DNA‐PKcs is a key regulator of DNA double‐strand break repair. Apart from its canonical role in t... more DNA‐PKcs is a key regulator of DNA double‐strand break repair. Apart from its canonical role in the DNA damage response, DNA‐PKcs is involved in the cellular response to oxidative stress (OS), but its exact role remains unclear. Here, we report that DNA‐PKcs‐deficient human cells display depolarized mitochondria membrane potential (MMP) and reoriented metabolism, supporting a role for DNA‐PKcs in oxidative phosphorylation (OXPHOS). DNA‐PKcs directly interacts with mitochondria proteins ANT2 and VDAC2, and formation of the DNA‐PKcs/ANT2/VDAC2 (DAV) complex supports optimal exchange of ADP and ATP across mitochondrial membranes to energize the cell via OXPHOS and to maintain MMP. Moreover, we demonstrate that the DAV complex temporarily dissociates in response to oxidative stress to attenuate ADP‐ATP exchange, a rate‐limiting step for OXPHOS. Finally, we found that dissociation of the DAV complex is mediated by phosphorylation of DNA‐PKcs at its Thr2609 cluster by ATM kinase. Based on these findings, we propose that the coordination between the DAV complex and ATM serves as a novel oxidative stress checkpoint to decrease ROS production from mitochondrial OXPHOS and to hasten cellular recovery from OS.
Introduction: Methamphetamine, an addictive stimulant, may lead to psychosis of which little is k... more Introduction: Methamphetamine, an addictive stimulant, may lead to psychosis of which little is known about the impact in acute stroke. Despite its short half-life, we hypothesize that methamphetamine use in acute stroke is associated with the development of psychosis and extends hospital length of stay (LOS). Methods: Single-center retrospective analysis (2016-2019) of consecutive adult patients admitted for acute ischemic stroke, intracerebral hemorrhage (ICH), aneurysmal subarachnoid hemorrhage (SAH), and transient ischemic attack (TIA) with methamphetamine detected on urine drug screen and were compared to those who did not. Psychosis was defined as disturbed thoughts or perceptions with abnormal psychomotor behavior. Psychosis onset and duration, clinical characteristics, total hospitalization time and intensive care unit (ICU) LOS, as well as psychotic treatment interventions were documented. Results: 138 patients were admitted for acute cerebrovascular events (87 ischemic strokes, 40ICH, 7 SAH, 2 TIAs). 69 patients tested positive for methamphetamine (68% male; mean age 53(range 26-68)) and were compared to 69 who did not (65% male, mean age 64 (range 30-93).Despite no differences in having any psychiatric illness history, 25% (17/69) of methamphetamine users experienced psychosis compared to only 3% (2/69) who did not test positive (p <0.0002). Although there was no statistical difference in hospital LOS (3.6 days in methamphetamine positive versus 2.9 days ( p =.113)), substance use abusers had significantly longer ICU stays (48 hours versus 24 hours; p =.006). NIHSS and ICH Scores were not statistically different between those who tested positive or negative for methamphetamine. Conclusions: Methamphetamine use is strongly associated with developing psychosis and when present, leads to longer ICU stay.
Trex1−/− mice suffer from systemic inflammation caused largely by chronic activation of the cGAS-... more Trex1−/− mice suffer from systemic inflammation caused largely by chronic activation of the cGAS-STING-TBK1-IRF3 signaling pathway. We showed previously that Trex1-deficient cells have reduced mTORC1 activity, although the underlying mechanism is unclear. Here, we performed detailed metabolic analysis in Trex1−/− mice and cells that revealed defects in mitochondrial respiration, reduced adiposity, increased energy expenditure and glycolysis. We also found that Trex1−/− mice and cells exhibit chronically suppressed mTORC1 activity. Furthermore, we provide genetic evidence corroborated with cellular and biochemical validation to show that metabolic dysregulation in Trex1−/− mice is caused by STING-dependent activation of TBK1, but not the downstream IRF3-mediated signaling and inflammation, and that TBK1 binds to the mTORC1 complex and inhibits its activity in Trex1−/− cells. Our data thus establish chronic STING-dependent activation of TBK1 as a novel regulatory axis of mTORC1 and cellular metabolism.
Debates have long held an important role in history. They can be traced back to the philosophers ... more Debates have long held an important role in history. They can be traced back to the philosophers and political debates in Ancient Greece and Rome, the Shastrartha philosophical and religious debates in India, to the evolution of Parliament from its roots in Medieval England. And, in our own time—for better or worse—they have determined the outcome of presidential elections. When Covid-19 travel bans struck, they precluded the possibility of holding our traditional Neuroethics Network meeting at ICM, the Paris Brain Institute. Reimagining was required to capture the spirit of onsite energy within a new virtual world. Our solution lay in acknowledging that Ernest Hemingway was right—Paris really is a moveable feast. The virtual “Paris is a Moveable Feast” meeting introduced a new format, “The Great Debates,” in which leading neuroethicists defended opposite sides of current controversial questions: “Does a Mind Need a Body?” “Should Cerebral Organoids be Used for Research if They Have the Capacity for Consciousness?” “Has the Time Come to Eliminate Controls that Involve Burr Hoes in Neurosurgical Sham Research?” and “Should We Use Technology to Merge Minds?” This intellectual jousting is being offered as exercises rather than necessarily representing the debaters’ own positions. And, unlike the original meaning of the word “debate” as a fight or an argument, in our “Great Debates,” there were no winners or losers; but something more difficult and far-reaching: the goal was to prompt a critical examination of our own, often strongly held, positions. By including transcriptions of those debates in this issue, we hope they may prompt the same response in readers.
Introduction Disruption of sleep may have significant implications in acute brain injury, functio... more Introduction Disruption of sleep may have significant implications in acute brain injury, functional recovery, and critical illness. Few data exist characterizing sleep architecture in patients admitted to an intensive care unit (ICU). We aim to describe sleep and clinical characteristics in patients with acute brain injury and critical illness. Methods Retrospective analysis was performed in ICU patients who underwent continuous electroencephalographic (EEG) monitoring from 2018-2019. Sleep was scored based on AASM-defined EEG criteria. Clinical variables, EEG characteristics, and modified Ranking Scale (mRS) were collected. Good outcome was defined as mRS<3. Differences were assessed using chi-square analysis and t-test. Results 205 patients were reviewed with a mean age of 57 years (range 18-91) and a majority (57%) were male. Patients carried a primary neurologic/neurosurgical (61%) or medical/surgical (39%) diagnosis. Status epilepticus, subdural hemorrhage, traumatic brain ...
Selenium induces a senescence response through induction of ataxia-telangiectasia mutated (ATM) a... more Selenium induces a senescence response through induction of ataxia-telangiectasia mutated (ATM) and reactive oxygen species (ROS). Although a role of the DNA-PK complex, including the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), Ku70 and Ku80, in DNA double strand break repair is established, it is unclear how these proteins function in the response to selenium-induced oxidative stress and senescence induction. In this study we demonstrate that pre-treating normal human diploid fibroblasts with DNA-PK kinase inhibitor NU 7026 suppresses selenium-induced senescence response. Selenium treatment induces phosphorylation of DNA-PKcs on Thr-2647 and Ser-2056, the extent of which is decreased in the presence of ATM kinase inhibitor KU 55933 or the antioxidant N-acetylcysteine or 2,2,6,6-tetramethylpiperidine-1-oxyl. In contrast, the selenium-induced phosphorylation of ATM on Ser-1981 is not affected by NU 7026. Cells deficient in DNA-PKcs or pre-treated with NU 7026 or N-a...
Trex1−/− mice suffer from systemic inflammation caused largely by chronic activation of the cGAS-... more Trex1−/− mice suffer from systemic inflammation caused largely by chronic activation of the cGAS-STING-TBK1-IRF3 signaling pathway. We showed previously that Trex1-deficient cells have reduced mTORC1 activity, although the underlying mechanism is unclear. Here, we performed detailed metabolic analysis in Trex1−/− mice and cells that revealed defects in mitochondrial respiration, reduced adiposity, increased energy expenditure and glycolysis. We also found that Trex1−/− mice and cells exhibit chronically suppressed mTORC1 activity. Furthermore, we provide genetic evidence corroborated with cellular and biochemical validation to show that metabolic dysregulation in Trex1−/− mice is caused by STING-dependent activation of TBK1, but not the downstream IRF3-mediated signaling and inflammation, and that TBK1 binds to the mTORC1 complex and inhibits its activity in Trex1−/− cells. Our data thus establish chronic STING-dependent activation of TBK1 as a novel regulatory axis of mTORC1 and ce...
Introduction: Methamphetamine, an addictive stimulant, may lead to psychosis of which little is k... more Introduction: Methamphetamine, an addictive stimulant, may lead to psychosis of which little is known about the impact in acute stroke. Despite its short half-life, we hypothesize that methamphetamine use in acute stroke is associated with the development of psychosis and extends hospital length of stay (LOS). Methods: Single-center retrospective analysis (2016-2019) of consecutive adult patients admitted for acute ischemic stroke, intracerebral hemorrhage (ICH), aneurysmal subarachnoid hemorrhage (SAH), and transient ischemic attack (TIA) with methamphetamine detected on urine drug screen and were compared to those who did not. Psychosis was defined as disturbed thoughts or perceptions with abnormal psychomotor behavior. Psychosis onset and duration, clinical characteristics, total hospitalization time and intensive care unit (ICU) LOS, as well as psychotic treatment interventions were documented. Results: 138 patients were admitted for acute cerebrovascular events (87 ischemic str...
Proceedings of the National Academy of Sciences, 2014
Significance Although the hippocampus has a well-documented role for spatial navigation across sp... more Significance Although the hippocampus has a well-documented role for spatial navigation across species, its role for spatial memory in nonnavigational tasks is uncertain. Thus, when monkeys are tested in tasks that do not require navigation through space, spatial memory seems unaffected by hippocampal lesions. However, the interpretation of these results is compromised by long-term compensatory adaptation occurring in the days and weeks after lesions. To preclude long-term compensation, we transiently inactivated hippocampus at the time of testing. Hippocampal inactivation reduced performance on a nonnavigational spatial memory task to chance levels. These data align the role of hippocampus for spatial memory in monkeys with the broader literature while simultaneously demonstrating the efficacy of inactivation of hippocampus in monkeys.
DNA‐PKcs is a key regulator of DNA double‐strand break repair. Apart from its canonical role in t... more DNA‐PKcs is a key regulator of DNA double‐strand break repair. Apart from its canonical role in the DNA damage response, DNA‐PKcs is involved in the cellular response to oxidative stress (OS), but its exact role remains unclear. Here, we report that DNA‐PKcs‐deficient human cells display depolarized mitochondria membrane potential (MMP) and reoriented metabolism, supporting a role for DNA‐PKcs in oxidative phosphorylation (OXPHOS). DNA‐PKcs directly interacts with mitochondria proteins ANT2 and VDAC2, and formation of the DNA‐PKcs/ANT2/VDAC2 (DAV) complex supports optimal exchange of ADP and ATP across mitochondrial membranes to energize the cell via OXPHOS and to maintain MMP. Moreover, we demonstrate that the DAV complex temporarily dissociates in response to oxidative stress to attenuate ADP‐ATP exchange, a rate‐limiting step for OXPHOS. Finally, we found that dissociation of the DAV complex is mediated by phosphorylation of DNA‐PKcs at its Thr2609 cluster by ATM kinase. Based on these findings, we propose that the coordination between the DAV complex and ATM serves as a novel oxidative stress checkpoint to decrease ROS production from mitochondrial OXPHOS and to hasten cellular recovery from OS.
Introduction: Methamphetamine, an addictive stimulant, may lead to psychosis of which little is k... more Introduction: Methamphetamine, an addictive stimulant, may lead to psychosis of which little is known about the impact in acute stroke. Despite its short half-life, we hypothesize that methamphetamine use in acute stroke is associated with the development of psychosis and extends hospital length of stay (LOS). Methods: Single-center retrospective analysis (2016-2019) of consecutive adult patients admitted for acute ischemic stroke, intracerebral hemorrhage (ICH), aneurysmal subarachnoid hemorrhage (SAH), and transient ischemic attack (TIA) with methamphetamine detected on urine drug screen and were compared to those who did not. Psychosis was defined as disturbed thoughts or perceptions with abnormal psychomotor behavior. Psychosis onset and duration, clinical characteristics, total hospitalization time and intensive care unit (ICU) LOS, as well as psychotic treatment interventions were documented. Results: 138 patients were admitted for acute cerebrovascular events (87 ischemic strokes, 40ICH, 7 SAH, 2 TIAs). 69 patients tested positive for methamphetamine (68% male; mean age 53(range 26-68)) and were compared to 69 who did not (65% male, mean age 64 (range 30-93).Despite no differences in having any psychiatric illness history, 25% (17/69) of methamphetamine users experienced psychosis compared to only 3% (2/69) who did not test positive (p &amp;amp;lt;0.0002). Although there was no statistical difference in hospital LOS (3.6 days in methamphetamine positive versus 2.9 days ( p =.113)), substance use abusers had significantly longer ICU stays (48 hours versus 24 hours; p =.006). NIHSS and ICH Scores were not statistically different between those who tested positive or negative for methamphetamine. Conclusions: Methamphetamine use is strongly associated with developing psychosis and when present, leads to longer ICU stay.
Trex1−/− mice suffer from systemic inflammation caused largely by chronic activation of the cGAS-... more Trex1−/− mice suffer from systemic inflammation caused largely by chronic activation of the cGAS-STING-TBK1-IRF3 signaling pathway. We showed previously that Trex1-deficient cells have reduced mTORC1 activity, although the underlying mechanism is unclear. Here, we performed detailed metabolic analysis in Trex1−/− mice and cells that revealed defects in mitochondrial respiration, reduced adiposity, increased energy expenditure and glycolysis. We also found that Trex1−/− mice and cells exhibit chronically suppressed mTORC1 activity. Furthermore, we provide genetic evidence corroborated with cellular and biochemical validation to show that metabolic dysregulation in Trex1−/− mice is caused by STING-dependent activation of TBK1, but not the downstream IRF3-mediated signaling and inflammation, and that TBK1 binds to the mTORC1 complex and inhibits its activity in Trex1−/− cells. Our data thus establish chronic STING-dependent activation of TBK1 as a novel regulatory axis of mTORC1 and cellular metabolism.
Debates have long held an important role in history. They can be traced back to the philosophers ... more Debates have long held an important role in history. They can be traced back to the philosophers and political debates in Ancient Greece and Rome, the Shastrartha philosophical and religious debates in India, to the evolution of Parliament from its roots in Medieval England. And, in our own time—for better or worse—they have determined the outcome of presidential elections. When Covid-19 travel bans struck, they precluded the possibility of holding our traditional Neuroethics Network meeting at ICM, the Paris Brain Institute. Reimagining was required to capture the spirit of onsite energy within a new virtual world. Our solution lay in acknowledging that Ernest Hemingway was right—Paris really is a moveable feast. The virtual “Paris is a Moveable Feast” meeting introduced a new format, “The Great Debates,” in which leading neuroethicists defended opposite sides of current controversial questions: “Does a Mind Need a Body?” “Should Cerebral Organoids be Used for Research if They Have the Capacity for Consciousness?” “Has the Time Come to Eliminate Controls that Involve Burr Hoes in Neurosurgical Sham Research?” and “Should We Use Technology to Merge Minds?” This intellectual jousting is being offered as exercises rather than necessarily representing the debaters’ own positions. And, unlike the original meaning of the word “debate” as a fight or an argument, in our “Great Debates,” there were no winners or losers; but something more difficult and far-reaching: the goal was to prompt a critical examination of our own, often strongly held, positions. By including transcriptions of those debates in this issue, we hope they may prompt the same response in readers.
Introduction Disruption of sleep may have significant implications in acute brain injury, functio... more Introduction Disruption of sleep may have significant implications in acute brain injury, functional recovery, and critical illness. Few data exist characterizing sleep architecture in patients admitted to an intensive care unit (ICU). We aim to describe sleep and clinical characteristics in patients with acute brain injury and critical illness. Methods Retrospective analysis was performed in ICU patients who underwent continuous electroencephalographic (EEG) monitoring from 2018-2019. Sleep was scored based on AASM-defined EEG criteria. Clinical variables, EEG characteristics, and modified Ranking Scale (mRS) were collected. Good outcome was defined as mRS<3. Differences were assessed using chi-square analysis and t-test. Results 205 patients were reviewed with a mean age of 57 years (range 18-91) and a majority (57%) were male. Patients carried a primary neurologic/neurosurgical (61%) or medical/surgical (39%) diagnosis. Status epilepticus, subdural hemorrhage, traumatic brain ...
Selenium induces a senescence response through induction of ataxia-telangiectasia mutated (ATM) a... more Selenium induces a senescence response through induction of ataxia-telangiectasia mutated (ATM) and reactive oxygen species (ROS). Although a role of the DNA-PK complex, including the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), Ku70 and Ku80, in DNA double strand break repair is established, it is unclear how these proteins function in the response to selenium-induced oxidative stress and senescence induction. In this study we demonstrate that pre-treating normal human diploid fibroblasts with DNA-PK kinase inhibitor NU 7026 suppresses selenium-induced senescence response. Selenium treatment induces phosphorylation of DNA-PKcs on Thr-2647 and Ser-2056, the extent of which is decreased in the presence of ATM kinase inhibitor KU 55933 or the antioxidant N-acetylcysteine or 2,2,6,6-tetramethylpiperidine-1-oxyl. In contrast, the selenium-induced phosphorylation of ATM on Ser-1981 is not affected by NU 7026. Cells deficient in DNA-PKcs or pre-treated with NU 7026 or N-a...
Trex1−/− mice suffer from systemic inflammation caused largely by chronic activation of the cGAS-... more Trex1−/− mice suffer from systemic inflammation caused largely by chronic activation of the cGAS-STING-TBK1-IRF3 signaling pathway. We showed previously that Trex1-deficient cells have reduced mTORC1 activity, although the underlying mechanism is unclear. Here, we performed detailed metabolic analysis in Trex1−/− mice and cells that revealed defects in mitochondrial respiration, reduced adiposity, increased energy expenditure and glycolysis. We also found that Trex1−/− mice and cells exhibit chronically suppressed mTORC1 activity. Furthermore, we provide genetic evidence corroborated with cellular and biochemical validation to show that metabolic dysregulation in Trex1−/− mice is caused by STING-dependent activation of TBK1, but not the downstream IRF3-mediated signaling and inflammation, and that TBK1 binds to the mTORC1 complex and inhibits its activity in Trex1−/− cells. Our data thus establish chronic STING-dependent activation of TBK1 as a novel regulatory axis of mTORC1 and ce...
Introduction: Methamphetamine, an addictive stimulant, may lead to psychosis of which little is k... more Introduction: Methamphetamine, an addictive stimulant, may lead to psychosis of which little is known about the impact in acute stroke. Despite its short half-life, we hypothesize that methamphetamine use in acute stroke is associated with the development of psychosis and extends hospital length of stay (LOS). Methods: Single-center retrospective analysis (2016-2019) of consecutive adult patients admitted for acute ischemic stroke, intracerebral hemorrhage (ICH), aneurysmal subarachnoid hemorrhage (SAH), and transient ischemic attack (TIA) with methamphetamine detected on urine drug screen and were compared to those who did not. Psychosis was defined as disturbed thoughts or perceptions with abnormal psychomotor behavior. Psychosis onset and duration, clinical characteristics, total hospitalization time and intensive care unit (ICU) LOS, as well as psychotic treatment interventions were documented. Results: 138 patients were admitted for acute cerebrovascular events (87 ischemic str...
Proceedings of the National Academy of Sciences, 2014
Significance Although the hippocampus has a well-documented role for spatial navigation across sp... more Significance Although the hippocampus has a well-documented role for spatial navigation across species, its role for spatial memory in nonnavigational tasks is uncertain. Thus, when monkeys are tested in tasks that do not require navigation through space, spatial memory seems unaffected by hippocampal lesions. However, the interpretation of these results is compromised by long-term compensatory adaptation occurring in the days and weeks after lesions. To preclude long-term compensation, we transiently inactivated hippocampus at the time of testing. Hippocampal inactivation reduced performance on a nonnavigational spatial memory task to chance levels. These data align the role of hippocampus for spatial memory in monkeys with the broader literature while simultaneously demonstrating the efficacy of inactivation of hippocampus in monkeys.
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