Ketamine for postoperative avoidance of depressive symptoms: the K-PASS feasibility randomised trial
(2024) BJA Open, 9, art. no. 100245, .
Fritz, B.A.a , Tellor Pennington, B.R.a , Dalton, C.a , Horan, C.b , Palanca, B.J.A.a b , Schweiger, J.A.b , Griffin, L.b , Tumwesige, W.b , Willie, J.T.c , Farber, N.B.b
a Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, United States
b Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, United States
c Department of Neurosurgery, Washington University School of Medicine, Saint Louis, MO, United States
Abstract
Background: Surgical patients with previous depression frequently experience postoperative depressive symptoms. This study’s objective was to determine the feasibility of a placebo-controlled trial testing the impact of a sustained ketamine infusion on postoperative depressive symptoms. Methods: This single-centre, triple-blind, placebo-controlled randomised clinical trial included adult patients with depression scheduled for inpatient surgery. After surgery, patients were randomly allocated to receive ketamine (0.5 mg kg−1 over 10 min followed by 0.3 mg kg−1 h−1 for 3 h) or an equal volume of normal saline. Depressive symptoms were measured using the Montgomery–Asberg Depression Rating Scale. On post-infusion day 1, participants guessed which intervention they received. Feasibility endpoints included the fraction of patients approached who were randomised, the fraction of randomised patients who completed the study infusion, and the fraction of scheduled depression assessments that were completed. Results: In total, 32 patients were allocated a treatment, including 31/101 patients approached after a protocol change (31%, 1.5 patients per week). The study infusion was completed without interruption in 30/32 patients (94%). In each group, 7/16 participants correctly guessed which intervention they received. Depression assessments were completed at 170/192 scheduled time points (89%). Between baseline and post-infusion day 4 (pre-specified time point of interest), median depressive symptoms decreased in both groups, with difference-in-differences of −1.00 point (95% confidence interval −3.23 to 1.73) with ketamine compared with placebo. However, the between-group difference did not persist at other time points. Conclusions: Patient recruitment, medication administration, and clinical outcome measurement appear to be highly feasible, with blinding maintained. A fully powered trial may be warranted. Clinical trial registration: NCT05233566. © 2023 The Authors
Author Keywords
clinical trial; depression; feasibility trial; ketamine; postoperative depression
Funding details
National Institute of Mental HealthNIMHP50 MH122351
Foundation for Anesthesia Education and ResearchFAERMRTG08152020
Document Type: Article
Publication Stage: Final
Source: Scopus
Longitudinal Analysis of Early Hearing Detection and Intervention Program Performance
(2024) Ear and Hearing, 45 (1), pp. 62-71.
Mahal, R., Bluher, A., Kallogjeri, D., Seeser, J., Piccirillo, J., Buchman, C.A.
Department of Otolaryngology – Head and Neck Surgery, Washington University School of Medicine, St Louis, MO, United States
Abstract
Objectives: Early hearing detection and intervention (EHDI) is a newborn hearing screening system created to detect infants with hearing loss (HL) and intervene to reduce language and communication impairment. Early hearing detection (EHD) consists of three sequential stages: identification, screening, and diagnostic testing. This study longitudinally reviews each stage of EHD in each state and proposes a framework to improve utilization of EHD data. Design: A retrospective public database review was conducted, accessing publicly available data from the Centers for Disease Control and Prevention. Summary descriptive statistics were utilized to generate a descriptive study of EHDI programs in each U.S. state from 2007 to 2016. Results: Data over 10 years from 50 states as well as Washington, DC were included in this analysis, creating up to 510 data points per analysis. Hundred percent (85 to 105) (median [min to max]) of newborns were identified by and entered EHDI programs. Ninety-eight percent (51 to 100) of identified infants completed screening. Of the infants who screened positive for HL, the proportion that received diagnostic testing was 55% (1 to 100). The overall proportion of infants who failed to complete EHD was 3% (1 to 51). Of the infants who fail to complete EHD 70% (0 to 100) are from missed screenings, 24% (0 to 95) are from missed diagnostic testing, and 0% (0 to 93) are from missed identification. Although there are more infants missed at screening, it was estimated, with limitations, that there is an order of magnitude more infants with HL among those who did not complete diagnostic testing compared with those who did not complete screening. Conclusions: Analysis demonstrates high completion rates at both identification and screening stages, whereas the diagnostic testing stage demonstrates low and highly variable completion rates. The low completion rates at diagnostic testing create a bottleneck in the EHD process and the large variability impedes the comparison of HL outcomes across states. Analysis also demonstrates that among all stages of EHD, whereas the largest number of infants are missed at screening, the largest number of children with HL are likely missed at diagnostic testing. Therefore, a focus by individual EHDI programs on addressing causes of low diagnostic testing completion rates would yield the greatest increase in the identification of children with HL. Potential causes of low diagnostic testing completion rates are further discussed. Finally, a new vocabulary framework is proposed to facilitate further study of EHD outcomes. © 2024 Lippincott Williams and Wilkins. All rights reserved.
Author Keywords
EHDI; Hearing; Lost; Missing; Screening; UNHS
Funding details
Washington University School of Medicine in St. LouisWUSM
Document Type: Article
Publication Stage: Final
Source: Scopus
Speech Perception Training in Children: The Retention of Benefits and Booster Training
(2024) Ear and Hearing, 45 (1), pp. 164-173.
Spehar, B.a , Tye-Murray, N.a , Mauzé, E.a , Sommers, M.b , Barcroft, J.c
a Department of Otolaryngology, St Louis School of Medicine, Washington University, St. Louis, MO, United States
b Department of Psychological and Brain Sciences, Washington University, St. Louis, MO, United States
c Department of Romance Language and Literatures, Washington University, St. Louis, MO, United States
Abstract
Objectives: Speech perception training can be a highly effective intervention to improve perception and language abilities in children who are deaf or hard of hearing. Most studies of speech perception training, however, only measure gains immediately following training. Only a minority of cases include a follow-up assessment after a period without training. A critical unanswered question was whether training-related benefits are retained for a period of time after training has stopped. A primary goal of this investigation was to determine whether children retained training-related benefits 4 to 6 weeks after they completed 16 hours of formal speech perception training. Training was comprised of either auditory or speechreading training, or a combination of both. Also important is to determine if “booster” training can help increase gains made during the initial intensive training period. Another goal of the study was to investigate the benefits of providing home-based booster training during the 4- to 6-week interval after the formal training ceased. The original investigation (Tye-Murray et al. 2022) compared the effects of talker familiarity and the relative benefits of the different types of training. We predicted that the children who received no additional training would retain the gains after the completing the formal training. We also predicted that those children who completed the booster training would realize additional gains. Design: Children, 6 to 12 years old, with hearing loss who had previously participated in the original randomized control study returned 4 to 6 weeks after the conclusion to take a follow-up speech perception assessment. The first group (n = 44) returned after receiving no formal intervention from the research team before the follow-up assessment. A second group of 40 children completed an additional 16 hours of speech perception training at home during a 4- to 6-week interval before the follow-up speech perception assessment. The home-based speech perception training was a continuation of the same training that was received in the laboratory formatted to work on a PC tablet with a portable speaker. The follow-up speech perception assessment included measures of listening and speechreading, with test items spoken by both familiar (trained) and unfamiliar (untrained) talkers. Results: In the group that did not receive the booster training, follow-up testing showed retention for all gains that were obtained immediately following the laboratory-based training. The group that received booster training during the same interval also maintained the benefits from the formal training, with some indication of minor improvement. Conclusions: Clinically, the present findings are extremely encouraging; the group that did not receive home-based booster training retained the benefits obtained during the laboratory-based training regimen. Moreover, the results suggest that self-paced booster training maintained the relative training gains associated with talker familiarity and training type seen immediately following laboratory-based training. Future aural rehabilitation programs should include maintenance training at home to supplement the speech perception training conducted under more formal conditions at school or in the clinic. © 2024 Lippincott Williams and Wilkins. All rights reserved.
Author Keywords
Auditory training; Children with hearing loss; Pediatric audiology; Pediatric aural rehabilitation
Funding details
National Institutes of HealthNIH
National Institute on Deafness and Other Communication DisordersNIDCDRO1 DC014722
Document Type: Article
Publication Stage: Final
Source: Scopus
Investigating the Relationship Between Smoking Behavior and Global Brain Volume
(2024) Biological Psychiatry Global Open Science, 4 (1), pp. 74-82.
Chang, Y.a , Thornton, V.a , Chaloemtoem, A.a , Anokhin, A.P.a , Bijsterbosch, J.b , Bogdan, R.c , Hancock, D.B.d , Johnson, E.O.e , Bierut, L.J.a
a Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, United States
b Department of Radiology, Washington University School of Medicine, St. Louis, Missouri, United States
c Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, Missouri, United States
d Social, Statistical and Environmental Sciences, Research Triangle Institute International, Research Triangle ParkNorth Carolina, United States
e Fellow Program, Research Triangle Institute International, Research Triangle ParkNorth Carolina, United States
Abstract
Background: Previous studies have shown that brain volume is negatively associated with cigarette smoking, but there is an ongoing debate about whether smoking causes lowered brain volume or a lower brain volume is a risk factor for smoking. We address this debate through multiple methods that evaluate directionality: Bradford Hill’s criteria, which are commonly used to understand a causal relationship in epidemiological studies, and mediation analysis. Methods: In 32,094 participants of European descent from the UK Biobank dataset, we examined the relationship between a history of daily smoking and brain volumes, as well as an association of genetic risk score to ever smoking with brain volume. Results: A history of daily smoking was strongly associated with decreased brain volume, and a history of heavier smoking was associated with a greater decrease in brain volume. The strongest association was between total gray matter volume and a history of daily smoking (effect size = −2964 mm3, p = 2.04 × 10−16), and there was a dose-response relationship with more pack years smoked associated with a greater decrease in brain volume. A polygenic risk score for smoking initiation was strongly associated with a history of daily smoking (effect size = 0.05, p = 4.20 × 10−84), but only modestly associated with total gray matter volume (effect size = −424 mm3, p = .01). Mediation analysis indicated that a history of daily smoking mediated the relationship between the smoking initiation polygenic risk score and total gray matter volume. Conclusions: A history of daily smoking is strongly associated with a decreased total brain volume. © 2023
Author Keywords
Genetics; Global brain volume; Smoking; UK Biobank
Funding details
National Institutes of HealthNIHR01MH128286
National Institute on Drug AbuseNIDAK12DA041449, R01DA044014
National Institute on Alcohol Abuse and AlcoholismNIAAAR01AA027049, U10AA008401
National Institute on AgingNIAR56AG058726
Institute of Clinical and Translational SciencesICTSR01AG061162, R01DA054750, R21AA027827, TL1TR002344, U01DA055367
McDonnell Center for Systems NeuroscienceR01AA025646, R01DA89801
Document Type: Article
Publication Stage: Final
Source: Scopus
MeCP2 represses the activity of topoisomerase IIβ in long neuronal genes
(2023) Cell Reports, 42 (12), art. no. 113538, .
Nettles, S.A., Ikeuchi, Y., Lefton, K.B., Abbasi, L., Erickson, A., Agwu, C., Papouin, T., Bonni, A., Gabel, H.W.
Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
A unique signature of neurons is the high expression of the longest genes in the genome. These genes have essential neuronal functions, and disruption of their expression has been implicated in neurological disorders. DNA topoisomerases resolve DNA topological constraints and facilitate neuronal long gene expression. Conversely, the Rett syndrome protein, methyl-CpG-binding protein 2 (MeCP2), can transcriptionally repress long genes. How these factors regulate long genes is not well understood, and whether they interact is not known. Here, we identify and map a functional interaction between MeCP2 and topoisomerase IIβ (TOP2β) in mouse neurons. We profile neuronal TOP2β activity genome wide, detecting enrichment at regulatory regions and gene bodies of long genes, including MeCP2-regulated genes. We show that loss and overexpression of MeCP2 alter TOP2β activity at MeCP2-regulated genes. These findings uncover a mechanism of TOP2β inhibition by MeCP2 in neurons and implicate TOP2β dysregulation in disorders caused by MeCP2 disruption. © 2023 The Authors
Author Keywords
brain; CP: Neuroscience; enhancer; gene regulation; long genes; MeCP2; neurodevelopmental disorders; Rett syndrome; TOP2β; transcription
Funding details
U.S. Department of DefenseDOD28616, W911NF-21-1-0312
National Institute of Mental HealthNIMHR01MH117405
National Institute of Neurological Disorders and StrokeNINDS1R01MH127163-01, R01NS04102
Whitehall Foundation2020-08-35
Washington University in St. LouisWUSTL
McDonnell Center for Cellular and Molecular Neurobiology, Washington University in St. Louis22-3930-26275U
Genome Technology Access CenterGTAC
Document Type: Article
Publication Stage: Final
Source: Scopus
Conserved and divergent gene regulatory programs of the mammalian neocortex
(2023) Nature, 624 (7991), pp. 390-402. Cited 1 time.
Zemke, N.R.a b , Armand, E.J.a c , Wang, W.d , Lee, S.a , Zhou, J.c d , Li, Y.E.a , Liu, H.d e , Tian, W.d , Nery, J.R.d , Castanon, R.G.d , Bartlett, A.d , Osteen, J.K.f , Li, D.g , Zhuo, X.g , Xu, V.g , Chang, L.a , Dong, K.a b , Indralingam, H.S.a b , Rink, J.A.f , Xie, Y.a , Miller, M.a b , Krienen, F.M.h i , Zhang, Q.j k , Taskin, N.l , Ting, J.l , Feng, G.j k , McCarroll, S.A.i j , Callaway, E.M.m n , Wang, T.g o , Lein, E.S.l p , Behrens, M.M.f , Ecker, J.R.d q , Ren, B.a b r
a Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La JollaCA, United States
b Center for Epigenomics, University of California, San Diego School of Medicine, La JollaCA, United States
c Bioinformatics and Systems Biology Program, University of California, San Diego, La JollaCA, United States
d Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La JollaCA, United States
e Division of Biological Sciences, University of California, San Diego, La JollaCA, United States
f Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La JollaCA, United States
g Department of Genetics, The Edison Family Center for Genome Sciences & Systems Biology, Washington University School of Medicine, St Louis, MO, United States
h Princeton Neuroscience Institute, Princeton University, Princeton, NJ, United States
i Department of Genetics, Harvard Medical School, Boston, United States
j Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, United States
k McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, United States
l Allen Institute for Brain Science, Seattle, WA, United States
m Systems Neurobiology Laboratories, The Salk Institute for Biological Studies, La JollaCA, United States
n Department of Neurosciences, University of California San Diego, La JollaCA, United States
o McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, United States
p Department of Neurological Surgery, University of Washington, Seattle, WA, United States
q Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La JollaCA, United States
r Institute of Genomic Medicine, Moores Cancer Center, School of Medicine, University of California San Diego, La JollaCA, United States
Abstract
Divergence of cis-regulatory elements drives species-specific traits1, but how this manifests in the evolution of the neocortex at the molecular and cellular level remains unclear. Here we investigated the gene regulatory programs in the primary motor cortex of human, macaque, marmoset and mouse using single-cell multiomics assays, generating gene expression, chromatin accessibility, DNA methylome and chromosomal conformation profiles from a total of over 200,000 cells. From these data, we show evidence that divergence of transcription factor expression corresponds to species-specific epigenome landscapes. We find that conserved and divergent gene regulatory features are reflected in the evolution of the three-dimensional genome. Transposable elements contribute to nearly 80% of the human-specific candidate cis-regulatory elements in cortical cells. Through machine learning, we develop sequence-based predictors of candidate cis-regulatory elements in different species and demonstrate that the genomic regulatory syntax is highly preserved from rodents to primates. Finally, we show that epigenetic conservation combined with sequence similarity helps to uncover functional cis-regulatory elements and enhances our ability to interpret genetic variants contributing to neurological disease and traits. © 2023, The Author(s).
Funding details
UM1HG011585
National Institutes of HealthNIH5U01MH121282, P510D01425, U19MH11483, U19MH114831-04s1, U420D011123
Howard Hughes Medical InstituteHHMI
School of Medicine, University of California, San DiegoSOMS10 OD026929
Document Type: Article
Publication Stage: Final
Source: Scopus
Single-cell analysis of chromatin accessibility in the adult mouse brain
(2023) Nature, 624 (7991), pp. 378-389. Cited 2 times.
Zu, S.a , Li, Y.E.a b , Wang, K.a , Armand, E.J.a , Mamde, S.a , Amaral, M.L.a , Wang, Y.a , Chu, A.a , Xie, Y.a , Miller, M.c , Xu, J.a , Wang, Z.a , Zhang, K.a , Jia, B.a , Hou, X.c , Lin, L.c , Yang, Q.c , Lee, S.a , Li, B.a , Kuan, S.a , Liu, H.d , Zhou, J.d , Pinto-Duarte, A.e , Lucero, J.e , Osteen, J.e , Nunn, M.f , Smith, K.A.g , Tasic, B.g , Yao, Z.g , Zeng, H.g , Wang, Z.h , Shang, J.h , Behrens, M.M.e , Ecker, J.R.f , Wang, A.c , Preissl, S.c i , Ren, B.a c
a Department of Cellular and Molecular Medicine, University of California San Diego, School of Medicine, La JollaCA, United States
b Department of Neurosurgery and Genetics, Washington University School of Medicine, St Louis, MO, United States
c Center for Epigenomics, University of California San Diego, School of Medicine, La JollaCA, United States
d Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La JollaCA, United States
e The Salk Institute for Biological Studies, La JollaCA, United States
f Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La JollaCA, United States
g Allen Institute for Brain Science, Seattle, WA, United States
h Department of Computer Science and Engineering, University of California San Diego, La JollaCA, United States
i Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Abstract
Recent advances in single-cell technologies have led to the discovery of thousands of brain cell types; however, our understanding of the gene regulatory programs in these cell types is far from complete1–4. Here we report a comprehensive atlas of candidate cis-regulatory DNA elements (cCREs) in the adult mouse brain, generated by analysing chromatin accessibility in 2.3 million individual brain cells from 117 anatomical dissections. The atlas includes approximately 1 million cCREs and their chromatin accessibility across 1,482 distinct brain cell populations, adding over 446,000 cCREs to the most recent such annotation in the mouse genome. The mouse brain cCREs are moderately conserved in the human brain. The mouse-specific cCREs—specifically, those identified from a subset of cortical excitatory neurons—are strongly enriched for transposable elements, suggesting a potential role for transposable elements in the emergence of new regulatory programs and neuronal diversity. Finally, we infer the gene regulatory networks in over 260 subclasses of mouse brain cells and develop deep-learning models to predict the activities of gene regulatory elements in different brain cell types from the DNA sequence alone. Our results provide a resource for the analysis of cell-type-specific gene regulation programs in both mouse and human brains. © 2023, The Author(s).
Funding details
National Institutes of HealthNIHU19MH114830, U19MH114831
Howard Hughes Medical InstituteHHMI
Life Sciences Research FoundationLSRF
School of Medicine, University of California, San DiegoSOMS10 OD026929
Document Type: Article
Publication Stage: Final
Source: Scopus
Accentuated paralimbic and reduced mesolimbic D2/3-impulsivity associations in Parkinson’s disease
(2023) Journal of Neuroscience, 43 (50), .
Stark, A.J.a , Song, A.K.b , Petersen, K.J.c , Hay, K.R.b , Lin, Y.-C.d e , Trujillo, P.b , Kang, H.d e , Collazzo, J.M.f , Donahue, M.J.b , Zald, D.H.g , Claassen, D.O.b
a School of Medicine, Vanderbilt University, Nashville, TN 37232, United States
b Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37232, United States
c Department of Neurology, Washington University School of Medicine, St. Louis, MO 63310, United States
d Biostatistics, Vanderbilt University Medical Center, Nashville, TN 37232, United States
e Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, United States
f School of Medicine, Temple University, Philadelphia, PA 19140, United States
g Department of Psychiatry, Rutgers University, Piscataway, NJ 08901, United States
Abstract
Impulsivity is a behavioral trait that is elevated in many neuropsychiatric disorders. Parkinson’s disease (PD) patients can exhibit a specific pattern of reward-seeking impulsive-compulsive behaviors (ICBs), as well as more subtle changes to generalized trait impulsivity. Prior studies in healthy controls (HCs) suggest that trait impulsivity is regulated by D2/3 autoreceptors in mesocorticolimbic circuits. While altered D2/3 binding is noted in ICB+ PD patients, there is limited prior assessment of the trait impulsivity-D2/3 relationship in PD, and no prior direct comparison with patterns in HCs. We examined 54 PD (36M; 18F) and 31 sex- and age-matched HC (21M; 10F) subjects using [18F]fallypride, a high-affinity D2/3 receptor ligand, to measure striatal and extrastriatal D2/3 nondisplaceable binding potential (BPND). Subcortical and cortical assessment exclusively utilized region-of-interest or exploratory-voxelwise methods, respectively. All completed the Barratt Impulsiveness Scale (BIS-11), a measure of trait impulsivity. Subcortical region-of-interest analyses indicated a negative relationship between trait impulsivity and D2/3 BPND in the ventral striatum and amygdala of HCs but not in PD. By contrast, voxelwise methods demonstrated a positive trait impulsivity-D2/3 BPND correlation in ventral frontal olfactocentric-paralimbic cortex of subjects with PD but not HCs. Subscale analysis also highlighted different aspects of impulsivity, with significant interactions between group and motor impulsivity in the ventral striatum, and attentional impulsivity in the amygdala and frontal paralimbic cortex. These results suggest that dopamine functioning in distinct regions of the mesocorticolimbic circuit influence aspects of impulsivity, with the relative importance of regional dopamine functions shifting in the neuropharmacological context of PD. Copyright © 2023 the authors.
Author Keywords
dopamine; impulsivity; mesocorticolimbic; paralimbic; Parkinson’s disease; PET
Funding details
National Institutes of HealthNIH
National Institute on AgingNIAR01AG044838, UL1TR000445
National Institute of Neurological Disorders and StrokeNINDSK23NS080988, R01NS097783
National Center for Advancing Translational SciencesNCATS
Document Type: Article
Publication Stage: Final
Source: Scopus
Effort Foraging Task reveals positive correlation between individual differences in the cost of cognitive and physical effort in humans
(2023) Proceedings of the National Academy of Sciences of the United States of America, 120 (50), pp. e2221510120.
Bustamante, L.A.a b , Oshinowo, T.a , Lee, J.R.a , Tong, E.a , Burton, A.R.a , Shenhav, A.c d , Cohen, J.D.a , Daw, N.D.a
a Princeton Neuroscience Institute, Princeton University, Princeton, NJ 08544, United States
b Department of Psychological and Brain Sciences, Washington University in Saint LouisSaint Louis MO 63130, Seychelles
c Department of Cognitive, Linguistic, and Psychological Sciences, Brown University, Providence, RI 02912
d Carney Institute for Brain Science, Brown University, Providence, RI 02906
Abstract
Effort-based decisions, in which people weigh potential future rewards against effort costs required to achieve those rewards involve both cognitive and physical effort, though the mechanistic relationship between them is not yet understood. Here, we use an individual differences approach to isolate and measure the computational processes underlying effort-based decisions and test the association between cognitive and physical domains. Patch foraging is an ecologically valid reward rate maximization problem with well-developed theoretical tools. We developed the Effort Foraging Task, which embedded cognitive or physical effort into patch foraging, to quantify the cost of both cognitive and physical effort indirectly, by their effects on foraging choices. Participants chose between harvesting a depleting patch, or traveling to a new patch that was costly in time and effort. Participants’ exit thresholds (reflecting the reward they expected to receive by harvesting when they chose to travel to a new patch) were sensitive to cognitive and physical effort demands, allowing us to quantify the perceived effort cost in monetary terms. The indirect sequential choice style revealed effort-seeking behavior in a minority of participants (preferring high over low effort) that has apparently been missed by many previous approaches. Individual differences in cognitive and physical effort costs were positively correlated, suggesting that these are perceived and processed in common. We used canonical correlation analysis to probe the relationship of task measures to self-reported affect and motivation, and found correlations of cognitive effort with anxiety, cognitive function, behavioral activation, and self-efficacy, but no similar correlations with physical effort.
Author Keywords
cognitive control; computational psychiatry; effort-based decision-making; foraging; motivation
Document Type: Article
Publication Stage: Final
Source: Scopus
Evaluating whether a peer-led dissonance-based eating disorder prevention program prevents onset of each eating disorder type
(2023) Psychological Medicine, 53 (15), pp. 7214-7221.
D’Adamo, L.a b , Ghaderi, A.c , Rohde, P.d , Gau, J.M.d , Shaw, H.e , Stice, E.e
a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b Department of Psychology, Center for Weight, Eating, and Lifestyle Science, Drexel University, Philadelphia, PA, United States
c Division of Psychology, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
d Oregon Research Institute, Eugene, OR, United States
e Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, United States
Abstract
Background This study tested whether the dissonance-based Body Project eating disorder prevention program reduced onset of subthreshold/threshold anorexia nervosa (AN), bulimia nervosa (BN), binge eating disorder (BED), and purging disorder (PD) over long-term follow-up. Methods Data were combined from three prevention trials that targeted young women at high-risk for eating disorders (N = 1092; M age = 19.3). Participants were randomized to Body Project groups led by peer educators or expressive writing/educational controls and completed masked diagnostic interviews over 2- to 4-year follow-ups. Logistic regressions tested whether onset of each eating disorder over follow-up differed between Body Project and control participants. Results Peer-led Body Project groups produced a 46% reduction in onset of subthreshold/threshold BN and a 62% reduction in onset of PD relative to controls over follow-up. Rates of onset of subthreshold/threshold AN and BED did not significantly differ between peer-led Body Project participants and control participants. Conclusions Results support the dissemination of the peer-led Body Project for reducing future onset of BN and PD. This study and recent research suggest that thin-ideal internalization, the risk factor for eating disorders targeted in the Body Project, may be more relevant for predicting onset of BN and PD compared to AN and BED. Findings support the development of a version of the Body Project aimed to reduce risk factors that have predicted future onset of all four types of eating disorders (e.g. overvaluation of weight/shape, fear of weight gain), which may more effectively prevent all eating disorder types. © The Author(s), 2023. Published by Cambridge University Press.
Author Keywords
Dissonance; eating disorder; peer educators; prevention; thin-ideal internalization
Funding details
National Institutes of HealthNIHMH/DK061957and MH097720
National Heart, Lung, and Blood InstituteNHLBIT32 HL130357
Riksbankens JubileumsfondRJP14-0838:1
Document Type: Article
Publication Stage: Final
Source: Scopus
The association between reasons for first using cannabis, later pattern of use, and risk of first-episode psychosis: the EU-GEI case-control study
(2023) Psychological Medicine, 53 (15), pp. 7418-7427.
Spinazzola, E.a , Quattrone, D.b c d , Rodriguez, V.a , Trotta, G.b , Alameda, L.a e f , Tripoli, G.a g , Gayer-Anderson, C.h , Freeman, T.P.i j , Johnson, E.C.k , Jongsma, H.E.l , Stilo, S.a m , La Cascia, C.g , Ferraro, L.g , La Barbera, D.g , Lasalvia, A.n , Tosato, S.n , Tarricone, I.o , D’Andrea, G.o , Galatolo, M.o , Tortelli, A.p q , Tagliabue, I.r s , Turco, M.r , Pompili, M.t , Selten, J.-P.u v , de Haan, L.w , Rossi Menezes, P.x , Del Ben, C.M.x , Santos, J.L.y , Arrojo, M.z , Bobes, J.aa , Sanjuán, J.ab , Bernardo, M.ac , Arango, C.ad , Kirkbride, J.B.ae , Jones, P.B.af ag , O’Donovan, M.ah , Rutten, B.P.v , Van Os, J.a u ai , Morgan, C.h , Sham, P.C.aj , Austin-Zimmerman, I.b , Li, Z.b , Vassos, E.b , Murray, R.M.a , Di Forti, M.b d ak , EU-GEI WP2 Groupal
a Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College of London, London, United Kingdom
b Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, United Kingdom
c National Institute for Health Research, Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College, London, United Kingdom
d South London and Maudsley NHS Mental Health Foundation Trust, London, United Kingdom
e Service of General Psychiatry, Treatment and Early Intervention in Psychosis Program, University Hospital (CHUV), Lausanne, Switzerland
f Centro Investigacion Biomedica en Red de Salud Mental (CIBERSAM); Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocio, Departamento de Psiquiatria, Universidad de Sevilla, Sevilla, Spain
g Biomedicine, Neuroscience and Advanced Diagnostic Department, Psychiatry Section, University of Palermo, Palermo, Italy
h Department of Health Service and Population Research, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
i Addiction and Mental Health Group (AIM), Department of Psychology, University of Bath, Bath, United Kingdom
j National Addiction Centre, Institute of Psychiatry, King’s College London, London, United Kingdom
k Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
l Psylife Group, Division of Psychiatry, University College London, London, United Kingdom
m Department of Mental Health and Addiction Services, Crotone, Italy
n Section of Psychiatry, Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
o Department of Medical and Surgical Science, Psychiatry Unit, Alma Mater Studiorum Università di Bologna, Bologna, Italy
p Institut Mondor de recherché biomedicale, Creteil, France
q Etablissement Public de Sante Maison Blanche, Paris, France
r Department of Medicine and Surgery, University of Milano Bicocca, Monza, Italy
s Department of Mental Health and Addiction Services, ASST Lecco, Lecco, Italy
t Department of Neurosciences, Mental Health and Sensory Organs, Suicide Prevention Center, Sant’Andrea Hospital, Sapienza University of Rome, Rome, Italy
u Rivierduinen Institute for Mental Health Care, Leiden, Netherlands
v Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, South Limburg Mental Health Research and Teaching Network, Maastricht University Medical Centre, Maastricht, Netherlands
w Early Psychosis Section, Academic Medical Centre, University of Amsterdam, Meibergdreef 5, Netherlands
x Department of Preventive Medicine, Faculdade de Medicina, Universidade of São Paulo, São Paulo, Brazil
y Department of Psychiatry, Servicio de Psiquiatría Hospital “Virgen de la Luz”, Cuenca, Spain
z Department of Psychiatry, Psychiatric Genetic Group, Instituto de Investigación Sanitaria de Santiago de Compostela, Complejo Hospitalario Universitario de Santiago de CompostelaSantiago, Spain
aa Department of Medicine, Psychiatry Area, School of Medicine, Universidad de Oviedo, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Oviedo, Spain
ab Department of Psychiatry, School of Medicine, Universidad de Valencia, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM)Valencia, Spain
ac Barcelona Clinic Schizophrenia Unit, Neuroscience Institute, Hospital Clinic of Barcelona, University of Barcelona, Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Biomedical Research Networking Centre in Mental Health (CIBERSAM), Barcelona, Spain
ad Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, School of Medicine, IiSGM, CIBERSAM, Universidad ComplutenseMadrid, Spain
ae Reader; Psylife Group, Division of Psychiatry, University College London, London, UK
af Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
ag CAMEO Early Intervention Service, Cambridgeshire & Peterborough NHS Foundation Trust, Cambridge, United Kingdom
ah Division of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom
ai Department Psychiatry, Brain Centre Rudolf Magnus, Utrecht University Medical CentreUtrecht, Netherlands
aj Department of Psychiatry, Centre for PanorOmic Sciences, State Key Laboratory of Brain and Cognitive Sciences, Li KaShing Faculty of Medicine, University of Hong Kong, Hong Kong, China
ak Research Foundation, National Institute for Health Research Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London and the NIHR BRC at University College London, London, United Kingdom
Abstract
BACKGROUND: While cannabis use is a well-established risk factor for psychosis, little is known about any association between reasons for first using cannabis (RFUC) and later patterns of use and risk of psychosis. METHODS: We used data from 11 sites of the multicentre European Gene-Environment Interaction (EU-GEI) case-control study. 558 first-episode psychosis patients (FEPp) and 567 population controls who had used cannabis and reported their RFUC.We ran logistic regressions to examine whether RFUC were associated with first-episode psychosis (FEP) case-control status. Path analysis then examined the relationship between RFUC, subsequent patterns of cannabis use, and case-control status. RESULTS: Controls (86.1%) and FEPp (75.63%) were most likely to report ‘because of friends’ as their most common RFUC. However, 20.1% of FEPp compared to 5.8% of controls reported: ‘to feel better’ as their RFUC (χ2 = 50.97; p < 0.001). RFUC ‘to feel better’ was associated with being a FEPp (OR 1.74; 95% CI 1.03-2.95) while RFUC ‘with friends’ was associated with being a control (OR 0.56; 95% CI 0.37-0.83). The path model indicated an association between RFUC ‘to feel better’ with heavy cannabis use and with FEPp-control status. CONCLUSIONS: Both FEPp and controls usually started using cannabis with their friends, but more patients than controls had begun to use ‘to feel better’. People who reported their reason for first using cannabis to ‘feel better’ were more likely to progress to heavy use and develop a psychotic disorder than those reporting ‘because of friends’.
Author Keywords
Cannabis use; path analysis; psychotic disorders
Document Type: Article
Publication Stage: Final
Source: Scopus
Weak Relationships Between Psychological Factors and Experimental Pain Outcomes in Pain-Free Individuals: An Aggregate Analysis of 8 Studies
(2023) Journal of Pain, .
Boggero, I.A.a b , Nahman-Averbuch, H.c d e , Hunter, B.M.c , Peugh, J.c f , Leon, E.c , Schneider II, V.J.c , Emerson, N.M.g , Thomas, P.L.c , Kashikar-Zuck, S.c e , Hughes, C.c , Hoeppli, M.-E.c e , King, C.D.c , Coghill, R.C.e f
a Department of Oral Health Science, Division of Orofacial Pain, University of Kentucky College of Dentistry, Lexington, Kentucky, United States
b Department of Anesthesiology, University of Kentucky College of Medicine, Lexington, Kentucky, United States
c Department of Pediatrics, Division of Behavioral Medicine and Clinical Psychology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States
d Washington University Pain Center, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri, United States
e Department of Pediatrics, Pediatric Pain Research Center, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States
f Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States
g Department of Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC, United States
Abstract
Although psychological factors such as anxiety, depression, and pain catastrophizing are known to influence pain outcomes in chronic pain populations, there are mixed results regarding whether they influence experimental pain outcomes in pain-free individuals. The objectives of this study were to determine the associations between psychological factors and experimental pain outcomes in pain-free adolescents and adults. Relationships between anxiety, depression, and pain catastrophizing and experimental pain outcomes across 8 different studies (total N = 595) were examined in different populations of pain-free adult and adolescent participants. Analyses were conducted with and without controlling for sex, age, and race. Studies were analyzed separately and as part of an aggregate analysis. Individual study analyses resulted in 136 regression models. Of these, only 8 models revealed a significant association between psychological factors and pain outcomes. The significant results were small and likely due to Type 1 error. Controlling for demographic factors had minimal effect on the results. The aggregate analyses revealed weak relationships between anxiety and pressure pain threshold (Fisher’s z = −.10 [−.19, −.01]), anxiety and cold pain intensity ratings (Fisher’s z = .18 [.04, .32]), and pain catastrophizing and pressure pain threshold (Fisher’s z = −.14 [−.26, −.02]). Sample size calculations based on the aggregate analyses indicated that several hundred participants would be required to detect true relationships between these psychological factors and pain measures. The overall negative findings suggest that in pain-free individuals, anxiety, depression, and pain catastrophizing are not meaningfully related to experimental pain outcomes. Perspective: Psychological variables have been shown to predict pain outcomes in chronic pain populations but these relationships may not generalize to pain-free populations. An analysis of 595 pain-free individuals across 8 studies in our lab revealed that anxiety, depression, and pain catastrophizing were not meaningfully related to experimental pain outcomes. © 2023 United States Association for the Study of Pain, Inc.
Author Keywords
Anxiety; Depression; Pain catastrophizing; Psychological factors; Quantitative sensory testing
Funding details
National Institutes of HealthNIHK23DE031807
National Institute of Neurological Disorders and StrokeNINDSR01NS085391
National Institute of Dental and Craniofacial ResearchNIDCRR00DE022368, R01NS039426 RCC
Cincinnati Children’s Hospital Medical Center
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
APOE Genotype and Alzheimer Disease Risk Across Age, Sex, and Population Ancestry
(2023) JAMA Neurology, . Cited 2 times.
Belloy, M.E.a b c , Andrews, S.J.d , Le Guen, Y.a , Cuccaro, M.e f , Farrer, L.A.g h i j k , Napolioni, V.l , Greicius, M.D.a
a Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, United States
b NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, United States
e John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, United States
f Dr. John T. Macdonald Foundation, Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, United States
g Department of Medicine, Biomedical Genetics, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, United States
h Department of Neurology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, United States
i Department of Ophthalmology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, United States
j Department of Biostatistics, Boston University School of Public Health, Boston, MA, United States
k Department of Epidemiology, Boston University School of Public Health, Boston, MA, United States
l School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy
Abstract
IMPORTANCE Apolipoprotein E (APOE)*2 and APOE*4 are, respectively, the strongest protective and risk-increasing, common genetic variants for late-onset Alzheimer disease (AD), making APOE status highly relevant toward clinical trial design and AD research broadly. The associations of APOE genotypes with AD are modulated by age, sex, race and ethnicity, and ancestry, but these associations remain unclear, particularly among racial and ethnic groups understudied in the AD and genetics research fields. OBJECTIVE To assess the stratified associations of APOE genotypes with AD risk across sex, age, race and ethnicity, and global population ancestry. DESIGN, SETTING, PARTICIPANTS This genetic association study included case-control, family-based, population-based, and longitudinal AD-related cohorts that recruited referred and volunteer participants. Data were analyzed between March 2022 and April 2023. Genetic data were available from high-density, single-nucleotide variant microarrays, exome microarrays, and whole-exome and whole-genome sequencing. Summary statistics were ascertained from published AD genetic studies. MAIN OUTCOMES AND MEASURES The main outcomes were risk for AD (odds ratios [ORs]) and risk of conversion to AD (hazard ratios [HRs]), with 95% CIs. Risk for AD was evaluated through case-control logistic regression analyses. Risk of conversion to AD was evaluated through Cox proportional hazards regression survival analyses. RESULTS Among 68 756 unique individuals, analyses included 21 852 East Asian (demographic data not available), 5738 Hispanic (68.2% female; mean [SD] age, 75.4 [8.8] years), 7145 non-Hispanic Black (hereafter referred to as Black) (70.8% female; mean [SD] age, 78.4 [8.2] years), and 34 021 non-Hispanic White (hereafter referred to as White) (59.3% female; mean [SD] age, 77.0 [9.1] years) individuals. There was a general, stepwise pattern of ORs for APOE*4 genotypes and AD risk across race and ethnicity groups. Odds ratios for APOE*34 and AD risk attenuated following East Asian (OR, 4.54; 95% CI, 3.99-5.17),White (OR, 3.46; 95% CI, 3.27-3.65), Black (OR, 2.18; 95% CI, 1.90-2.49) and Hispanic (OR, 1.90; 95% CI, 1.65-2.18) individuals. Similarly, ORs for APOE*22+23 and AD risk attenuated following White (OR, 0.53, 95% CI, 0.48-0.58), Black (OR, 0.69, 95% CI, 0.57-0.84), and Hispanic (OR, 0.89; 95% CI, 0.72-1.10) individuals, with no association for Hispanic individuals. Deviating from the global pattern of ORs, APOE*22+23 was not associated with AD risk in East Asian individuals (OR, 0.97; 95% CI, 0.77-1.23). Global population ancestry could not explain why Hispanic individuals showed APOE associations with less pronounced AD risk compared with Black and White individuals. Within Black individuals, decreased global African ancestry or increased global European ancestry showed a pattern of APOE*4 dosage associated with increasing AD risk, but no such pattern was apparent for APOE*2 dosage with AD risk. The sex-by-age–specific interaction effect of APOE*34 among White individuals (higher risk in women) was reproduced but shifted to ages 60 to 70 years (OR, 1.48; 95% CI, 1.10-2.01) and was additionally replicated in a meta-analysis of Black individuals and Hispanic individuals (OR, 1.72; 95% CI, 1.01-2.94). CONCLUSION AND RELEVANCE Through recent advances in AD-related genetic cohorts, this study provided the largest-to-date overview of the association of APOE with AD risk across age, sex, race and ethnicity, and population ancestry. These novel insights are critical to guide AD clinical trial design and research. © 2023 American Medical Association. All rights reserved.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Efficacy of Gabapentin For Post–COVID-19 Olfactory Dysfunction The GRACE Randomized Clinical Trial
(2023) JAMA Otolaryngology – Head and Neck Surgery, .
Mahadev, A.a b c , Hentati, F.a d e , Miller, B.a b c , Bao, J.a f , Perrin, A.a , Kallogjeri, D.a , Piccirillo, J.F.a
a Clinical Outcomes Research Office, Department of Otolaryngology–Head and Neck Surgery, Washington University, School of Medicine in St Louis, St Louis, MO, United States
b University of Missouri-Kansas City, School of Medicine, Kansas City, MO, United States
c Family Care Health Centers, St Louis, MO, United States
d Case Western Reserve University, School of Medicine, Cleveland, OH, United States
e Beth Israel Deaconess Medical Center, Boston, MA, United States
f University of Miami Miller, School of Medicine, Miami, FL, United States
Abstract
IMPORTANCE The COVID-19 pandemic affected millions of people and has become a dominant etiology of olfactory dysfunction (OD). No interventions with definitive clinical utility exist. Gabapentin represents a potential therapy for COVID-19–induced OD. OBJECTIVE To evaluate the efficacy of oral gabapentin on olfactory function and olfaction-related quality of life in patients with COVID-19–induced OD. DESIGN, SETTING, AND PARTICIPANTS This pilot double-blinded, placebo-controlled randomized clinical trial (RCT) was conducted at Washington University School of Medicine in St Louis from January 7, 2022, to February 3, 2023. Adults with at least 3 months of OD after COVID-19 infection were eligible for inclusion. Participants with a history of other causes of OD or contraindications to gabapentin were excluded. INTERVENTION Patients were randomized 1:1 to oral gabapentin or placebo. All patients underwent titration to a maximum tolerable dose, which was maintained during an 8-week fixed-dose (FD) phase then tapered off. Participants were monitored for 4 weeks following cessation of study medication. MAIN OUTCOMES AND MEASURES Outcomes were assessed following the 8-week FD phase and 4 weeks after taper completion. The primary outcome measure was the response rate determined by subjective improvement in OD on the Clinical Global Impression of Improvement (CGI-I) after the FD phase. Other subjective and objective measures of olfactory function were also assessed as secondary outcome measures. RESULTS Sixty-eight participants were enrolled (34 randomized to each arm), a total of 44 participants completed the FD period and 20 (45.4%) reported response to treatment with at least slight improvement in olfaction from baseline. Of those randomized, 51 (75%) were women and 56 were White (82%) with a mean (SD) age of 43 (13.5) years. Baseline demographic features including age, sex, and race and ethnicity were not significantly different between the groups. Of the 18 participants in the gabapentin group, 8 (44%) were responders and of the 26 participants in the placebo group, 12 (46%) reported response to treatment (percent difference, 1.7%; 95% CI, −31.6% to 28.2%). Mixed-model analysis of all secondary outcome measures demonstrated no clinically meaningful or statistically significant difference between the gabapentin and placebo groups throughout the trial. There were no serious adverse events. CONCLUSIONS AND RELEVANCE In this randomized clinical trial, gabapentin was not associated with statistically significant or clinically meaningful benefit over placebo and likely is not an efficacious therapy for COVID-19–induced OD. © 2023 American Medical Association. All rights reserved.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Roles of Sphingosine Kinase and Sphingosine-1-Phosphate Receptor 2 in Endotoxin-Induced Acute Retinal Inflammation
(2023) Ocular Immunology and Inflammation, .
Ahmed, T.a , Suzuki, T.a , Terao, R.a b , Yamagishi, R.a , Fujino, R.a , Azuma, K.a , Soga, H.a , Ueta, T.a , Honjo, M.a , Watanabe, S.a , Yoshioka, K.c , Takuwa, Y.c , Aihara, M.a
a Department of Ophthalmology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
b Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States
c Department of Physiology, Kanazawa University School of Medicine, Ishikawa, Kanazawa, Japan
Abstract
Purpose: To investigate the roles of sphingosine kinases (SphKs) and sphingosine-1-phosphate receptors (S1PRs) in endotoxin-induced uveitis (EIU) mice. Methods: EIU model was induced using an intraperitoneal injection of lipopolysaccharide (LPS). The expression of SphKs and S1PRs in the retina was assessed using quantitative polymerase chain reaction (qPCR) and immunofluorescence. The effects of S1PR antagonists on the expression of inflammatory cytokines in the retina were evaluated using qPCR and western blotting. Effects of leukocyte infiltration of the retinal vessels were evaluated to determine the effects of the S1PR2 antagonist and genetic deletion of S1PR2 on retinal inflammation. Results: Retinal SphK1 expression was significantly upregulated in EIU. SphK1 was expressed in the GCL, IPL, and OPL and S1PR2 was expressed in the GCL, INL, and OPL. Positive cells in IPL and OPL of EIU retina were identified as endothelial cells. S1PR2 antagonist and genetic deletion of S1PR2 significantly suppressed the expression of IL-1α, IL-6, TNF-α, and ICAM-1, whereas S1PR1/3 antagonist did not. Use of S1PR2 antagonist and S1PR2 knockout in mice significantly ameliorated leukocyte adhesion induced by LPS. Conclusion: SphK1/S1P/S1PR2 signaling was upregulated in EIU and S1PR2 inhibition suppressed inflammatory response. Targeting this signaling pathway has potential for treating retinal inflammatory diseases. © 2023 Taylor & Francis Group, LLC.
Author Keywords
Acute inflammation; endotoxin-induced uveitis; retina; sphingosine 1-phosphate; sphingosine 1-phosphate receptor 2
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Proximity proteomic analysis of the NRF family reveals the Parkinson’s disease protein ZNF746/PARIS as a co-complexed repressor of NRF2
(2023) Science Signaling, 16 (815), art. no. eadi9018, .
LaPak, K.M.a , Saeidi, S.a , Bok, I.a , Wamsley, N.T.a , Plutzer, I.B.a , Bhatt, D.P.a , Luo, J.b , Ashrafi, G.a c , Major, M.B.a
a Department of Cell Biology and Physiology, Washington University, St. Louis, MO 63110, United States
b Division of Public Health Sciences, Department of Surgery, WUSM and Siteman Cancer Center Biostatistics and Qualitative Research Shared Resource, Washington University, St. Louis, MO 63110, United States
c Department of Genetics, Washington University, St. Louis, MO 63110, United States
Abstract
The nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor activates cytoprotective and metabolic gene expression in response to various electrophilic stressors. Constitutive NRF2 activity promotes cancer progression, whereas decreased NRF2 function contributes to neurodegenerative diseases. We used proximity proteomic analysis to define protein networks for NRF2 and its family members NRF1, NRF3, and the NRF2 heterodimer MAFG. A functional screen of co-complexed proteins revealed previously uncharacterized regulators of NRF2 transcriptional activity. We found that ZNF746 (also known as PARIS), a zinc finger transcription factor implicated in Parkinson’s disease, physically associated with NRF2 and MAFG, resulting in suppression of NRF2-driven transcription. ZNF746 overexpression increased oxidative stress and apoptosis in a neuronal cell model of Parkinson’s disease, phenotypes that were reversed by chemical and genetic hyperactivation of NRF2. This study presents a functionally annotated proximity network for NRF2 and suggests a link between ZNF746 overexpression in Parkinson’s disease and inhibition of NRF2-driven neuroprotection. Copyright © 2023 The Authors, some rights reserved.
Funding details
National Institutes of HealthNIHR01CA244236, T32CA009547-34
Document Type: Article
Publication Stage: Final
Source: Scopus