Adolescent chemogenetic activation of dopaminergic neurons leads to reversible decreases in amphetamine-induced stereotypic behavior
(2024) Molecular Brain, 17 (1), art. no. 36, .
Chohan, M.O.a b , Lewandowski, A.B.b c , Siegel, R.N.a b , O’Reilly, K.C.a b , Veenstra-VanderWeele, J.a b
a Department of Psychiatry, Columbia University Medical Center, New York, NY 10032, United States
b New York State Psychiatric Institute, New York, NY 10032, United States
c Department of Psychological & amp; Brain Sciences, Washington University in St. Louis, St. Louis, MO 63130, United States
Abstract
Chronic perturbations of neuronal activity can evoke homeostatic and new setpoints for neurotransmission. Using chemogenetics to probe the relationship between neuronal cell types and behavior, we recently found reversible decreases in dopamine (DA) transmission, basal behavior, and amphetamine (AMPH) response following repeated stimulation of DA neurons in adult mice. It is unclear, however, whether altering DA neuronal activity via chemogenetics early in development leads to behavioral phenotypes that are reversible, as alterations of neuronal activity during developmentally sensitive periods might be expected to induce persistent effects on behavior. To examine the impact of developmental perturbation of DA neuron activity on basal and AMPH behavior, we expressed excitatory hM3D(Gq) in postnatal DA neurons in TH-Cre and WT mice. Basal and CNO- or AMPH-induced locomotion and stereotypy was evaluated in a longitudinal design, with clozapine N-oxide (CNO, 1.0 mg/kg) administered across adolescence (postnatal days 15–47). Repeated CNO administration did not impact basal behavior and only minimally reduced AMPH-induced hyperlocomotor response in adolescent TH-CrehM3Dq mice relative to WThM3Dq littermate controls. Following repeated CNO administration, however, AMPH-induced stereotypic behavior robustly decreased in adolescent TH-CrehM3Dq mice relative to controls. A two-month CNO washout period rescued the diminished AMPH-induced stereotypic behavior. Our findings indicate that the homeostatic compensations that take place in response to chronic hM3D(Gq) stimulation during adolescence are temporary and are dependent on ongoing chemogenetic stimulation. © The Author(s) 2024.
Author Keywords
Adolescence; Amphetamine; Chemogenetics; Dopamine; EAAT3; hM3D(Gq); Locomotion; Stereotypic behavior
Document Type: Article
Publication Stage: Final
Source: Scopus
Debriefer cognitive load during Traditional Reflective Debriefing vs. Rapid Cycle Deliberate Practice interdisciplinary team training
(2024) Advances in Simulation, 9 (1), art. no. 23, .
Wiltrakis, S.a , Hwu, R.b , Holmes, S.b , Iyer, S.b , Goodwin, N.c , Mathai, C.c , Gillespie, S.d , Hebbar, K.B.e , Colman, N.e
a Division of Emergency Medicine, Department of Pediatrics, Washington University in St. Louis, 660 S. Euclid Ave, St. Louis, MO 63110, United States
b Division of Emergency Medicine, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United States
c Children’s Healthcare of Atlanta, Atlanta, GA, United States
d Department of Biostatistics, Emory University School of Medicine, Atlanta, GA, United States
e Division of Critical Care Medicine, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United States
Abstract
Background: Cognitive load impacts performance of debriefers and learners during simulations, but limited data exists examining debriefer cognitive load. The aim of this study is to compare the cognitive load of the debriefers during simulation-based team training (SbTT) with Rapid Cycle Deliberate Practice (RCDP) debriefing and Traditional Reflective Debriefing (TRD). We hypothesize that cognitive load will be reduced during RCDP compared to TRD. Methods: This study was part of a large-scale, interdisciplinary team training program at Children’s Healthcare of Atlanta Egleston Pediatric Emergency Department, with 164 learners (physicians, nurses, medical technicians, paramedics, and respiratory therapists (RTs)). Eight debriefers (main facilitators and discipline-specific coaches) led 28 workshops, which were quasi-randomized to either RCDP or TRD. Each session began with a baseline medical resuscitation scenario and cognitive load measurement using the NASA Task Load Index (TLX), and the NASA TLX was repeated immediately following either TRD or RCDP debriefing. Raw scores of the NASA TLX before and after intervention were compared. ANOVA tests were used to compare differences in NASA TLX scores before and after intervention between the RCDP and TRD groups. Results: For all debriefers, mean NASA TLX scores for physical demands and frustration significantly decreased (− 0.8, p = 0.004 and − 1.3, p = 0.002) in TRD and mean perceived performance success significantly increased (+ 2.4, p < 0.001). For RCDP, perceived performance success increased post-debriefing (+ 3.6, p < 0.001), time demands decreased (− 1.0, p = 0.04), and frustration decreased (− 2.0, p < 0.001). Comparing TRD directly to RCDP, perceived performance success was greater in RCDP than TRD (3.6 vs. 2.4, p = 0.04). Main facilitators had lower effort and mental demand in RCDP and greater perceived success (p < 0.001). Conclusion: RCDP had greater perceived success than TRD for debriefers. Main facilitators also report reduced effort and baseline mental demand in RCDP. For less experienced debriefers, newer simulation programs, or large team training sessions such as our study, RCDP may be a less mentally demanding debriefing methodology for facilitators. © The Author(s) 2024.
Author Keywords
Cognitive Load Theory; Facilitator cognitive load; Interdisciplinary simulation education
Document Type: Article
Publication Stage: Final
Source: Scopus
Cis-regulatory evolution of the recently expanded Ly49 gene family
(2024) Nature Communications, 15 (1), art. no. 4839, .
Fan, C.a b , Xing, X.a b , Murphy, S.J.H.c d , Poursine-Laurent, J.e , Schmidt, H.a b , Parikh, B.A.f , Yoon, J.e , Choudhary, M.N.K.a b , Saligrama, N.c f g h i , Piersma, S.J.e j , Yokoyama, W.M.e f , Wang, T.a b k
a Department of Genetics, Washington University School of Medicine, St. Louis, 63110, United States
b The Edison Family Center for Genome Sciences & amp; Systems Biology, Washington University School of Medicine, St. Louis, 63110, United States
c Department of Neurology, Washington University School of Medicine, St. Louis, 63110, United States
d Medical Scientist Training Program, Washington University School of Medicine, St. Louis, 63110, United States
e Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, 63110, United States
f Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, 63110, United States
g Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, 63110, United States
h Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, 63110, United States
i Center for Brain Immunology and Glia (BIG), Washington University School of Medicine, St. Louis, 63110, United States
j Siteman Cancer Center, Washington University School of Medicine, St. Louis, 63110, United States
k McDonnell Genome Institute, Washington University School of Medicine, St. Louis, 63110, United States
Abstract
Comparative genomics has revealed the rapid expansion of multiple gene families involved in immunity. Members within each gene family often evolved distinct roles in immunity. However, less is known about the evolution of their epigenome and cis-regulation. Here we systematically profile the epigenome of the recently expanded murine Ly49 gene family that mainly encode either inhibitory or activating surface receptors on natural killer cells. We identify a set of cis-regulatory elements (CREs) for activating Ly49 genes. In addition, we show that in mice, inhibitory and activating Ly49 genes are regulated by two separate sets of proximal CREs, likely resulting from lineage-specific losses of CRE activity. Furthermore, we find that some Ly49 genes are cross-regulated by the CREs of other Ly49 genes, suggesting that the Ly49 family has begun to evolve a concerted cis-regulatory mechanism. Collectively, we demonstrate the different modes of cis-regulatory evolution for a rapidly expanding gene family. © The Author(s) 2024.
Document Type: Article
Publication Stage: Final
Source: Scopus
Relationship between sex biases in gene expression and sex biases in autism and Alzheimer’s disease
(2024) Biology of Sex Differences, 15 (1), art. no. 47, .
Fass, S.B.a b , Mulvey, B.a b c , Chase, R.a b , Yang, W.a d , Selmanovic, D.a b , Chaturvedi, S.M.a b , Tycksen, E.a d , Weiss, L.A.f g h , Dougherty, J.D.a b e i
a Department of Genetics, Washington University School of Medicine, 660 S. Euclid Ave, Saint Louis, MO 63110, United States
b Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave, Saint Louis, MO 63110, United States
c Lieber Institute for Brain Development, 855 North Wolfe St. Ste 300, Baltimore, MD 21205, United States
d McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63110, United States
e Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, 660 S. Euclid Ave, Saint Louis, MO 63110, United States
f Institute for Human Genetics, University of California, San Francisco, 513 Parnassus Ave, HSE901, San Francisco, CA 94143, United States
g Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, 513 Parnassus Ave, HSE901, San Francisco, CA 94143, United States
h Weill Institute for Neurosciences, University of California, San Francisco, 513 Parnassus Ave, HSE901, San Francisco, CA 94143, United States
i Department of Genetics, 4566 Scott Ave., St. Louis, MO 63110-1093, United States
Abstract
Background: Sex differences in the brain may play an important role in sex-differential prevalence of neuropsychiatric conditions. Methods: In order to understand the transcriptional basis of sex differences, we analyzed multiple, large-scale, human postmortem brain RNA-Seq datasets using both within-region and pan-regional frameworks. Results: We find evidence of sex-biased transcription in many autosomal genes, some of which provide evidence for pathways and cell population differences between chromosomally male and female individuals. These analyses also highlight regional differences in the extent of sex-differential gene expression. We observe an increase in specific neuronal transcripts in male brains and an increase in immune and glial function-related transcripts in female brains. Integration with single-nucleus data suggests this corresponds to sex differences in cellular states rather than cell abundance. Integration with case–control gene expression studies suggests a female molecular predisposition towards Alzheimer’s disease, a female-biased disease. Autism, a male-biased diagnosis, does not exhibit a male predisposition pattern in our analysis. Conclusion: Overall, these analyses highlight mechanisms by which sex differences may interact with sex-biased conditions in the brain. Furthermore, we provide region-specific analyses of sex differences in brain gene expression to enable additional studies at the interface of gene expression and diagnostic differences. Graphical Abstract: (Figure presented.) © The Author(s) 2024.
Author Keywords
Alzheimer’s; Autism; Brain; Expression; Human; Immune; Neuronal; rna-seq; Sex; Sex-bias
Document Type: Article
Publication Stage: Final
Source: Scopus
DNA methylation and stroke prognosis: an epigenome-wide association study
(2024) Clinical Epigenetics, 16 (1), art. no. 75, .
Jiménez-Balado, J.a , Fernández-Pérez, I.a k , Gallego-Fábrega, C.b , Lazcano, U.c , Soriano-Tárraga, C.d , Vallverdú-Prats, M.a , Mola-Caminal, M.e , Rey-Álvarez, L.a , Macias-Gómez, A.a , Suárez-Pérez, A.a , Giralt-Steinhauer, E.a , Rodríguez-Campello, A.a f , Cuadrado-Godia, E.a f , Ois, Á.a f , Esteller, M.g h i j , Roquer, J.a , Fernández-Cadenas, I.b , Jiménez-Conde, J.a f
a Neurovascular Research Group, Department of Neurology, Hospital del Mar Research Institute, C/ del Dr. Aiguader, 88, Barcelona, 08003, Spain
b Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí, Barcelona, Spain
c Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Biscaia, Spain
d Department of Psychiatry, NeuroGenomics and Informatics, Washington University School of Medicine, St. Louis, MO 63110, United States
e Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
f Medicine Department, DCEXS-Universitat Pompeu Fabra (UPF), Barcelona, 08002, Spain
g Cancer Epigenetics Group, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Catalonia, Barcelona, Spain
h Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, Spain
i Institucio Catalana de Recerca I Estudis Avançats (ICREA), Catalonia, Barcelona, Spain
j Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Catalonia, Barcelona, Spain
k Medicine Department, Autonomous University of Barcelona, Barcelona, Spain
Abstract
Background and aims: Stroke is the leading cause of adult-onset disability. Although clinical factors influence stroke outcome, there is a significant variability among individuals that may be attributed to genetics and epigenetics, including DNA methylation (DNAm). We aimed to study the association between DNAm and stroke prognosis. Methods and results: To that aim, we conducted a two-phase study (discovery-replication and meta-analysis) in Caucasian patients with ischemic stroke from two independent centers (BasicMar [discovery, N = 316] and St. Pau [replication, N = 92]). Functional outcome was assessed using the modified Rankin Scale (mRS) at three months after stroke, being poor outcome defined as mRS > 2. DNAm was determined using the 450K and EPIC BeadChips in whole-blood samples collected within the first 24 h. We searched for differentially methylated positions (DMPs) in 370,344 CpGs, and candidates below p-value < 10–5 were subsequently tested in the replication cohort. We then meta-analyzed DMP results from both cohorts and used them to identify differentially methylated regions (DMRs). After doing the epigenome-wide association study, we found 29 DMPs at p-value < 10–5 and one of them was replicated: cg24391982, annotated to thrombospondin-2 (THBS2) gene (p-valuediscovery = 1.54·10–6; p-valuereplication = 9.17·10–4; p-valuemeta-analysis = 6.39·10–9). Besides, four DMRs were identified in patients with poor outcome annotated to zinc finger protein 57 homolog (ZFP57), Arachidonate 12-Lipoxygenase 12S Type (ALOX12), ABI Family Member 3 (ABI3) and Allantoicase (ALLC) genes (p-value < 1·10–9 in all cases). Discussion: Patients with poor outcome showed a DMP at THBS2 and four DMRs annotated to ZFP57, ALOX12, ABI3 and ALLC genes. This suggests an association between stroke outcome and DNAm, which may help identify new stroke recovery mechanisms. © The Author(s) 2024.
Author Keywords
DNA methylation; Epigenetics; Stroke outcome; Thrombospondin-2
Document Type: Article
Publication Stage: Final
Source: Scopus
Compressive response of white matter in the brain at low strain rates
(2024) International Journal of Mechanical Sciences, 277, art. no. 109415, .
Su, L.a b , Qi, B.a b , Yin, J.a b , Qin, X.a b , Genin, G.M.c , Liu, S.a b , Lu, T.J.a b
a State Key Laboratory of Mechanics and Control for Aerospace Structures, Nanjing University of Aeronautics and Astronautics, Nanjing, 210016, China
b MIIT Key Laboratory of Multifunctional Lightweight Materials and Structures, Nanjing University of Aeronautics and Astronautics, Nanjing, 210016, China
c National Science Foundation Science and Technology Center for Engineering Mechanobiology, Washington University, St. Louis, MO 63130, United States
Abstract
The low strain-rate response of brain parenchyma is critical to predicting prognosis in cases of hydrocephalus or cerebral edema, including in the prediction of brain stem herniation. Although rate-dependent responses of brain parenchyma are well known to arise from both viscoelasticity at higher strain rates, and it is not clear whether the tissue behaves as a fluid or a solid when loaded over periods of hours to days, and the extrapolation of rate sensitivity to lower strain rates is not clear. To address this, unconfined compression-isometric hold tests were performed on samples of white matter from porcine brains at strain rates ranging from 2/s to 2 × 10−6/s. Results showed that the apparent Young’s modulus dropped from ∼3000 Pa to ∼160 Pa over this range following a power law, and that an equilibrium Young’s modulus of ∼100 Pa was reached. Results reveal that brain parenchyma behaves as a compliant solid at low strain rates, and suggest that brain stem herniation is resisted by an elastic energy barrier. © 2024 Elsevier Ltd
Author Keywords
Apparent Young’s modulus; Brain tissue; Hydrocephalus; Hyper-viscoelasticity; Strain rate; Unconfined compression-isometric hold
Funding details
National Natural Science Foundation of ChinaNSFC12032010, 12272179
National Natural Science Foundation of ChinaNSFC
KYCX23_0349
Document Type: Article
Publication Stage: Final
Source: Scopus
Prevalence of Suicidality in Adolescents With Newly Diagnosed Focal Epilepsy at Diagnosis and Over the Following 36 Months
(2024) Neurology, 103 (1), p. e209397.
Greenwood, H.T., French, J., Ferrer, M., Jandhyala, N., Thio, L.L., Dlugos, D.J., Park, K.L., Kanner, A.M., Human Epilepsy Project Investigators
From the Department of Neurology (H.T.G., J.F., M.F., N.J.), and Department of Pediatrics (M.F.), NYU Grossman School of Medicine, New York; Department of Neurology (L.L.T.), Washington University in St. Louis School of Medicine, MO; Department of Pediatrics and Neurology (D.J.D.), Children’s Hospital of Philadelphia, PA; Department of Pediatrics and Neurology (K.L.P.), University of Colorado School of Medicine, Aurora; and Department of Neurology (A.M.K.), Miller School of Medicine, University of Miami, FL
Abstract
BACKGROUND AND OBJECTIVES: Individuals with epilepsy have increased risk of suicidal ideation (SI) and behaviors when compared with the general population. This relationship has remained largely unexplored in adolescents. We investigated the prevalence of suicidality in adolescents with newly diagnosed focal epilepsy within 4 months of treatment initiation and over the following 36 months. METHODS: This was a post hoc analysis of the enrollment and follow-up data from the Human Epilepsy Project, an international, multi-institutional study that enrolled participants between 2012 and 2017. Participants enrolled were 11-17 years of age within 4 months of treatment initiation for focal epilepsy. We used data from the Columbia Suicide Severity Rating Scale (C-SSRS), administered at enrollment and over the 36-month follow-up period, along with data from medical records. RESULTS: A total of 66 adolescent participants were enrolled and completed the C-SSRS. At enrollment, 14 (21%) had any lifetime SI and 5 (8%) had any lifetime suicidal behaviors (SBs). Over the following 36 months, 6 adolescents reported new onset SI and 5 adolescents reported new onset SB. Thus, the lifetime prevalence of SI within this population increased from 21% to 30% (14-20 adolescents), and the lifetime prevalence of SB increased from 8% to 15% (5-10). DISCUSSION: The prevalence of suicidality in adolescents with newly diagnosed focal epilepsy reported in our study is consistent with previous findings of significant suicidality observed in epilepsy. We identify adolescents as an at-risk population at the time of epilepsy diagnosis and in the following years.
Document Type: Article
Publication Stage: Final
Source: Scopus
Links Between Daily Life and Laboratory Emotion Regulation Processes: The Role of Age and Cognitive Status
(2024) Journals of Gerontology – Series B Psychological Sciences and Social Sciences, 79 (7), art. no. gbae073, .
Growney, C.M.a , English, T.b
a Department of Psychology, Stanford University, Stanford, CA, United States
b Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Objectives: This study investigates how daily use of emotion regulation (ER) strategies predicts ER processes in the laboratory among young adults and cognitively diverse older adults. Methods: Young adults (aged 21–34, n = 66), cognitively normal (CN) older adults (aged 70–83, n = 87), and older adults with researcher-defined mild cognitive impairment (MCI; aged 70–84; n = 58) completed an experience sampling procedure (7×/day for 9 days) reporting their distraction and reappraisal use in daily life. In a laboratory task inducing high-arousal negative emotion, they reported their (a) distraction and reappraisal use when instructed to reduce negative emotion and (b) ER success and perceptions when randomly assigned to regulate using distraction or reappraisal. Results: Among CN older adults, a higher frequency of using a strategy in daily life predicted greater success deploying the strategy when instructed to do so but was unrelated to spontaneous strategy use in the laboratory. In contrast, among older adults with researcher-defined MCI, greater daily life strategy use predicted greater laboratory use, but not greater success. Daily strategy use in younger adults was unrelated to strategy use and success in the laboratory. Older adults with researcher-defined MCI experienced ER as more demanding but did not differ from non-impaired individuals in terms of perceived ER effort. Discussion: Cognitively normal older adults may be better able to leverage their ER experience in novel contexts than younger adults. Older adults with MCI may be motivated to manage their emotions but experience more ER difficulty, perhaps in part due to reliance on default strategies. © The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved.
Author Keywords
Age differences; Cognition; Process model of emotion regulation
Document Type: Article
Publication Stage: Final
Source: Scopus
A disease-associated gene desert directs macrophage inflammation through ETS2
(2024) Nature, 630 (8016), pp. 447-456.
Stankey, C.T.a b c , Bourges, C.a , Haag, L.M.d , Turner-Stokes, T.a b , Piedade, A.P.a , Palmer-Jones, C.e f , Papa, I.a , Silva dos Santos, M.g , Zhang, Q.h , Cameron, A.J.i , Legrini, A.i , Zhang, T.i , Wood, C.S.i , New, F.N.j , Randzavola, L.O.b , Speidel, L.k l , Brown, A.C.m , Hall, A.n o , Saffioti, F.f n , Parkes, E.C.a , Edwards, W.p , Direskeneli, H.q , Grayson, P.C.r , Jiang, L.s , Merkel, P.A.t u , Saruhan-Direskeneli, G.v , Sawalha, A.H.w x y z , Tombetti, E.aa ab , Quaglia, A.o ac , Thorburn, D.f n , Knight, J.C.m ad ae , Rochford, A.P.e f , Murray, C.D.e f , Divakar, P.j , Green, M.af , Nye, E.af , MacRae, J.I.g , Jamieson, N.B.i , Skoglund, P.k , Cader, M.Z.p ag , Wallace, C.p ah , Thomas, D.C.p ag , Lee, J.C.a e f
a Genetic Mechanisms of Disease Laboratory, The Francis Crick Institute, London, United Kingdom
b Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
c Washington University School of Medicine, St Louis, MO, United States
d Division of Gastroenterology, Infectious Diseases and Rheumatology, Charité–Universitätsmedizin Berlin, Berlin, Germany
e Department of Gastroenterology, Royal Free Hospital, London, United Kingdom
f Institute for Liver and Digestive Health, Division of Medicine, University College London, London, United Kingdom
g Metabolomics STP, The Francis Crick Institute, London, United Kingdom
h Genomics of Inflammation and Immunity Group, Human Genetics Programme, Wellcome Sanger Institute, Hinxton, United Kingdom
i Wolfson Wohl Cancer Centre, School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
j NanoString Technologies, Seattle, WA, United States
k Ancient Genomics Laboratory, The Francis Crick Institute, London, United Kingdom
l Genetics Institute, University College London, London, United Kingdom
m Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
n The Sheila Sherlock Liver Centre, Royal Free Hospital, London, United Kingdom
o Department of Cellular Pathology, Royal Free Hospital, London, United Kingdom
p Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, United Kingdom
q Department of Internal Medicine, Division of Rheumatology, Marmara University, Istanbul, Turkey
r Systemic Autoimmunity Branch, NIAMS, National Institutes of Health, Bethesda, MD, United States
s Department of Rheumatology, Zhongshan Hospital, Fudan University, Shanghai, China
t Division of Rheumatology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, United States
u Division of Epidemiology, Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA, United States
v Department of Physiology, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey
w Division of Rheumatology, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, United States
x Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
y Lupus Center of Excellence, University of Pittsburgh, Pittsburgh, PA, United States
z Department of Immunology, University of Pittsburgh, Pittsburgh, PA, United States
aa Department of Biomedical and Clinical Sciences, Milan University, Milan, Italy
ab Internal Medicine and Rheumatology, ASST FBF-Sacco, Milan, Italy
ac UCL Cancer Institute, London, United Kingdom
ad Chinese Academy of Medical Sciences Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
ae NIHR Comprehensive Biomedical Research Centre, Oxford, United Kingdom
af Experimental Histopathology STP, The Francis Crick Institute, London, United Kingdom
ag Department of Medicine, University of Cambridge, Cambridge, United Kingdom
ah MRC Biostatistics Unit, Cambridge Institute of Public Health, Cambridge, United Kingdom
Abstract
Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health1. This is compounded by the limited efficacy of available treatments1 and high failure rates during drug development2, highlighting an urgent need to better understand disease mechanisms. Here we show how functional genomics could address this challenge. By investigating an intergenic haplotype on chr21q22—which has been independently linked to inflammatory bowel disease, ankylosing spondylitis, primary sclerosing cholangitis and Takayasu’s arteritis3–6—we identify that the causal gene, ETS2, is a central regulator of human inflammatory macrophages and delineate the shared disease mechanism that amplifies ETS2 expression. Genes regulated by ETS2 were prominently expressed in diseased tissues and more enriched for inflammatory bowel disease GWAS hits than most previously described pathways. Overexpressing ETS2 in resting macrophages reproduced the inflammatory state observed in chr21q22-associated diseases, with upregulation of multiple drug targets, including TNF and IL-23. Using a database of cellular signatures7, we identified drugs that might modulate this pathway and validated the potent anti-inflammatory activity of one class of small molecules in vitro and ex vivo. Together, this illustrates the power of functional genomics, applied directly in primary human cells, to identify immune-mediated disease mechanisms and potential therapeutic opportunities. © The Author(s) 2024.
Document Type: Article
Publication Stage: Final
Source: Scopus
Severe Pediatric Neurological Manifestations With SARS-CoV-2 or MIS-C Hospitalization and New Morbidity
(2024) JAMA Network Open, p. E2414122. Cited 1 time.
Francoeur, C.a , Alcamo, A.M.b c d , Robertson, C.L.e , Wainwright, M.S.f , Roa, J.D.g h , Lovett, M.E.i , Stulce, C.j , Yacoub, M.k , Potera, R.M.l , Zivick, E.m , Holloway, A.n , Nagpal, A.o , Wellnitz, K.p , Even, K.M.q , Brunow De Carvalho, W.r , Rodriguez, I.S.r , Schwartz, S.P.s , Walker, T.C.s , Campos-Miño, S.t , Dervan, L.A.u , Geneslaw, A.S.v , Sewell, T.B.v , Pryce, P.w , Silver, W.G.x , Lin, J.E.x , Vargas, W.S.x , Topjian, A.b c d , Mcguire, J.L.d y z , Domínguez Rojas, J.A.aa , Tasayco-Muñoz, J.aa , Hong, S.J.e , Muller, W.J.ab , Doerfler, M.ab , Williams, C.N.ac ad , Drury, K.ad , Bhagat, D.ae , Nelson, A.ae , Price, D.ae , Dapul, H.af , Santos, L.af , Kahoud, R.ag , Appavu, B.ah , Guilliams, K.P.ai aj ak , Agner, S.C.ai aj ak , Walson, K.H.al , Rasmussen, L.am , Pal, R.an , Janas, A.am , Ferrazzano, P.ao , Farias-Moeller, R.ap , Snooks, K.C.aq , Chang, C.-C.H.ar , Iolster, T.as , Erklauer, J.C.at au , Jorro Baron, F.av , Wassmer, E.aw ax ay , Yoong, M.az , Jardine, M.ba , Mohammad, Z.bb , Deep, A.bc , Kendirli, T.bd , Lidsky, K.be , Dallefeld, S.bf , Flockton, H.bg , Agrawal, S.bh , Siruguppa, K.S.bi bj bk , Waak, M.bl , Gutiérrez-Mata, A.bm , Butt, W.bn bo , Bogantes-Ledezma, S.bm , Sevilla-Acosta, F.bp , Umaña-Calderón, A.bm , Ulate-Campos, A.bm , Yock-Corrales, A.bq , Talisa, V.B.ar , Kanthimathinathan, H.K.br , Schober, M.E.bs , Fink, E.L.ar
a Division of Pediatric Critical Care Medicine, Department of Pediatrics, Montreal Children’s Hospital, McGill University Health Center, Montreal, QC, Canada
b Division of Critical Care Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
c Department of Anesthesiology and Critical Care, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States
d Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States
e Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
f Division of Pediatric Neurology, University of Washington, Seattle Children’s Hospital, Seattle, United States
g Department of Pediatrics, Universidad Nacional de Colombia, Bogotá, Colombia
h Department of Pediatric Neurology, Faculty of Medicine, Fundación Universitaria de Ciencias de la Salud, Bogotá, Colombia
i Division of Critical Care Medicine, Department of Pediatrics, Nationwide Children’s Hospital, Ohio State University, Columbus, United States
j Department of Pediatrics, University of Chicago, Chicago, IL, United States
k Division of Critical Care, Department of Pediatrics, University Medical Center Children’s Hospital, Las Vegas, NV, United States
l Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, United States
m Division of Pediatric Critical Care Medicine, Department of Pediatrics, Medical University of South Carolina, Charleston, United States
n Division of Critical Care, Department of Pediatrics, University of Maryland Medical Center, Baltimore, United States
o Department of Pediatrics, Section of Critical Care Medicine, Oklahoma Children’s Hospital, Oklahoma University Health, College of Medicine, University of Oklahoma Health Sciences, Oklahoma City, United States
p Division of Pediatric Critical Care, Department of Pediatrics, Carver College of Medicine, University of Iowa Health Care, Iowa City, United States
q Division of Pediatric Critical Care Medicine, Penn State College of Medicine, Pennsylvania State University, Hershey, United States
r Department of Pediatrics, University of São Paulo, São Paulo, Brazil
s Department of Pediatrics, University of North Carolina, Chapel Hill Hospitals, Chapel Hill, United States
t Pediatric Intensive Care Unit, Hospital Metropolitano, Quito, Ecuador
u Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, United States
v Division of Pediatric Critical Care and Hospital Medicine, Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States
w Division of Pediatric Critical Care and Hospital Medicine, Department of Pediatrics, Columbia University Irving Medical Center, New York-Presbyterian Morgan Stanley Children’s Hospital, New York, NY, United States
x Division of Child Neurology, Department of Neurology, Columbia University Irving Medical Center, New York, NY, United States
y Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
z Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States
aa Division of Pediatric Critical Care, Department of Pediatrics, Hospital de Emergencia Villa El Salvador, Lima, Peru
ab Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
ac Pediatric Critical Care and Neurotrauma Recovery Program, Department of Pediatrics, Oregon Health & Science University, Portland, United States
ad Division of Pediatric Critical Care, Department of Pediatrics, Oregon Health & Science University, Portland, United States
ae Department of Neurology, New York University Langone Health, New York, United States
af Division of Pediatric Critical Care, Department of Pediatrics, Hassenfeld Children’s Hospital, New York University Langone Health, New York, United States
ag Division of Pediatric Critical Care Medicine, Department of Pediatrics and Adolescent Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, United States
ah Division of Neurology, Barrow Neurological Institute, Phoenix Children’s Hospital, University of Arizona, College of Medicine, Phoenix, United States
ai Department of Neurology, Washington University School of Medicine in St Louis, St Louis, MO, United States
aj Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine in St Louis, St Louis, MO, United States
ak Mallinckrodt Institute of Radiology, Washington University School of Medicine in St Louis, St Louis, MO, United States
al Division of Pediatric Critical Care Medicine, Emory University School of Medicine, Children’s Healthcare of Atlanta, Atlanta, GA, United States
am Division of Pediatric Critical Care Medicine, Department of Pediatrics, Standford University Medicine, Lucile Packard Children’s Hospital Stanford, Stanford, CA, United States
an Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, United States
ao Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, United States
ap Division of Child Neurology, Department of Neurology, Medical College of Wisconsin, Children’s Wisconsin, Milwaukee, United States
aq Department of Pediatrics, Medical College of Wisconsin, Children’s Wisconsin, Milwaukee, United States
ar Division of Pediatric Critical Care Medicine, UPMC Children’s Hospital of Pittsburgh, 4401 Penn Ave, Faculty Pavilion, 2nd Floor, Pittsburgh, PA 15224, United States
as Department of Pediatrics, Hospital Universitario Austral, Buenos Aires, Argentina
at Division of Pediatric Critical Care Medicine, Department of Pediatrics, Baylor College of Medicine, Texas Children’s Hospital, Houston, United States
au Division of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Texas Children’s Hospital, Houston, United States
av Department of Pediatrics, Hospital General de Niños Pedro Elizade, Buenos Aires, Argentina
aw Birmingham Children’s Hospital, Birmingham, United Kingdom
ax Aston Institute of Health and Neurodevelopment, Birmingham, United Kingdom
ay Aston University, Birmingham, United Kingdom
az Department of Neurology, Royal London Children’s Hospital, London, United Kingdom
ba Pediatric Critical Care Unit, University Hospital of Wales, Cardiff, United Kingdom
bb Pediatric Intensive Care Unit, University Hospitals Leicester NHS Trust, Leicester, United Kingdom
bc Department of Women and Children’s Health, King’s College Hospital, London, United Kingdom
bd Department of Pediatric Critical Care Medicine, Ankara University School of Medicine, Ankara, Turkey
be Division of Pediatric Critical Care Medicine, Wolfson Children’s Hospital, Jacksonville, FL, United States
bf Department of Pediatrics, Dell Children’s Hospital, Austin, TX, United States
bg Paediatric Critical Care Unit, Oxford University Hospitals, Oxford, United Kingdom
bh Paediatric Intensive Care Unit, Cambridge University Hospitals, Cambridge, United Kingdom
bi Division of Pediatric Critical Care, Department of Pediatrics, University of California, San Francisco, United States
bj Fresno Medical Education and Research Program, Department of Medicine, University of California, San Francisco, Fresno, United States
bk Department of Pediatrics, Community Medical Centers, Fresno, CA, United States
bl Child Health Research Centre, University of Queensland, Brisbane, QLD, Australia
bm Department of Pediatric Neurology, Dr. Carlos Sáenz Herrera National Children’s Hospital, San José, Costa Rica
bn Department of Critical Care, Melbourne Medical School, University of Melbourne, Royal Children’s Hospital Melbourne, Melbourne, VIC, Australia
bo Clinical Sciences, Murdoch Children’s Research Institute, Parkville, VIC, Australia
bp Department of Pediatrics, La Anexión Hospital, Guanacaste, Costa Rica
bq Department of Emergency Service, Dr. Carlos Sáenz Herrera National Children’s Hospital, San José, Costa Rica
br West Midlands Regional Genetics Laboratory, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, United Kingdom
bs Division of Critical Care, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, United States
Abstract
Importance: Neurological manifestations during acute SARS-CoV-2-related multisystem inflammatory syndrome in children (MIS-C) are common in hospitalized patients younger than 18 years and may increase risk of new neurocognitive or functional morbidity. Objective: To assess the association of severe neurological manifestations during a SARS-CoV-2-related hospital admission with new neurocognitive or functional morbidities at discharge. Design, Setting, and Participants: This prospective cohort study from 46 centers in 10 countries included patients younger than 18 years who were hospitalized for acute SARS-CoV-2 or MIS-C between January 2, 2020, and July 31, 2021. Exposure: Severe neurological manifestations, which included acute encephalopathy, seizures or status epilepticus, meningitis or encephalitis, sympathetic storming or dysautonomia, cardiac arrest, coma, delirium, and stroke. Main Outcomes and Measures: The primary outcome was new neurocognitive (based on the Pediatric Cerebral Performance Category scale) and/or functional (based on the Functional Status Scale) morbidity at hospital discharge. Multivariable logistic regression analyses were performed to examine the association of severe neurological manifestations with new morbidity in each SARS-CoV-2-related condition. Results: Overall, 3568 patients younger than 18 years (median age, 8 years [IQR, 1-14 years]; 54.3% male) were included in this study. Most (2980 [83.5%]) had acute SARS-CoV-2; the remainder (588 [16.5%]) had MIS-C. Among the patients with acute SARS-CoV-2, 536 (18.0%) had a severe neurological manifestation during hospitalization, as did 146 patients with MIS-C (24.8%). Among survivors with acute SARS-CoV-2, those with severe neurological manifestations were more likely to have new neurocognitive or functional morbidity at hospital discharge compared with those without severe neurological manifestations (27.7% [n = 142] vs 14.6% [n = 356]; P <.001). For survivors with MIS-C, 28.0% (n = 39) with severe neurological manifestations had new neurocognitive and/or functional morbidity at hospital discharge compared with 15.5% (n = 68) of those without severe neurological manifestations (P =.002). When adjusting for risk factors in those with severe neurological manifestations, both patients with acute SARS-CoV-2 (odds ratio, 1.85 [95% CI, 1.27-2.70]; P =.001) and those with MIS-C (odds ratio, 2.18 [95% CI, 1.22-3.89]; P =.009) had higher odds of having new neurocognitive and/or functional morbidity at hospital discharge. Conclusions and Relevance: The results of this study suggest that children and adolescents with acute SARS-CoV-2 or MIS-C and severe neurological manifestations may be at high risk for long-term impairment and may benefit from screening and early intervention to assist recovery. © 2024 American Medical Association. All rights reserved.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
AmyloidPETNet: Classification of Amyloid Positivity in Brain PET Imaging Using End-to-End Deep Learning
(2024) Radiology, 311 (3), p. e231442.
Fan, S., Ponisio, M.R., Xiao, P., Ha, S.M., Chakrabarty, S., Lee, J.J., Flores, S., LaMontagne, P., Gordon, B., Raji, C.A., Marcus, D.S., Nazeri, A., Ances, B.M., Bateman, R.J., Morris, J.C., Benzinger, T.L.S., Sotiras, A., Alzheimer’s Disease Neuroimaging Initiative
From the Department of Bioengineering, Rice University, Houston, Tex (S. Fan); Department of Radiology (S. Fan, M.R.P., P.X., S.M.H., J.J.L., S. Flores, P.L., B.G., C.A.R., D.S.M., A.N., T.L.S.B., A.S.), Charles F. and Joanne Knight Alzheimer Disease Research Center (B.G., B.M.A., R.B., J.C.M., T.L.S.B.), Department of Neurology (C.A.R., B.M.A., R.J.B., J.C.M.), and Institute for Informatics, Data Science and Biostatistics (A.S.), Washington University School of Medicine, 660 S Euclid Ave, Campus Box 8132, St Louis, MO 63110; Duke-NUS Medical School, Singapore (S. Fan); Department of Electrical and Systems Engineering, Washington University in St Louis, St Louis, Mo (S.C., A.S.); Brain Health Imaging Centre, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada (A.N.); and Tracy Family SILQ Center for Neurodegenerative Biology, St Louis, Mo (R.J.B.)
Abstract
Background Visual assessment of amyloid PET scans relies on the availability of radiologist expertise, whereas quantification of amyloid burden typically involves MRI for processing and analysis, which can be computationally expensive. Purpose To develop a deep learning model to classify minimally processed brain PET scans as amyloid positive or negative, evaluate its performance on independent data sets and different tracers, and compare it with human visual reads. Materials and Methods This retrospective study used 8476 PET scans (6722 patients) obtained from late 2004 to early 2023 that were analyzed across five different data sets. A deep learning model, AmyloidPETNet, was trained on 1538 scans from 766 patients, validated on 205 scans from 95 patients, and internally tested on 184 scans from 95 patients in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) fluorine 18 (18F) florbetapir (FBP) data set. It was tested on ADNI scans using different tracers and scans from independent data sets. Scan amyloid positivity was based on mean cortical standardized uptake value ratio cutoffs. To compare with model performance, each scan from both the Centiloid Project and a subset of the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) study were visually interpreted with a confidence level (low, intermediate, high) of amyloid positivity/negativity. The area under the receiver operating characteristic curve (AUC) and other performance metrics were calculated, and Cohen κ was used to measure physician-model agreement. Results The model achieved an AUC of 0.97 (95% CI: 0.95, 0.99) on test ADNI 18F-FBP scans, which generalized well to 18F-FBP scans from the Open Access Series of Imaging Studies (AUC, 0.95; 95% CI: 0.93, 0.97) and the A4 study (AUC, 0.98; 95% CI: 0.98, 0.98). Model performance was high when applied to data sets with different tracers (AUC ≥ 0.97). Other performance metrics provided converging evidence. Physician-model agreement ranged from fair (Cohen κ = 0.39; 95% CI: 0.16, 0.60) on a sample of mostly equivocal cases from the A4 study to almost perfect (Cohen κ = 0.93; 95% CI: 0.86, 1.0) on the Centiloid Project. Conclusion The developed model was capable of automatically and accurately classifying brain PET scans as amyloid positive or negative without relying on experienced readers or requiring structural MRI. Clinical trial registration no. NCT00106899 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Bryan and Forghani in this issue.
Document Type: Article
Publication Stage: Final
Source: Scopus
Astrocytes as a mechanism for contextually-guided network dynamics and function
(2024) PLoS Computational Biology, 20 (5), art. no. e1012186, .
Gong, L.a , Pasqualetti, F.b , Papouin, T.c , Ching, S.a
a Department of Electrical and Systems Engineering, Washington University, St. Louis, MO, United States
b Department of Mechanical Engineering, University of California, Riverside, CA, United States
c Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Astrocytes are a ubiquitous and enigmatic type of non-neuronal cell and are found in the brain of all vertebrates. While traditionally viewed as being supportive of neurons, it is increasingly recognized that astrocytes play a more direct and active role in brain function and neural computation. On account of their sensitivity to a host of physiological covariates and ability to modulate neuronal activity and connectivity on slower time scales, astrocytes may be particularly well poised to modulate the dynamics of neural circuits in functionally salient ways. In the current paper, we seek to capture these features via actionable abstractions within computational models of neuron-astrocyte interaction. Specifically, we engage how nested feedback loops of neuron-astrocyte interaction, acting over separated timescales, may endow astrocytes with the capability to enable learning in context-dependent settings, where fluctuations in task parameters may occur much more slowly than within-task requirements. We pose a general model of neuron-synapse-astrocyte interaction and use formal analysis to characterize how astrocytic modulation may constitute a form of meta-plasticity, altering the ways in which synapses and neurons adapt as a function of time. We then embed this model in a bandit-based reinforcement learning task environment, and show how the presence of time-scale separated astrocytic modulation enables learning over multiple fluctuating contexts. Indeed, these networks learn far more reliably compared to dynamically homogeneous networks and conventional non-network-based bandit algorithms. Our results fuel the notion that neuron-astrocyte interactions in the brain benefit learning over different time-scales and the conveyance of task-relevant contextual information onto circuit dynamics. © 2024 Gong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding details
U.S. Department of DefenseDODW911NF2110312
U.S. Department of DefenseDOD
National Institutes of HealthNIHR01MH127163
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Final
Source: Scopus
Creating Computational Models of Ion Channel Dynamics
(2024) Methods in Molecular Biology (Clifton, N.J.), 2796, pp. 139-156.
Schoening, M.E., Silva, J.R.
Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Markov models are widely used to represent ion channel protein configurations as different states in the model’s topology. Such models allow for dynamic simulation of ion channel kinetics through the simulated application of voltage potentials across a cell membrane. In this chapter, we present a general method for creating Markov models of ion channel kinetics using computational optimization alongside a fully featured example model of a cardiac potassium channel. Our methods cover designing training protocols, iteratively testing potential model topologies for structure identification, creation of algorithms for model simulation, as well as methods for assessing the quality of fit for a finalized model. © 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.
Author Keywords
Action potentials; Computational optimization; Ion channels; Markov models; Model creation; Modeling; Simulation
Document Type: Article
Publication Stage: Final
Source: Scopus
Pick a PACC: Comparing Domain-Specific and General Cognitive Composites in Alzheimer Disease Research
(2024) Neuropsychology, .
McKay, N.S.a , Millar, P.R.b , Nicosia, J.b , Aschenbrenner, A.J.b , Gordon, B.A.a , Benzinger, T.L.S.a , Cruchaga, C.C.c , Schindler, S.E.b , Morris, J.C.b , Hassenstab, J.b
a Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, United States
b Department of Neurology, Washington University School of Medicine, St. Louis, United States
c Department of Psychiatry, Washington University School of Medicine, St. Louis, United States
Abstract
Objective: We aimed to illustrate how complex cognitive data can be used to create domain-specific and general cognitive composites relevant to Alzheimer disease research. Method: Using equipercentile equating, we combined data from the Charles F. and Joanne Knight Alzheimer Disease Research Center that spanned multiple iterations of the Uniform Data Set. Exploratory factor analyses revealed four domain-specific composites representing episodic memory, semantic memory, working memory, and attention/processing speed. The previously defined preclinical Alzheimer disease cognitive composite (PACC) and a novel alternative, the Knight-PACC, were also computed alongside a global composite comprising all available tests. These three composites allowed us to compare the usefulness of domain and general composites in the context of predicting common Alzheimer disease biomarkers. Results: General composites slightly outperformed domain-specific metrics in predicting imaging-derived amyloid, tau, and neurodegeneration burden. Power analyses revealed that the global, Knight-PACC, and attention and processing speed composites would require the smallest sample sizes to detect cognitive change in a clinical trial, while the Alzheimer Disease Cooperative Study-PACC required two to three times as many participants. Conclusions: Analyses of cognition with the Knight-PACC and our domain-specific composites offer researchers flexibility by providing validated outcome assessments that can equate across test versions to answer a wide range of questions regarding cognitive decline in normal aging and neurodegenerative disease. © 2024 American Psychological Association
Author Keywords
Alzheimer; factor analysis; magnetic resonance imaging; positron emission tomography; preclinical Alzheimer disease cognitive composite
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Maternal Smoking During Pregnancy Is Associated With DNA Methylation in Early Adolescence: A Sibling Comparison Design
(2024) Developmental Psychology, .
Nonkovic, N.a , Marceau, K.a , McGeary, J.E.b , Ramos, A.M.c , Palmer, R.H.C.d , Heath, A.C.e , Knopik, V.S.a
a Department of Human Development and Family Science, Purdue University, United States
b Department of Psychiatry and Human Behavior, Brown University, United States
c Department of Epidemiology, University of North Carolina at Chapel Hill, United States
d Behavioral Genetics of Addiction Laboratory, Department of Psychology, Emory University, United States
e Department of Psychiatry, Washington University School of Medicine in St. Louis, United States
Abstract
Maternal smoking during pregnancy (MSDP) may impact offspring biological (e.g., deoxyribonucleic acid methylation [DNAm]) and behavioral (e.g., attention-deficit/hyperactivity disorder hyperactive/impulsive [ADHD-HI] symptoms) development. There has been consistency in findings of differential methylation in global DNAm, and the specific genes AHRR, CYP1A1, CNTNAP2, MYO1G, and GFI1 in relation to MSDP. The current study aims to (a) replicate the associations of MSDP and DNAm in prior literature in middle childhood–adolescence (cross-sectionally) using a sibling-comparison design where siblings were discordant for MSDP (n = 328 families; Mage Sibling 1 = 13.02; Sibling 2 = 10.20), adjusting for prenatal and postnatal covariates in order to isolate the MSDP exposure on DNAm. We also (b) cross-sectionally explored the role of DNAm in the most robust MSDP–ADHD associations (i.e., with ADHD-HI) previously found in this sample. We quantified smoking exposure severity for each sibling reflecting time and quantity of MSDP, centered relative to the sibling pair’s average (i.e., within-family centered, indicating child-specific effects attributable MSDP exposure) and controlling for the sibling average MSDP (i.e., between-family component, indicating familial confounding related to MSDP). We found that child-specific MSDP was associated with global DNAm, and CNTNAP2, CYP1A1, and MYO1G methylation after covariate adjustment, corroborating emerging evidence for a potentially causal pathway between MSDP and DNAm. There was some evidence that child-specific CNTNAP2 and MYO1G methylation partially explained associations between MSDP and ADHD-HI symptoms, though only on one measure (of two). Future studies focused on replication of these findings in a longitudinal genetic design could further solidify the associations found in the current study. © 2024 American Psychological Association
Author Keywords
adolescence; epigenetics; maternal smoking; prenatal
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
How undergraduate students learn: uncovering interrelationships between factors that support self-regulated learning and strategy use
(2024) Metacognition and Learning, .
Hey, R.a , McDaniel, M.b , Hodis, F.A.a
a Faculty of Education, Victoria University of Wellington, Wellington, New Zealand
b Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Being an effective learner is an important pillar supporting success in higher education and beyond. This research aimed to uncover the extent to which undergraduate students use a set of commonly researched learning strategies, as well as to understand how learning strategy usage relates to key self-regulation factors proposed in influential models of self-regulated learning. Undergraduate students from New Zealand (N = 140) were recruited through course management systems, social media, and campus posters. Data were analysed using correlation and multiple regression. Results show that students reported using more learning strategies that are relatively effective than learning strategies that are somewhat less effective. In addition, effort regulation and student engagement were the most consistent predictors of both learning strategy use and self-reported academic achievement. Building on these findings, this research provides important new insights into the associations between learning strategy usage and pivotal factors that support effective self-regulated learning and academic achievement. As we highlight in the article, these insights have key implications for advancing theory and research on self-regulated learning. © The Author(s) 2024.
Author Keywords
Effort regulation; Learning; Learning strategies; Self-regulated learning and academic achievement; Self-regulation; Student engagement
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Neurocognitive outcome in children with sickle cell disease after myeloimmunoablative conditioning and haploidentical hematopoietic stem cell transplantation: a non-randomized clinical trial
(2024) Frontiers in Neurology, 15, art. no. 1263373, .
Braniecki, S.a , Vichinsky, E.b , Walters, M.C.b , Shenoy, S.c , Shi, Q.d , Moore, T.B.e , Talano, J.-A.f , Parsons, S.K.g , Flower, A.a , Panarella, A.a , Fabricatore, S.a , Morris, E.a , Mahanti, H.a , Milner, J.a , McKinstry, R.C.e h , Duncan, C.N.i , van de Ven, C.a , Cairo, M.S.a j k l m
a Department of Pediatrics, New York Medical College, Valhalla, NY, United States
b Department of Pediatrics, UCSF Benioff Children’s Hospital, Oakland, CA, United States
c Department of Pediatrics, Washington University, St Louis, MO, United States
d Department of Epidemiology, New York Medical College, Valhalla, NY, United States
e Department of Pediatrics, University of California, Los Angeles, Los Angeles, CA, United States
f Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, United States
g Department of Medicine and Pediatrics, Tufts Medical Center, Boston, MA, United States
h Department of Radiology, Washington University, St Louis, MO, United States
i Dana-Faber/Children’s Cancer and Blood Disorders Center, Boston, MA, United States
j Department of Medicine, New York Medical College, Valhalla, NY, United States
k Department of Pathology, New York Medical College, Valhalla, NY, United States
l Department of Microbiology and Immunology, New York Medical College, Valhalla, NY, United States
m Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, United States
Abstract
Background: Due to the risk of cerebral vascular injury, children and adolescents with high-risk sickle cell disease (SCD) experience neurocognitive decline over time. Haploidentical stem cell transplantation (HISCT) from human leukocyte antigen-matched sibling donors may slow or stop progression of neurocognitive changes. Objectives: The study is to determine if HISCT can ameliorate SCD-associated neurocognitive changes and prevent neurocognitive progression, determine which specific areas of neurocognitive functioning are particularly vulnerable to SCD, and determine if there are age-related differences in neurocognitive functioning over time. Methods: We performed neurocognitive and neuroimaging in SCD recipients following HISCT. Children and adolescents with high-risk SCD who received parental HISCT utilizing CD34+ enrichment and mononuclear cell (T-cell) addback following myeloimmunoablative conditioning received cognitive evaluations and neuroimaging at three time points: pre-transplant, 1 and 2 years post-transplant. Results: Nineteen participants (13.1 ± 1.2 years [3.3–20.0]) received HISCT. At 2 years post-transplant, neuroimaging and cognitive function were stable. Regarding age-related differences pre-transplantation, older children (≥13 years) had already experienced significant decreases in language functioning (p < 0.023), verbal intelligence quotient (p < 0.05), non-verbal intelligence quotient (p < 0.006), and processing speed (p < 0.05), but normalized post-HISCT in all categories. Conclusion: Thus, HISCT has the potential to ameliorate SCD-associated neurocognitive changes and prevent neurocognitive progression. Further studies are required to determine if neurocognitive performance remains stable beyond 2 years post-HISCT. Clinical trial registration: The study was conducted under an investigator IND (14359) (MSC) and registered at clinicaltrials.gov (NCT01461837). Copyright © 2024 Braniecki, Vichinsky, Walters, Shenoy, Shi, Moore, Talano, Parsons, Flower, Panarella, Fabricatore, Morris, Mahanti, Milner, McKinstry, Duncan, van de Ven and Cairo.
Author Keywords
cognitive functioning; pediatric; processing speed; sickle cell disease; transplant
Funding details
Pediatric Cancer Research FoundationPCRF
Johnson & Johnson Innovative Medicine
Document Type: Article
Publication Stage: Final
Source: Scopus