathfinding, dendritic arborization, and synaptic plasticity.There is growing evidence for nonlethal, yet damaging caspase responses to commonly used chemical agents such as ethanol and anesthetics.Nonlethal, excess caspase activation may result in impaired neuronal arborization and synaptic transmission, leading to long-term behavioral deficits.Children undergoing surgeries, such as those with congenital heart defects, may be at increased risks for nonapoptotic caspase injuries due to exposure to anesthetics and accompanying genetic susceptibility.Understanding the molecular and cellular differences between apoptotic and nonlethal caspase activity is crucial for more targeted neuroprotection.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background Reduced oxygen delivery in congenital heart disease causes delayed brain maturation and white matter abnormalities in utero. No treatment currently exists. Tetrahydrobiopterin (BH4) is a ...cofactor for neuronal nitric oxide synthase. BH4 availability is reduced upon NOS activation, such as during hypoxic conditions, and leads to toxin production. We hypothesize that BH4 levels are depleted in the hypoxic brain and that BH4 replacement therapy mitigates the toxic effects of hypoxia on white matter. Methods and Results Transgenic mice were used to visualize oligodendrocytes. Hypoxia was introduced during a period of white matter development equivalent to the human third trimester. BH4 was administered during hypoxia. BH4 levels were depleted in the hypoxic brain by direct quantification (n=7-12). The proliferation (n=3-6), apoptosis (n=3-6), and developmental stage (n=5-8) of oligodendrocytes were determined immunohistologically. Total oligodendrocytes increased after hypoxia, consistent with hypoxia-induced proliferation seen previously; however, mature oligodendrocytes were less prevalent in hypoxia, and there was accumulation of immature oligodendrocytes. BH4 treatment improved the mature oligodendrocyte number such that it did not differ from normoxia, and accumulation of immature oligodendrocytes was not observed. These results persisted beyond the initial period of hypoxia (n=3-4). Apoptosis increased with hypoxia but decreased with BH4 treatment to normoxic levels. White matter myelin levels decreased following hypoxia by western blot. BH4 treatment normalized myelination (n=6-10). Hypoxia worsened sensory-motor coordination on balance beam tasks, and BH4 therapy normalized performance (n=5-9). Conclusions Suboptimal BH4 levels influence hypoxic white matter abnormalities. Repurposing BH4 for use during fetal brain development may limit white matter dysmaturation in congenital heart disease.
Abstract only
Background:
Neurodevelopmental impairment is one the most important challenges in children with congenital heart disease. Cardiopulmonary bypass (CPB) causes substantial ...oxidative/inflammatory stress and microglial activation. The present study tested CPB itself as a unique delivery system of bone marrow-derived mesenchymal stromal cells (BM-MSCs), known to possess significant immunomodulatory properties.
Methods:
Two-week old piglets were randomly assigned to one of three groups: Control, CPB, and CPB with BM-MSC administration. BM-MSCs (10x10
6
/kg) were delivered through CPB. In addition to cellular/molecular assays, structural and behavioral changes were assessed up to 4 weeks after surgery.
Results:
Intra-arterial delivery through CPB uniformly distributed BM-MSCs to most of the organs analyzed, including the brain, heart and kidney. In the brain, BM-MSCs were equally distributed between two hemispheres and within the cortex and white matter. While approximately half of the BM-MSCs were localized to parenchyma shortly after CPB, there were no residual MSCs at 4 weeks post-CPB. In the developing cortex, enhanced p53 and JAK-STAT3 pathway activation were revealed post-CPB. BM-MSCs suppressed CPB-induced microglial STAT3 phosphorylation, thereby inhibiting microglial activation. In addition to an increase in anti-inflammatory cytokines, BM-MSCs reduced caspase-3 activation in cortical neurons and limited the induction of apoptotic signals. BM-MSC-treated animals demonstrated improved post-operative recovery and reduced behavioral impairments due to cardiac surgery. Concurrently, CPB-induced structural alterations of the developing cortex were mitigated possibly through the inhibition of prolonged microglia activation by BM-MSCs. No evidence of any detrimental effects was observed. Our transcriptomic analyses suggest that BM-MSC exosome-derived micro-RNA, miR-21-5p, may be the key mediator of apoptosis suppression and reduced microglial activation.
Conclusions:
BM-MSC delivery via CPB minimizes inflammatory/oxidative stress and reduces neuronal caspase and microglial activation, with subsequent rescue of behavioral/structural impairments in children undergoing cardiac surgery.
It has recently been shown that state estimation (SE), which is the most important real-time function in modern energy management systems (EMSs), is vulnerable to false data injection attacks, due to ...the undetectability of those attacks using standard bad data detection techniques, which are typically based on normalized measurement residuals. Therefore, it is of the utmost importance to develop novel and efficient methods that are capable of detecting such malicious attacks. In this paper, we propose using the unscented Kalman filter (UKF) in conjunction with a weighted least square (WLS) based SE algorithm in real-time, to detect discrepancies between SV estimates and, as a consequence, to identify false data attacks. After an attack is detected and an appropriate alarm is raised, an operator can take actions to prevent or minimize the potential consequences. The proposed algorithm was successfully tested on benchmark IEEE 14-bus and 300-bus test systems, making it suitable for implementation in commercial EMS software.
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