- Teasing apart NAD(+) metabolism in inflammation: commentary on Zhou et al. (2016). Br J Pharmacol 173: 2352-2368. British journal of pharmacology 2017; 174 (3): 281–83
Reevaluating the role of IDO1: Examining NAD+ metabolism in inflammation
Journal of Neuroimmunology
2017; 307: 31-32
View details for DOI 10.1016/j.jneuroim.2017.03.016
Histone deacetylase 3 associates with MeCP2 to regulate FOXO and social behavior.
2016; 19 (11): 1497-1505
Mutations in MECP2 cause the neurodevelopmental disorder Rett syndrome (RTT). The RTT missense MECP2(R306C) mutation prevents MeCP2 from interacting with the NCoR/histone deacetylase 3 (HDAC3) complex; however, the neuronal function of HDAC3 is incompletely understood. We found that neuronal deletion of Hdac3 in mice elicited abnormal locomotor coordination, sociability and cognition. Transcriptional and chromatin profiling revealed that HDAC3 positively regulated a subset of genes and was recruited to active gene promoters via MeCP2. HDAC3-associated promoters were enriched for the FOXO transcription factors, and FOXO acetylation was elevated in Hdac3 knockout (KO) and Mecp2 KO neurons. Human RTT-patient-derived MECP2(R306C) neural progenitor cells had deficits in HDAC3 and FOXO recruitment and gene expression. Gene editing of MECP2(R306C) cells to generate isogenic controls rescued HDAC3-FOXO-mediated impairments in gene expression. Our data suggest that HDAC3 interaction with MeCP2 positively regulates a subset of neuronal genes through FOXO deacetylation, and disruption of HDAC3 contributes to cognitive and social impairment.
View details for DOI 10.1038/nn.4347
View details for PubMedID 27428650
View details for PubMedCentralID PMC5083138
Cyclooxygenase inhibition targets neurons to prevent early behavioural decline in Alzheimer's disease model mice
2016; 139: 2063-2081
Identifying preventive targets for Alzheimer's disease is a central challenge of modern medicine. Non-steroidal anti-inflammatory drugs, which inhibit the cyclooxygenase enzymes COX-1 and COX-2, reduce the risk of developing Alzheimer's disease in normal ageing populations. This preventive effect coincides with an extended preclinical phase that spans years to decades before onset of cognitive decline. In the brain, COX-2 is induced in neurons in response to excitatory synaptic activity and in glial cells in response to inflammation. To identify mechanisms underlying prevention of cognitive decline by anti-inflammatory drugs, we first identified an early object memory deficit in APPSwe-PS1ΔE9 mice that preceded previously identified spatial memory deficits in this model. We modelled prevention of this memory deficit with ibuprofen, and found that ibuprofen prevented memory impairment without producing any measurable changes in amyloid-β accumulation or glial inflammation. Instead, ibuprofen modulated hippocampal gene expression in pathways involved in neuronal plasticity and increased levels of norepinephrine and dopamine. The gene most highly downregulated by ibuprofen was neuronal tryptophan 2,3-dioxygenase (Tdo2), which encodes an enzyme that metabolizes tryptophan to kynurenine. TDO2 expression was increased by neuronal COX-2 activity, and overexpression of hippocampal TDO2 produced behavioural deficits. Moreover, pharmacological TDO2 inhibition prevented behavioural deficits in APPSwe-PS1ΔE9 mice. Taken together, these data demonstrate broad effects of cyclooxygenase inhibition on multiple neuronal pathways that counteract the neurotoxic effects of early accumulating amyloid-β oligomers.
View details for DOI 10.1093/brain/aww117
View details for Web of Science ID 000379763000026
View details for PubMedID 27190010
View details for PubMedCentralID PMC4939702
- Neuropathology: bridging psychiatry and neurology in medical education. The lancet. Psychiatry 2016; 3 (2): 98-100
Modulation of mitochondrial complex I activity averts cognitive decline in multiple animal models of familial Alzheimer's Disease.
2015; 2 (4): 294–305
Development of therapeutic strategies to prevent Alzheimer's Disease (AD) is of great importance. We show that mild inhibition of mitochondrial complex I with small molecule CP2 reduces levels of amyloid beta and phospho-Tau and averts cognitive decline in three animal models of familial AD. Low-mass molecular dynamics simulations and biochemical studies confirmed that CP2 competes with flavin mononucleotide for binding to the redox center of complex I leading to elevated AMP/ATP ratio and activation of AMP-activated protein kinase in neurons and mouse brain without inducing oxidative damage or inflammation. Furthermore, modulation of complex I activity augmented mitochondrial bioenergetics increasing coupling efficiency of respiratory chain and neuronal resistance to stress. Concomitant reduction of glycogen synthase kinase 3β activity and restoration of axonal trafficking resulted in elevated levels of neurotrophic factors and synaptic proteins in adult AD mice. Our results suggest metabolic reprogramming induced by modulation of mitochondrial complex I activity represents promising therapeutic strategy for AD.
View details for DOI 10.1016/j.ebiom.2015.03.009
View details for PubMedID 26086035
View details for PubMedCentralID PMC4465115
The effects of passive and active learning on student preference and performance in an undergraduate basic science course
ANATOMICAL SCIENCES EDUCATION
2012; 5 (4): 200-207
Active learning is based on self-directed and autonomous teaching methods, whereas passive learning is grounded in instructor taught lectures. An animal physiology course was studied over a two-year period (Year 1, n = 42 students; Year 2, n = 30 students) to determine the effects of student-led seminar (andragogical) and lecture (pedagogical) teaching methods on students' retention of information and performance. For each year of the study, the course was divided into two time periods. The first half was dedicated to instructor-led lectures, followed by a control survey in which the students rated the efficiency of pedagogical learning on a five-point Likert scale from one (strongly disagree) to five (strongly agree). During the second period, students engaged in andragogical learning via peer-led seminars. An experimental survey was then administered to students using the same scale as above to determine students' preferred teaching method. Raw examination scores and survey results from both halves of the course were statistically analyzed by ANOVA with Newman-Keuls multiple comparison test. By the end of the study, student preference for peer-led seminars increased [mean ± SD: (2.47 ± 0.94)/(4.03 ± 1.36), P < 0.04], and examination scores significantly increased [mean ± SD: (73.91% ± 13.18)/(85.77 ± 5.22), P < 0.001]. A majority of students (68.8%) preferred a method that contained peer-led seminars and instructor-led lectures. These results may indicate that integration of active and passive learning into undergraduate courses may have greater benefit in terms of student preference and performance than either method alone.
View details for DOI 10.1002/ase.1274
View details for Web of Science ID 000305886600002
View details for PubMedID 22434661
Risk factors for positive admission surveillance cultures for methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci in a neurocritical care unit
CRITICAL CARE MEDICINE
2011; 39 (10): 2322-2329
Hospitals are under increasing pressure to perform active surveillance cultures for methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus. This study aimed to identify patients at low and high risk for positive admission surveillance cultures for methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus in a neurocritical care unit using readily ascertainable historical factors.Before/after study with nested case/control study.Neurocritical care unit of an academic hospital.During the intervention period (July 2007 to June 2008), after implementation of an admission surveillance culture screening program for methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus, 2,059 patients were admitted to the neurocritical care unit for a total of 5,957 patient days.Cases had positive methicillin-resistant Staphylococcus aureus or vancomycin-resistant Enterococcus admission surveillance cultures within 48 hrs of hospital admission. Controls had negative cultures.Admission surveillance cultures grew methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus in 35 of 823 (4.3%) and 19 of 766 (2.5%) patients, respectively. Factors significantly associated with both methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus colonization were intravenous antibiotics and hospitalization in the past year, immunocompromised health status, intravenous drug use, long-term hemodialysis, and known prior carrier status. Transfer from an outside hospital and residence in a long-term care facility in the past year were associated with vancomycin-resistant Enterococcus colonization. Classification and regression tree analysis was used to identify variables that best predicted positive methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus surveillance cultures. A classification and regression tree model with six of these variables yielded an overall cross-validated predictive accuracy of 87.12% to detect methicillin-resistant Staphylococcus aureus colonization. For vancomycin-resistant Enterococcus, a four-variable classification and regression tree model (intravenous antibiotics, hospitalization and long-term patient care in the past year, and not being "admitted same day of procedure") optimized the predictive accuracy (94.91%). There were no cases of vancomycin-resistant Enterococcus colonization in patients admitted same day of procedure.Colonization with methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus in neurocritical care patients can be predicted with a high predictive accuracy using decision trees that include four to six readily attainable risk factors. In our setting, in the absence of these risk factors and in patients admitted from home for neurosurgical procedures, routine admission surveillance cultures to the intensive care unit may not be cost-effective.
View details for DOI 10.1097/CCM.0b013e3182227222
View details for Web of Science ID 000294958500017
View details for PubMedID 21705905