WashU weekly Neuroscience publications: May 22, 2022

Single-cell profiling of human dura and meningioma reveals cellular meningeal landscape and insights into meningioma immune response
(2022) Genome Medicine, 14 (1), art. no. 49, . 

Wang, A.Z.^{a b c d e} , Bowman-Kirigin, J.A.^a b c d , Desai, R.^a d , Kang, L.-I.^f , Patel, P.R.^g , Patel, B.^a d , Khan, S.M.^a d , Bender, D.^c , Marlin, M.C.^h , Liu, J.^i j , Osbun, J.W.^a d , Leuthardt, E.C.^a d , Chicoine, M.R.^a d , Dacey, R.G., Jr.^a d , Zipfel, G.J.^a d , Kim, A.H.^a d , DeNardo, D.G.^k , Petti, A.A.^a d i l , Dunn, G.P.^e

^a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
^c Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, United States
^d Brain Tumor Center, Washington University School of Medicine/Siteman Cancer Center, St. Louis, United States
^e Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, United States
^f Division of Anatomic and Molecular Pathology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
^g Washington University School of Medicine, St. Louis, MO, United States
^h Arthritis & Clinical Immunology Human Phenotyping Core, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States
ⁱ Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
^j McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, United States
^k Division of Oncology-Molecular Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, United States
^l Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background: Recent investigations of the meninges have highlighted the importance of the dura layer in central nervous system immune surveillance beyond a purely structural role. However, our understanding of the meninges largely stems from the use of pre-clinical models rather than human samples. Methods: Single-cell RNA sequencing of seven non-tumor-associated human dura samples and six primary meningioma tumor samples (4 matched and 2 non-matched) was performed. Cell type identities, gene expression profiles, and T cell receptor expression were analyzed. Copy number variant (CNV) analysis was performed to identify putative tumor cells and analyze intratumoral CNV heterogeneity. Immunohistochemistry and imaging mass cytometry was performed on selected samples to validate protein expression and reveal spatial localization of select protein markers. Results: In this study, we use single-cell RNA sequencing to perform the first characterization of both non-tumor-associated human dura and primary meningioma samples. First, we reveal a complex immune microenvironment in human dura that is transcriptionally distinct from that of meningioma. In addition, we characterize a functionally diverse and heterogenous landscape of non-immune cells including endothelial cells and fibroblasts. Through imaging mass cytometry, we highlight the spatial relationship among immune cell types and vasculature in non-tumor-associated dura. Utilizing T cell receptor sequencing, we show significant TCR overlap between matched dura and meningioma samples. Finally, we report copy number variant heterogeneity within our meningioma samples. Conclusions: Our comprehensive investigation of both the immune and non-immune cellular landscapes of human dura and meningioma at single-cell resolution builds upon previously published data in murine models and provides new insight into previously uncharacterized roles of human dura. © 2022, The Author(s).

Author Keywords
Dura;  Imaging mass cytometry;  Meninges;  Single-cell RNA sequencing

Funding details
National Institutes of HealthNIHOD021629
National Cancer InstituteNCI30 CA91842
National Center for Research ResourcesNCRR
Washington University in St. LouisWUSTL
Foundation for Barnes-Jewish HospitalFBJH3770, 4642
Institute of Clinical and Translational SciencesICTS
Oklahoma Medical Research FoundationOMRF
Georgia Clinical and Translational Science AllianceGaCTSAUL1TR002345
Office of Research Infrastructure Programs, National Institutes of HealthORIP, NIH
St. Louis Children’s HospitalSLCHCDI-CORE-2015-505, CDI-CORE-2019-813

Document Type: Article
Publication Stage: Final
Source: Scopus

Fluoxetine exposure throughout neurodevelopment differentially influences basilar dendritic morphology in the motor and prefrontal cortices
(2022) Scientific Reports, 12 (1), art. no. 7605, . 

Maloney, S.E.^a b , Tabachnick, D.R.^a c , Jakes, C.^a c , Avdagic, S.^a c , Bauernfeind, A.L.^d e , Dougherty, J.D.^a b c

^a Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8232, St. Louis, MO 63110-1093, United States
^b Intellectual and Developmental Disorders Research Center, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
^e Department of Anthropology, Washington University in St. Louis, St. Louis, MO 63110, United States

Abstract
The significance of serotonin (5HT) in mental health is underscored by the serotonergic action of many classes of psychiatric medication. 5HT is known to have a significant role in neurodevelopment, thus 5HT disruption during development may have a long term impact on brain structure and circuits. We previously generated a model of 5HT alteration throughout neurodevelopment by maternal administration of the selective serotonin reuptake inhibitor fluoxetine. We found resulting social behavior alterations in the offspring during both postnatal and adult ages. Previous work by others has indicated that early 5HT disruption influences neuronal morphology. Therefore, in the current study we sought to determine if dendritic morphological changes occur in areas involved in the social behavior deficits we previously observed, specifically the primary motor (M1) and medial prefrontal (mPFC) cortices. We quantified dendritic morphology of projection neurons in M1 and mPFC at postnatal day (P)10 and P79 in mice exposed to fluoxetine. Basilar dendritic complexity and spine density were persistently decreased in M1 fluoxetine-exposed neurons while in the mPFC, similar reductions were observed at P79 but were not present at P10. Our findings underscore that the developing brain, specifically the projection cortex, is vulnerable to 5HT system perturbation, which may be related to later behavioral disruptions. © 2022, The Author(s).

Funding details
National Institutes of HealthNIHP50 HD103525
Washington University in St. LouisWUSTL
Society for Experimental MechanicsSEM

Document Type: Article
Publication Stage: Final
Source: Scopus

Predicting brain age from functional connectivity in symptomatic and preclinical Alzheimer disease
(2022) NeuroImage, 256, art. no. 119228, . 

Millar, P.R.^a , Luckett, P.H.^a , Gordon, B.A.^b , Benzinger, T.L.S.^b , Schindler, S.E.^a , Fagan, A.M.^a , Cruchaga, C.^c k , Bateman, R.J.^a , Allegri, R.^d k , Jucker, M.^e f k , Lee, J.-H.^g , Mori, H.^h , Salloway, S.P.ⁱ , Yakushev, I.^j , Morris, J.C.^a , Ances, B.M.^a b , Adams, S.^k , Araki, A.^k , Barthelemy, N.^k , Bateman, R.^k , Bechara, J.^k , Benzinger, T.^k , Berman, S.^k , Bodge, C.^k , Brandon, S.^k , Brooks, W.B.^k , Brosch, J.^k , Buck, J.^k , Buckles, V.^k , Carter, K.^k , Cash, L.^k , Chen, C.^k , Chhatwal, J.^k , Mendez, P.C.^k , Chua, J.^k , Chui, H.^k , Courtney, L.^k , Day, G.S.^k , DeLaCruz, C.^k , Denner, D.^k , Diffenbacher, A.^k , Dincer, A.^k , Donahue, T.^k , Douglas, J.^k , Duong, D.^k , Egido, N.^k , Esposito, B.^k , Fagan, A.^k , Farlow, M.^k , Feldman, B.^k , Fitzpatrick, C.^k , Flores, S.^k , Fox, N.^k , Franklin, E.^k , Joseph-Mathurin, N.^k , Fujii, H.^k , Gardener, S.^k , Ghetti, B.^k , Goate, A.^k , Goldberg, S.^k , Goldman, J.^k , Gonzalez, A.^k , Gordon, B.^k , Gräber-Sultan, S.^k , Graff-Radford, N.^k , Graham, M.^k , Gray, J.^k , Gremminger, E.^k , Grilo, M.^k , Groves, A.^k , Haass, C.^k , Häsler, L.^k , Hassenstab, J.^k , Hellm, C.^k , Herries, E.^k , Hoechst-Swisher, L.^k , Hofmann, A.^k , Holtzman, D.^k , Hornbeck, R.^k , Igor, Y.^k , Ihara, R.^k , Ikeuchi, T.^k , Ikonomovic, S.^k , Ishii, K.^k , Jack, C.^k , Jerome, G.^k , Johnson, E.^k , Karch, C.^k , Käser, S.^k , Kasuga, K.^k , Keefe, S.^k , Klunk, W.^k , Koeppe, R.^k , Koudelis, D.^k , Kuder-Buletta, E.^k , Laske, C.^k , Levey, A.^k , Levin, J.^k , Li, Y.^k , Lopez, O.^k , Marsh, J.^k , Martins, R.^k , Mason, N.S.^k , Masters, C.^k , Mawuenyega, K.^k , McCullough, A.^k , McDade, E.^k , Mejia, A.^k , Morenas-Rodriguez, E.^k , Morris, J.^k , Mountz, J.^k , Mummery, C.^k , Nadkarni, N.E.^k , Nagamatsu, A.^k , Neimeyer, K.^k , Niimi, Y.^k , Noble, J.^k , Norton, J.^k , Nuscher, B.^k , Obermüller, U.^k , O’Connor, A.^k , Patira, R.^k , Perrin, R.^k , Ping, L.^k , Preische, O.^k , Renton, A.^k , Ringman, J.^k , Salloway, S.^k , Schofield, P.^k , Senda, M.^k , Seyfried, N.T.^k , Shady, K.^k , Shimada, H.^k , Sigurdson, W.^k , Smith, J.^k , Smith, L.^k , Snitz, B.^k , Sohrabi, H.^k , Stephens, S.^k , Taddei, K.^k , Thompson, S.^k , Vöglein, J.^k , Wang, P.^k , Wang, Q.^k , Weamer, E.^k , Xiong, C.^k , Xu, J.^k , Xu, X.^k , for the Dominantly Inherited Alzheimer Network^l

^a Department of Neurology, Washington University, St. Louis, MO 63110, United States
^b Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
^d Department of Cognitive Neurology, Institute for Neurological Research Fleni, Buenos Aires, Argentina
^e German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
^f Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
^g Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
^h Department of Clinical Neuroscience, Osaka City University Medical School, Nagaoka Sutoku University, Abenoku, Osaka, 545-8585, Japan
ⁱ Department of Neurology, Brown University, Providence, RI, United States
^j Department of Nuclear Medicine, Technical University of Munich, Munich, Germany

Abstract
“Brain-predicted age” quantifies apparent brain age compared to normative neuroimaging trajectories. Advanced brain-predicted age has been well established in symptomatic Alzheimer disease (AD), but is underexplored in preclinical AD. Prior brain-predicted age studies have typically used structural MRI, but resting-state functional connectivity (FC) remains underexplored. Our model predicted age from FC in 391 cognitively normal, amyloid-negative controls (ages 18–89). We applied the trained model to 145 amyloid-negative, 151 preclinical AD, and 156 symptomatic AD participants to test group differences. The model accurately predicted age in the training set. FC-predicted brain age gaps (FC-BAG) were significantly older in symptomatic AD and significantly younger in preclinical AD compared to controls. There was minimal correspondence between networks predictive of age and AD. Elevated FC-BAG may reflect network disruption during symptomatic AD. Reduced FC-BAG in preclinical AD was opposite to the expected direction, and may reflect a biphasic response to preclinical AD pathology or may be driven by inconsistency between age-related vs. AD-related networks. Overall, FC-predicted brain age may be a sensitive AD biomarker. © 2022

Author Keywords
Alzheimer disease;  Brain aging;  fMRI;  Machine learning;  Resting-state functional connectivity

Funding details
National Institutes of HealthNIH1-R01-AG067505-01, 1S10RR022984-01A1, 5-R01-AG052550-03, 5-R01-AG057680-03, P01AG003991, P01AG026276, P30 AG066444, U19 AG024904, U19 AG032438
National Institute on AgingNIA
Japan Agency for Medical Research and DevelopmentAMED
Korea Health Industry Development InstituteKHIDI
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE

Document Type: Article
Publication Stage: Final
Source: Scopus

De novo variants of CSNK2B cause a new intellectual disability-craniodigital syndrome by disrupting the canonical Wnt signaling pathway
(2022) Human Genetics and Genomics Advances, 3 (3), art. no. 100111, .

Asif, M.^a b c , Kaygusuz, E.^b d , Shinawi, M.^e , Nickelsen, A.^f , Hsieh, T.-C.^g , Wagle, P.^h , Budde, B.S.^a , Hochscherf, J.ⁱ , Abdullah, U.^j , Höning, S.^b , Nienberg, C.^f , Lindenblatt, D.ⁱ , Noegel, A.A.^b c , Altmüller, J.^a k l , Thiele, H.^a , Motameny, S.^a , Fleischer, N.^m , Segal, I.ⁿ , Pais, L.^o , Tinschert, S.^p , Samra, N.N.^n q , Savatt, J.M.^r , Rudy, N.L.^s , De Luca, C.^t , Paola Fortugno^t u , White, S.M.^v w , Krawitz, P.^g , Hurst, A.C.E.^s , Niefind, K.ⁱ , Jose, J.^f , Brancati, F.^t u , Nürnberg, P.^a c , Hussain, M.S.^a b c , Italian Undiagnosed Diseases Network^x 

^a Cologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, 50931, Germany
^b Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, 50931, Germany
^c Center for Molecular Medicine Cologne (CMMC), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, 50931, Germany
^d Bilecik Şeyh Edebali University, Molecular Biology and Genetics, Gülümbe Campus, Bilecik, 11230, Turkey
^e Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
^f Institute of Pharmaceutical and Medicinal Chemistry, Westphalian Wilhelms-University, Münster, Germany
^g Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich Wilhelms, Universität Bonn, Bonn, Germany
^h Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
ⁱ Department of Chemistry, Institute of Biochemistry, University of Cologne, Cologne, Germany
^j University Institute of Biochemistry and Biotechnology (UIBB), PMAS-Arid Agriculture University, Rawalpindi, Pakistan
^k Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Core Facility Genomics, Charitéplatz 1, Berlin, 10117, Germany
^l Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
^m FDNA Inc., Boston, MA, United States
ⁿ Hospital Center, Safed, Israel
^o Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, United States
^p Zentrum Medizinische Genetik, Medizinische Universität, Innsbruck, Austria
^q Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
^r Genomic Medicine Institute, Geisinger, Danville, PA, United States
^s Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, United States
^t Department of Life, Health and Environmental Science, University of L’Aquila, L’Aquila67100, Italy
^u IRCCS, San Raffaele Roma, Roma, 00163, Italy
^v Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Melbourne, VIC, Australia
^w Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia

Abstract
CSNK2B encodes for casein kinase II subunit beta (CK2β), the regulatory subunit of casein kinase II (CK2), which is known to mediate diverse cellular pathways. Variants in this gene have been recently identified as a cause of Poirier-Bienvenu neurodevelopmental syndrome (POBINDS), but functional evidence is sparse. Here, we report five unrelated individuals: two of them manifesting POBINDS, while three are identified to segregate a new intellectual disability-craniodigital syndrome (IDCS), distinct from POBINDS. The three IDCS individuals carried two different de novo missense variants affecting the same codon of CSNK2B. Both variants, NP_001311.3; p.Asp32His and NP_001311.3; p.Asp32Asn, lead to an upregulation of CSNK2B expression at transcript and protein level, along with global dysregulation of canonical Wnt signaling. We found impaired interaction of the two key players DVL3 and β-catenin with mutated CK2β. The variants compromise the kinase activity of CK2 as evident by a marked reduction of phosphorylated β-catenin and consequent absence of active β-catenin inside nuclei of the patient-derived lymphoblastoid cell lines (LCLs). In line with these findings, whole-transcriptome profiling of patient-derived LCLs harboring the NP_001311.3; p.Asp32His variant confirmed a marked difference in expression of genes involved in the Wnt signaling pathway. In addition, whole-phosphoproteome analysis of the LCLs of the same subject showed absence of phosphorylation for 313 putative CK2 substrates, enriched in the regulation of nuclear β-catenin and transcription of the target genes. Our findings suggest that discrete variants in CSNK2B cause dominant-negative perturbation of the canonical Wnt signaling pathway, leading to a new craniodigital syndrome distinguishable from POBINDS. © 2022 The Authors

Author Keywords
CK2;  CK2α;  CK2β;  CSNK2B;  DVL3;  GestaltMatcher;  intellectual disability-craniodigital syndrome;  POBINDS;  whole transcriptome profiling;  whole-phosphoproteome profiling;  Wnt signaling;  β-catenin

Funding details
2635/8029/01, 2635/8326/01
National Heart, Lung, and Blood InstituteNHLBIR01 HG009141, UM1 HG008900
National Human Genome Research InstituteNHGRI
National Eye InstituteNEI
Broad Institute
Murdoch Children’s Research InstituteMCRI
Royal Children’s Hospital Foundation
Deutsche ForschungsgemeinschaftDFGNI 643/4-2
Universität zu KölnUoC381/2020

Document Type: Article
Publication Stage: Final
Source: Scopus

Generation of gene-corrected isogenic control cell lines from a DYT1 dystonia patient iPSC line carrying a heterozygous GAG mutation in TOR1A gene
(2022) Stem Cell Research, 62, art. no. 102807, . 

Akter, M.^a b , Cui, H.^a , Chen, Y.-H.^c , Ding, B.^a

^a Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, United States
^b Department of Biology, University of Louisiana at Lafayette, Lafayette, LA 70503, United States
^c Genome Engineering and iPSC Center (GEiC), Washington University in St LouisMO 63110, United States

Abstract
Childhood-onset torsin dystonia (DYT1) is a rare hereditary movement disorder and usually caused by a heterozygous GAG deletion (c.907–909) in the TOR1A gene (ΔE, p.Glu303del). The neuronal functions of torsin proteins and the pathogenesis of ΔE mutation are not clear. Previously, we have generated a hiPSC line from DYT1 patient fibroblast cells. In this study, we genetically corrected GAG deletion and obtained two isogenic control lines. These hiPSC lines contain the wild-type TOR1A sequence, showed the normal stem cell morphology and karyotype, expressed pluripotency markers, and differentiated into three germ layers, providing a valuable resource in DYT1 research. © 2022 The Author(s)

Funding details
National Institutes of HealthNIH
U.S. Department of DefenseDODW81XWH2010186
National Institute of Neurological Disorders and StrokeNINDSNS112910

Document Type: Article
Publication Stage: Final
Source: Scopus

Midfoot and ankle movement coordination during heel rise is disrupted in people with diabetes and peripheral neuropathy
(2022) Clinical Biomechanics, 96, art. no. 105662, . 

Jeong, H.-J.^a b , Cha, B.^c , Zellers, J.A.^d , Chen, L.^e , Hastings, M.K.^d

^a Orthopaedic and Rehabilitation Engineering Center, Marquette University, 1515 W. Wisconsin Ave., Milwaukee, WI 53233, United States
^b Department of Rehabilitation Sciences & Technology, University of Wisconsin-Milwaukee, PO Box 413, Milwaukee, WI 53201, United States
^c Gwangju Institute of Science and Technology 123, Cheomdangwagi-ro, Buk-gu, Gwangju, 61005, South Korea
^d Program in Physical Therapy, Washington University School of Medicine, 4444 Forest Park Ave., St. Louis, MO 63108, United States
^e Division of Biostatistics, Washington University School of Medicine in St. Louis, 660 S. Euclid Ave., St. Louis, MO 63110, United States

Abstract
Background: A heel rise task can be used to evaluate midfoot and ankle movement dysfunction in people with diabetes mellitus and peripheral neuropathy. Quantifying movement coordination during heel rise is important to better understand potentially detrimental movement strategies in people with foot pathologies; however, coordination and the impact of limited excursion on coordination is not well-understood in people with diabetes. Methods: Sixty patients with diabetes mellitus and peripheral neuropathy, and 22 older and 25 younger controls performed single-limb heel rise task. Midfoot (forefoot relative to hindfoot) sagittal and ankle (hindfoot relative to shank) sagittal and frontal kinematics were measured and normalized to time (0 to 100%). Cross-correlation coefficients were calculated across individuals in each group. A graphical illustration was used to interpret the relationship of midfoot and ankle excursion and cross-correlation coefficient during heel rise. Findings: People with diabetes mellitus and peripheral neuropathy showed significantly lower midfoot and ankle cross-correlation coefficients during heel rise compared to older controls (p = 0.003–0.007). There was no difference in the midfoot and ankle cross-correlation coefficients during heel rise for the older and younger controls (p = 0.059–0.425). The graphic data illustrated a trend of greater excursion of two joints and a higher cross-correlation coefficient. Some individuals with lower excursion showed a high cross-correlation coefficient. Interpretation: Foot pathologies, but not aging, impairs midfoot and ankle movement coordination during heel rise task. Investigating both movement coordination as well as joint excursion would better inform and characterize the dynamic movements of midfoot and ankle during heel rise task. © 2022

Author Keywords
Aging;  Coupling;  Foot;  Heel rise;  Peripheral neuropathy

Funding details
U.S. Department of Health and Human ServicesHHS
National Institute of Diabetes and Digestive and Kidney DiseasesNIDDKF32 DK123916, R01 DK107809
National Institute on Disability, Independent Living, and Rehabilitation ResearchNIDILRR90ARHF0006

Document Type: Article
Publication Stage: Final
Source: Scopus

Structural basis of SARM1 activation, substrate recognition, and inhibition by small molecules
(2022) Molecular Cell, 82 (9), pp. 1643-1659.e10. 

Shi, Y.^a , Kerry, P.S.^b , Nanson, J.D.^c , Bosanac, T.^d , Sasaki, Y.^e , Krauss, R.^d , Saikot, F.K.^c , Adams, S.E.^b , Mosaiab, T.^a , Masic, V.^a , Mao, X.^e , Rose, F.^a , Vasquez, E.^a , Furrer, M.^f , Cunnea, K.^b , Brearley, A.^b , Gu, W.^c , Luo, Z.^c , Brillault, L.^g , Landsberg, M.J.^c , DiAntonio, A.^h , Kobe, B.^c , Milbrandt, J.^e , Hughes, R.O.^d , Ve, T.^a

^a Institute for Glycomics, Griffith University, Southport, QLD 4222, Australia
^b Evotec (UK) Ltd., 114 Innovation Drive, Milton Park, Oxfordshire, UK, Abingdon, OX14 4RZ, United Kingdom
^c School of Chemistry and Molecular Biosciences, Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre, University of QueenslandQLD 4072, Australia
^d Disarm Therapeutics, a wholly-owned subsidiary of Eli Lilly & Co., Cambridge, MA, United States
^e Needleman Center for Neurometabolism and Axonal Therapeutics and Department of Genetics, Washington University School of Medicine in Saint Louis, St. Louis, MO, United States
^f Evotec SE, Manfred Eigen Campus, Essener Bogen 7, Hamburg, 22419, Germany
^g Centre for Microscopy and Microanalysis, The University of Queensland, Brisbane, Australia
^h Needleman Center for Neurometabolism and Axonal Therapeutics and Department of Developmental Biology, Washington University School of Medicine in Saint Louis, St. Louis, MO, United States

Abstract
The NADase SARM1 (sterile alpha and TIR motif containing 1) is a key executioner of axon degeneration and a therapeutic target for several neurodegenerative conditions. We show that a potent SARM1 inhibitor undergoes base exchange with the nicotinamide moiety of nicotinamide adenine dinucleotide (NAD+) to produce the bona fide inhibitor 1AD. We report structures of SARM1 in complex with 1AD, NAD+ mimetics and the allosteric activator nicotinamide mononucleotide (NMN). NMN binding triggers reorientation of the armadillo repeat (ARM) domains, which disrupts ARM:TIR interactions and leads to formation of a two-stranded TIR domain assembly. The active site spans two molecules in these assemblies, explaining the requirement of TIR domain self-association for NADase activity and axon degeneration. Our results reveal the mechanisms of SARM1 activation and substrate binding, providing rational avenues for the design of new therapeutics targeting SARM1. © 2022 The Authors

Author Keywords
allosteric activator;  ARM domain;  base exchange;  cryo-EM;  NADase;  orthosteric inhibitor;  TIR domain;  X-ray crystallography

Funding details
National Institutes of HealthNIHR01NS087632
Disarm TherapeuticsDE170100783
University of LeicesterUoL
Australian Research CouncilARCFL180100109, FT200100572
National Health and Medical Research CouncilNHMRC1071659, 1107804, 1108859, 1160570, 1196590
University of QueenslandUQWO 2019/236879 Al

Document Type: Article
Publication Stage: Final
Source: Scopus

Analysis of Stimulant Prescriptions and Drug-Related Poisoning Risk Among Persons Receiving Buprenorphine Treatment for Opioid Use Disorder
(2022) JAMA Network Open, 5 (5), p. e2211634. 

Mintz, C.M.^a , Xu, K.Y.^a , Presnall, N.J.^b , Hartz, S.M.^b , Levin, F.R.^c d , Scherrer, J.F.^e f , Bierut, L.J.^a , Grucza, R.A.^e f

^a Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
^b Department of Social Work, Washington University in St Louis, St Louis, MO, United States
^c Department of Psychiatry, College of Physicians and Surgeons of Columbia UniversityNY
^d Division of Substance Use Disorders, New York State Psychiatric InstituteNY
^e Department of Family and Community Medicine, St Louis University, St. Louis, MO, United States
^f Department of Health and Outcomes Research, St. Louis University, St Louis, MO, United States

Abstract
Importance: Stimulant medication use is common among individuals receiving buprenorphine for opioid use disorder (OUD). Associations between prescription stimulant use and treatment outcomes in this population have been understudied. Objectives: To investigate whether use of prescription stimulants was associated with (1) drug-related poisoning and (2) buprenorphine treatment retention. Design, Setting, and Participants: This retrospective, recurrent-event cohort study with a case-crossover design used a secondary analysis of administrative claims data from IBM MarketScan Commercial and Multi-State Medicaid databases from January 1, 2006, to December 31, 2016. Primary analyses were conducted from March 1 through August 31, 2021. Individuals aged 12 to 64 years with an OUD diagnosis and prescribed buprenorphine who experienced at least 1 drug-related poisoning were included in the analysis. Unit of observation was the person-day. Exposures: Days of active stimulant prescriptions. Main Outcomes and Measures: Primary outcomes were drug-related poisoning and buprenorphine treatment retention. Drug-related poisonings were defined using International Classification of Diseases, Ninth Revision, and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, codes; treatment retention was defined by continuous treatment claims until a 45-day gap was observed. Results: There were 13 778 567 person-days of observation time among 22 946 individuals (mean [SD] age, 32.8 [11.8] years; 50.3% men) who experienced a drug-related poisoning. Stimulant treatment days were associated with 19% increased odds of drug-related poisoning (odds ratio [OR], 1.19 [95% CI, 1.06-1.34]) compared with nontreatment days; buprenorphine treatment days were associated with 38% decreased odds of poisoning (OR, 0.62 [95% CI, 0.59-0.65]). There were no significant interaction effects between use of stimulants and buprenorphine. Stimulant treatment days were associated with decreased odds of attrition from buprenorphine treatment (OR, 0.64 [95% CI, 0.59-0.70]), indicating that stimulants were associated with 36% longer mean exposure to buprenorphine and its concomitant protection. Conclusions and Relevance: Among persons with OUD, use of prescription stimulants was associated with a modest increase in per-day risk of drug-related poisoning, but this risk was offset by the association between stimulant use and improved retention to buprenorphine treatment, which is associated with protection against overdose.

Document Type: Article
Publication Stage: Final
Source: Scopus

A transition to the American Academy of Sleep Medicine-recommended hypopnea definition in adults: initiatives of the Hypopnea Scoring Rule Task Force
(2022) Journal of Clinical Sleep Medicine: JCSM: Official Publication of the American Academy of Sleep Medicine, 18 (5), pp. 1419-1425. 

Berry, R.B.^a , Abreu, A.R.^b , Krishnan, V.^c , Quan, S.F.^d e , Strollo, P.J.^f , Malhotra, R.K.^g

^a University of Florida, Gainesville, FL, United States
^b Miller School of Medicine, University of Miami, Miami, FL, United States
^c Case Western Reserve University, MetroHealth Campus, Cleveland, OH, United States
^d Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
^e University of Arizona College of Medicine, Tucson, AZ, United States
^f University of Pittsburgh/Veterans Administration Pittsburgh Health System, Pittsburgh, PA, United States
^g Sleep Medicine Center, Washington University School of Medicine, St. Louis, MO, United States

Abstract
The American Academy of Sleep Medicine (AASM) recommends that hypopneas be identified using a definition that is based on a ≥ 30% decrease in airflow associated with a ≥ 3% reduction in the oxygen saturation or an arousal (H3A) for diagnosis of obstructive sleep apnea (OSA) in adults. This conflicts with the Centers for Medicare & Medicaid Services definition, which requires a ≥ 4% decrease in the oxygen saturation to identify a hypopnea (H4) and does not acknowledge arousals. In 2018, the AASM Board of Directors constituted a Hypopnea Scoring Rule Task Force with a mandate to “create a strategy for adoption and implementation of the AASM recommended adult hypopnea scoring criteria among members, payers and device manufacturers.” The task force initiated several activities including a survey of AASM-accredited sleep facilities and discussions with polysomnography software vendors. Survey results indicated that most sleep facilities scored polysomnograms using only the Centers for Medicare & Medicaid Services definition. Vendors indicated that they could easily support dual scoring. Informal testing among task force members’ sleep facilities confirmed there would be little additional work if dual scoring was performed. The task force convened several meetings of a working group of OSA content experts and interested parties, with the purpose of creating research recommendations to study the impact on relevant clinical outcomes using the different definitions of hypopnea. Several possible prospective and retrospective approaches were discussed with emphasis on the group of patients diagnosed with OSA based on an apnea-hypopnea index using H3A but not H4. Based on the deliberations of the working group, the Hypopnea Scoring Rule Task Force submitted recommendations to the AASM Foundation concerning research project strategies for potential grant funding. Further discussions within the Hypopnea Scoring Rule Task Force focused on developing advocacy initiatives among patient stakeholder groups to change payer policy. CITATION: Berry RB, Abreu AR, Krishnan V, Quan SF, Strollo PJ Jr, Malhotra RK. A transition to the American Academy of Sleep Medicine-recommended hypopnea definition in adults: initiatives of the Hypopnea Scoring Rule Task Force. J Clin Sleep Med. 2022;18(5):1419-1425. © 2022 American Academy of Sleep Medicine.

Author Keywords
apnea-hypopnea index;  hypopnea;  sleep scoring

Document Type: Article
Publication Stage: Final
Source: Scopus

Neurosteroid Modulation of GABAA Receptor Function by Independent Action at Multiple Specific Binding Sites
(2022) Current Neuropharmacology, 20 (5), pp. 886-890. 

Wang, L.^a b , Covey, D.F.^a c d , Akk, G.^a e , Evers, A.S.^a c e

^a Department of Anesthesiology, Tongji Medical College, Huazhong University of Science and Technology, Hubei, Wuhan, China
^b Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, Wuhan, China
^c Department of Developmental Biology (Pharmacology), Washington University School of Medicine, St. Louis, MO 63110, United States
^d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
^e The Taylor Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Neurosteroids are endogenous modulators of GABAA receptors that mediate anxiety, pain, mood and arousal. The 3-hydroxyl epimers, allopregnanolone (3α-OH) and epi-allopregnanolone (3β-OH) are both prevalent in the mammalian brain and produce opposite effects on GABAA receptor function, acting as positive and negative allosteric modulators, respectively. This Perspective provides a model to explain the actions of 3α-OH and 3β-OH neurosteroids. The model is based on evidence that the neurosteroid epimers bind to an overlapping subset of specific sites on GABAA receptors, with their net functional effect on channel gating being the sum of their independent effects at each site. © 2022 Bentham Science Publishers.

Author Keywords
affinity labeling;  desensitization;  GABAA receptors;  ion channels;  Neurosteroids;  structural biology

Funding details
National Institute of General Medical SciencesNIGMSR35GM140947, RO1GM108580, RO1GM108799
Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine in St. Louis

Document Type: Article
Publication Stage: Final
Source: Scopus

Neuronal origins of reduced accuracy and biases in economic choices under sequential offers
(2022) eLife, 11, . 

Shi, W.^a , Ballesta, S.^a , Padoa-Schioppa, C.^a b c

^a Department of Neuroscience, Washington University in St. Louis, St. Louis, United States
^b Department of Economics, Washington University in St. Louis, St. Louis, United States
^c Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, United States

Abstract
Economic choices are characterized by a variety of biases. Understanding their origins is a long-term goal for neuroeconomics, but progress on this front has been limited. Here, we examined choice biases observed when two goods are offered sequentially. In the experiments, rhesus monkeys chose between different juices offered simultaneously or in sequence. Choices under sequential offers were less accurate (higher variability). They were also biased in favor of the second offer (order bias) and in favor of the preferred juice (preference bias). Analysis of neuronal activity recorded in the orbitofrontal cortex revealed that these phenomena emerged at different computational stages. Lower choice accuracy reflected weaker offer value signals (valuation stage), the order bias emerged during value comparison (decision stage), and the preference bias emerged late in the trial (post-comparison). By neuronal measures, each phenomenon reduced the value obtained on average in each trial and was thus costly to the monkey. © 2022, Shi et al.

Author Keywords
behavioral economics;  decision making;  monkey;  neuroeconomics;  neuroscience;  orbitofrontal cortex;  rationality;  rhesus macaque

Document Type: Article
Publication Stage: Final
Source: Scopus

A framework for quantifying the effects of transcranial magnetic stimulation on motor recovery from hemiparesis: Corticomuscular network
(2022) Journal of Neural Engineering, 19 (2), art. no. 026053, . 

Tan, G.^a b , Wang, J.^c , Liu, J.^a , Sheng, Y.^a e , Xie, Q.^d , Liu, H.^e

^a State Key Laboratory of Mechanical System and Vibration, School of Mechanical Engineering, Shanghai Jiao Tong University, Shanghai, China
^b Department of Biomedical Engineering, Washington University in St. Louis, St Louis, MO, United States
^c Department of Rehabilitation Medicine, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
^d Clinical Neuroscience Center, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
^e State Key Laboratory of Robotics and System, School of Mechanical Engineering and Automation, Harbin Institute of Technology, Shenzhen, China

Abstract
Objective. Transcranial magnetic stimulation (TMS) is an experimental therapy for promoting motor recovery from hemiparesis. At present, hemiparesis patients’ responses to TMS are variable. To maximize its therapeutic potential, we need an approach that relates the electrophysiology of motor recovery and TMS. To this end, we propose corticomuscular network (CMN) representing the holistic motor system, including the cortico-cortical pathway, corticospinal tract, and muscle co-activation. Approach. CMN is made up of coherence between pairs of electrode signals and spatial locations of the electrodes. We associated coherence and graph features of CMN with Fugl-Meyer Assessment (FMA) for the upper extremity. Besides, we compared CMN between 8 patients with hemiparesis and 6 healthy controls and contrasted CMN of patients before and after a 1 Hz TMS. Main results. Corticomuscular coherence (CMC) correlated positively with FMA. The regression model between FMA and CMC between five pairs of channels had 0.99 adjusted and a p-value less than 0.01. Compared to healthy controls, CMN of patients tended to be a small-world network and was more interconnected with higher CMC. CMC between cortex and triceps brachii long head was higher in patients. 15 min 1 Hz TMS protocol induced coherence changes beyond the stimulation side and had a limited impact on CMN parameters that are related to motor recovery. Significance. CMN is a potential clinical approach to quantify rehabilitating progress. It also sheds light on the desirable electrophysiological effects of TMS based on which rehabilitating strategies can be optimized. © 2022 IOP Publishing Ltd.

Author Keywords
electroencephalogram;  electromyography;  graph theory;  hemiparesis;  transcranial magnetic stimulation

Funding details
2020B1515120064
National Natural Science Foundation of ChinaNSFC61733011

Document Type: Article
Publication Stage: Final
Source: Scopus

How Movie Events Engage ‘ Childrens’ Brains to Combine Visual Attention with Domain-Specific Processing Involving Number and Theory of Mind in a Cinematic Arena
(2022) Projections (New York), 16 (1), pp. 67-83. 

Levin, D.T.^a , Mattarella-Micke, A.^b , Lee, M.^c , Baker, L.^d , Bezdek, M.^e , McCandliss, B.^f

^a Professor of Psychology in the Department of Psychology and Human Development at Vanderbilt University
^b Michigan State University
^c Currently a doctoral student in Vanderbilt, University’s Psychological Sciences
^d Loyola University New Orleans and his PhD from Vanderbilt University
^e Department of Psychological and Brain Sciences, Washington University in St. Louis.
^f Carnegie Mellon University, University of Pittsburg

Abstract
Using functional magnetic resonance imaging, we tested the hypothesis that cinematic structure shapes variation in social-cognitive brain activity. Using our film, we completed an exploratory analysis of how activations in the temporal-parietal junction (TPJ), and the intraparietal sulcus (IPS) are shaped by variations in insert shots (e.g., shots showing objects that a character has looked at), and by character entrances and exits. We found that IPS and TPJ consistently responded to insert shots, and the correlation between TPJ and IPS responses significantly predicted the prevalence of belief inferences during the sequence. In addition, TPJ responded significantly to entrances and exits of characters. We also completed a qualitative analysis of moments during a sequence that induced relative peaks in TPJ and IPS responding. These analyses not only demonstrate that consistent brain responses can distinguish among meaningful variations in cinematic events but also that these analyses confirm and refine our understanding of the apparent specializations for visual attention and domain-specific event processing in parietal attention networks. © 2022. The Author/s. All Rights Reserved.

Author Keywords
cinema;  cognition;  number;  theory of mind

Funding details
National Science FoundationNSF
National Institute of Mental HealthNIMH
John Templeton FoundationJTF

Document Type: Article
Publication Stage: Final
Source: Scopus

Proposed research criteria for prodromal behavioural variant frontotemporal dementia
(2022) Brain, 145 (3), pp. 1079-1097. Cited 1 time.

Barker, M.S.^a , Gottesman, R.T.^b , Manoochehri, M.^a , Chapman, S.^a , Appleby, B.S.^c , Brushaber, D.^d , Devick, K.L.^d , Dickerson, B.C.^e , Domoto-Reilly, K.^f , Fields, J.A.^g , Forsberg, L.K.^h , Galasko, D.R.ⁱ , Ghoshal, N.^j , Goldman, J.^a b , Graff-Radford, N.R.^k , Grossman, M.^l , Heuer, H.W.^m , Hsiung, G.-Y.ⁿ , Knopman, D.S.^h , Kornak, J.^o , Litvan, I.ⁱ , Mackenzie, I.R.^p , Masdeu, J.C.^q , Mendez, M.F.^r s , Pascual, B.^q , Staffaroni, A.M.^m , Tartaglia, M.C.^t , Boeve, B.F.^h , Boxer, A.L.^m , Rosen, H.J.^m , Rankin, K.P.^m , Cosentino, S.^a b u , Rascovsky, K.^l , Huey, E.D.^a b v

^a Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center, New York, NY, United States
^b Department of Neurology, Columbia University Medical Center, New York, NY, United States
^c Department of Neurology, Case Western Reserve University, Cleveland, OH, United States
^d Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States
^e Department of Neurology, Frontotemporal Disorders Unit, Massachusetts General Hospital, Boston, MA, United States
^f Department of Neurology, University of Washington, Seattle, WA, United States
^g Division of Neurocognitive Disorders, Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, United States
^h Department of Neurology, Mayo Clinic, Rochester, MN, United States
ⁱ Department of Neuroscience, University of California, San Diego, CA, United States
^j Department of Neurology, Washington University, St. Louis, MO, United States
^k Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
^l Penn Frontotemporal Degeneration Center, Department of Neurology, University of Pennsylvania, Philadelphia, PA, United States
^m Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA, United States
ⁿ Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada
^o Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, United States
^p Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
^q Nantz National Alzheimer Center, Houston Methodist Neurological Institute, Houston, TX, United States
^r Department of Neurology, University of California, Los Angeles, CA, United States
^s Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, United States
^t Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON, Canada
^u Gertrude H. Sergievsky Center, Columbia University Medical Center, New York, NY, United States
^v Department of Psychiatry and New York Psychiatric Institute, Columbia University Medical Center, New York, United States

Abstract
At present, no research criteria exist for the diagnosis of prodromal behavioural variant frontotemporal dementia (bvFTD), though early detection is of high research importance. Thus, we sought to develop and validate a proposed set of research criteria for prodromal bvFTD, termed ‘mild behavioural and/or cognitive impairment in bvFTD’ (MBCI-FTD). Participants included 72 participants deemed to have prodromal bvFTD; this comprised 55 carriers of a pathogenic mutation known to cause frontotemporal lobar degeneration, and 17 individuals with autopsy-confirmed frontotemporal lobar degeneration. All had mild behavioural and/or cognitive changes, as judged by an evaluating clinician. Based on extensive clinical workup, the prodromal bvFTD group was divided into a Development Group (n = 22) and a Validation Group (n = 50). The Development Group was selected to be the subset of the prodromal bvFTD group for whom we had the strongest longitudinal evidence of conversion to bvFTD, and was used to develop the MBCI-FTD criteria. The Validation Group was the remainder of the prodromal bvFTD group and was used as a separate sample on which to validate the criteria. Familial non-carriers were included as healthy controls (n = 165). The frequencies of behavioural and neuropsychiatric features, neuropsychological deficits, and social cognitive dysfunction in the prodromal bvFTD Development Group and healthy controls were assessed. Based on sensitivity and specificity analyses, seven core features were identified: Apathy without moderate-severe dysphoria, behavioural disinhibition, irritability/agitation, reduced empathy/sympathy, repetitive behaviours (simple and/or complex), joviality/gregariousness, and appetite changes/hyperorality. Supportive features include a neuropsychological profile of impaired executive function or naming with intact orientation and visuospatial skills, reduced insight for cognitive or behavioural changes, and poor social cognition. Three core features or two core features plus one supportive feature are required for the diagnosis of possible MBCI-FTD; probable MBCI-FTD requires imaging or biomarker evidence, or a pathogenic genetic mutation. The proposed MBCI-FTD criteria correctly classified 95% of the prodromal bvFTD Development Group, and 74% of the prodromal bvFTD Validation Group, with a false positive rate of <10% in healthy controls. Finally, the MBCI-FTD criteria were tested on a cohort of individuals with prodromal Alzheimer’s disease, and the false positive rate of diagnosis was 11-16%. Future research will need to refine the sensitivity and specificity of these criteria, and incorporate emerging biomarker evidence. © 2022 The Author(s) (2022). Published by Oxford University Press on behalf of the Guarantors of Brain.

Author Keywords
behavioural variant frontotemporal dementia;  criteria;  mild behavioural impairment;  mild cognitive impairment;  prodromal

Document Type: Article
Publication Stage: Final
Source: Scopus

Ion behavior in the selectivity filter of HCN1 channels
(2022) Biophysical Journal, . 

Ahrari, S.^a , Ozturk, T.N.^b c , D’Avanzo, N.^a

^a Département de pharmacologie et physiologie, Université de Montréal, Montréal, Canada
^b Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis, St. Louis, Missouri, United States
^c Theoretical Molecular Biophysics Laboratory, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States

Abstract
Hyperpolarization-activated cyclic-nucleotide gated channels (HCNs) are responsible for the generation of pacemaker currents (If or Ih) in cardiac and neuronal cells. Despite the overall structural similarity to voltage-gated potassium (Kv) channels, HCNs show much lower selectivity for K+ over Na+ ions. This increased permeability to Na+ is critical to their role in membrane depolarization. HCNs can also select between Na+ and Li+ ions. Here, we investigate the unique ion selectivity properties of HCNs using molecular-dynamics simulations. Our simulations suggest that the HCN1 pore is flexible and dilated compared with Kv channels with only one stable ion binding site within the selectivity filter. We also observe that ion coordination and hydration differ within the HCN1 selectivity filter compared with those in Kv and cyclic-nucleotide gated channels. Additionally, the C358T mutation further stabilizes the symmetry of the binding site and provides a more fit space for ion coordination, particularly for Li+. © 2022 Biophysical Society

Author Keywords
HCN1;  ion channel;  ion selectivity;  MD simulations

Funding details
Compute Canada
Canadian Institutes of Health ResearchIRSCFRN 173388
Natural Sciences and Engineering Research Council of CanadaNSERC
Université de MontréalUDEM

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Randomized phase 2 study of ACE-083, a muscle-promoting agent, in facioscapulohumeral muscular dystrophy
(2022) Muscle and Nerve, . 

Statland, J.M.^a , Campbell, C.^b , Desai, U.^c , Karam, C.^d , Díaz-Manera, J.^e f g , Guptill, J.T.^h , Korngut, L.ⁱ , Genge, A.^j , Tawil, R.N.^k , Elman, L.^l , Joyce, N.C.^m , Wagner, K.R.ⁿ , Manousakis, G.^o , Amato, A.A.^p , Butterfield, R.J.^q , Shieh, P.B.^r , Wicklund, M.^s , Gamez, J.^t , Bodkin, C.^u , Pestronk, A.^v , Weihl, C.C.^v , Vilchez-Padilla, J.J.^w x , Johnson, N.E.^y , Mathews, K.D.^z , Miller, B.^aa , Leneus, A.^aa , Fowler, M.^aa , van de Rijn, M.^aa , Attie, K.M.^aa

^a Department of Neurology, University of Kansas Medical Center, Kansas City, KS, United States
^b Department of Pediatrics and Clinical Neurological Sciences, University of Western Ontario, London, ON, Canada
^c Carolinas MDA Care Center, Atrium Health, Charlotte, NC, United States
^d Neuromuscular Division, Oregon Health & Science University, Portland, OR, United States
^e Neuromuscular Diseases Unit, Neurology Department, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain
^f Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain
^g John Walton Muscular Dystrophy Research Centre, Newcastle University Translational and Clinical Research Institute, Newcastle, United Kingdom
^h Department of Neurology, Duke University School of Medicine, Durham, NC, United States
ⁱ University of Calgary, Calgary, AB, Canada
^j Montreal Neurological Institute, Montreal, QC, Canada
^k University of Rochester School of Medicine, Rochester, NY, United States
^l University of Pennsylvania, Philadelphia, PA, United States
^m University of California Davis Medical Center, Davis, CA, United States
ⁿ Johns Hopkins School of Medicine, Kennedy Krieger Institute, Baltimore, MD, United States
^o Department of Neurology, University of Minnesota, Minneapolis, MN, United States
^p Brigham and Women’s Hospital, Boston, MA, United States
^q Departments of Neurology and Pediatrics, University of Utah, Salt Lake City, UT, United States
^r University of California Los Angeles, Los Angeles, CA, United States
^s University of Colorado, Aurora, CO, United States
^t Department of Medicine, GMA Clinic, European Reference Network on Rare Neuromuscular Diseases (ERN EURO-NMD) and Universitat Autònoma de Barcelona, Barcelona, Spain
^u Indiana University School of Medicine, Indianapolis, IN, United States
^v Washington University School of Medicine, St. Louis, MO, United States
^w Hospital UIP La Fe, Neuromuscular Reference Centre, Valencia, Spain
^x Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain
^y Virginia Commonwealth University, Richmond, VA, United States
^z Carver College of Medicine, University of Iowa, Iowa City, IA, United States
^aa Acceleron Pharma, Cambridge, MA, United States

Abstract
Introduction/Aims: Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive muscular dystrophy without approved therapies. In this study we evaluated whether locally acting ACE-083 could safely increase muscle volume and improve functional outcomes in adults with FSHD. Methods: Participants were at least 18 years old and had FSHD1/FSHD2. Part 1 was open label, ascending dose, assessing safety and tolerability (primary objective). Part 2 was randomized, double-blind for 6 months, evaluating ACE-083240 mg/muscle vs placebo injected bilaterally every 3 weeks in the biceps brachii (BB) or tibialis anterior (TA) muscles, followed by 6 months of open label. Magnetic resonance imaging measures included total muscle volume (TMV; primary objective), fat fraction (FF), and contractile muscle volume (CMV). Functional measures included 6-minute walk test, 10-meter walk/run, and 4-stair climb (TA group), and performance of upper limb midlevel/elbow score (BB group). Strength, patient-reported outcomes (PROs), and safety were also evaluated. Results: Parts 1 and 2 enrolled 37 and 58 participants, respectively. Among 55 participants evaluable in Part 2, the least-squares mean (90% confidence interval, analysis of covariance) treatment difference for TMV was 16.4% (9.8%-23.0%) in the BB group (P <.0001) and 9.5% (3.2%-15.9%) in the TA group (P =.01). CMV increased significantly in the BB and TA groups and FF decreased in the TA group. There were no consistent improvements in functional or PRO measures in either group. The most common adverse events were mild or moderate injection-site reactions. Discussion: Significant increases in TMV with ACE-083 vs placebo did not result in consistent functional or PRO improvements with up to 12 months of treatment. © 2022 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.

Author Keywords
controlled trial;  facioscapulohumeral muscular dystrophy;  FSHD;  randomized

Funding details
PI16/01673, PI19/00593
National Institutes of HealthNIH
Centers for Disease Control and PreventionCDCDD19‐002
U.S. Food and Drug AdministrationFDA7R01FD006071‐02
National Institute of Neurological Disorders and StrokeNINDS4K23NS091511, R01NS104010
Genzyme
Muscular Dystrophy AssociationMDA
CSL Behring
Boehringer Ingelheim
FSH Society
School of Public Health, University of California BerkeleyUCB
Sanofi Genzyme
AveXis
Sarepta TherapeuticsSRPT

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Using Digital Technology to Overcome Racial Disparities in Child and Adolescent Psychiatry
(2022) Journal of the American Academy of Child and Adolescent Psychiatry, . 

Jansen, M.O.^a , Brown, T.R.^a b , Xu, K.Y.^a , Glowinski, A.L.^a b c

^a Washington University School of Medicine, St. Louis, Missouri, United States
^b William Greenleaf Eliot Division of Child Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^c UCSF Weill Institute for Neurosciences, University of California, San Francisco

Funding details
National Institutes of HealthNIHR25 MH112473-01

Document Type: Editorial
Publication Stage: Article in Press
Source: Scopus

Transcriptomic mapping uncovers Purkinje neuron plasticity driving learning
(2022) Nature, . 

Chen, X.^a h , Du, Y.^b , Broussard, G.J.^c , Kislin, M.^c , Yuede, C.M.^d , Zhang, S.^b , Dietmann, S.^e f , Gabel, H.^a , Zhao, G.^a , Wang, S.S.-H.^c , Zhang, X.^b , Bonni, A.^a g

^a Department of Neuroscience, Washington University School of Medicine, St Louis, MO, United States
^b Shanghai East Hospital, Tongji University, School of Medicine, Shanghai, China
^c Neuroscience Institute, Washington Road, Princeton University, Princeton, NJ, United States
^d Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
^e Developmental Biology, Washington University School of Medicine, St Louis, MO, United States
^f Insitute for Informatics, Washington University School of Medicine, St Louis, MO, United States
^g Neuroscience and Rare Diseases, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, Basel, Switzerland
^h Department of Neurology, Hope Center for Neurological Disorders,Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Cellular diversification is critical for specialized functions of the brain including learning and memory1. Single-cell RNA sequencing facilitates transcriptomic profiling of distinct major types of neuron2–4, but the divergence of transcriptomic profiles within a neuronal population and their link to function remain poorly understood. Here we isolate nuclei tagged5 in specific cell types followed by single-nucleus RNA sequencing to profile Purkinje neurons and map their responses to motor activity and learning. We find that two major subpopulations of Purkinje neurons, identified by expression of the genes Aldoc and Plcb4, bear distinct transcriptomic features. Plcb4+, but not Aldoc+, Purkinje neurons exhibit robust plasticity of gene expression in mice subjected to sensorimotor and learning experience. In vivo calcium imaging and optogenetic perturbation reveal that Plcb4+ Purkinje neurons have a crucial role in associative learning. Integrating single-nucleus RNA sequencing datasets with weighted gene co-expression network analysis uncovers a learning gene module that includes components of FGFR2 signalling in Plcb4+ Purkinje neurons. Knockout of Fgfr2 in Plcb4+ Purkinje neurons in mice using CRISPR disrupts motor learning. Our findings define how diversification of Purkinje neurons is linked to their responses in motor learning and provide a foundation for understanding their differential vulnerability to neurological disorders. © 2022, The Author(s), under exclusive licence to Springer Nature Limited.

Funding details
National Institutes of HealthNIHNS041021
Washington University in St. LouisWUSTL
Foundation for Barnes-Jewish HospitalFBJH3770, 4642
McDonnell Center for Systems Neuroscience
St. Louis Children’s HospitalSLCHCDI-CORE-2015-505, CDI-CORE-2019-813
National Natural Science Foundation of ChinaNSFC82025020, F32 MH120887, R01 MH115750, R01 NS045193
National Key Research and Development Program of ChinaNKRDPC2018YFA0108000, 2019YFA0110300

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Comparative Effectiveness Associated With Buprenorphine and Naltrexone in Opioid Use Disorder and Cooccurring Polysubstance Use
(2022) JAMA Network Open, p. E2211363. 

Xu, K.Y.^a , Mintz, C.M.^a , Presnall, N.^a , Bierut, L.J.^a b , Grucza, R.A.^a c

^a Health and Behavior Research Center, Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^b Alvin J. Siteman Cancer Center, Barnes Jewish Hospital and Washington University, School of Medicine, St. Louis, MO, United States
^c Departments of Family and Community Medicine and Health and Outcomes Research, St. Louis University, St. Louis, MO, United States

Abstract
Importance: Despite prevalent polysubstance use, treatment patterns and outcomes for individuals with opioid use disorder (OUD) and cooccurring substance use disorders (SUD) are understudied. Objective: To evaluate the distribution of buprenorphine and naltrexone initiation among individuals with OUD with vs without cooccurring SUD and to assess the comparative effectiveness associated with buprenorphine and naltrexone against drug-related poisonings. Design, Setting, and Participants: This observational comparative effectiveness study used insurance claims from 2011 to 2016 from the US IBM MarketScan databases to study initiation of medications for OUD (MOUD) among treatment-seeking individuals aged 12 to 64 years with a primary diagnosis of OUD. Cooccurring SUD was defined as SUD diagnosed concurrent with or in the 6 months prior to OUD treatment initiation. Treatment was codified as psychosocial treatment without MOUD or initiation or buprenorphine or naltrexone (including extended-release or oral). Methadone recipients were excluded from analysis. Data were analyzed from February 3, 2021, through February 26, 2022. Exposures: MOUD. Main Outcomes and Measures: Associations between cooccurring SUD diagnoses with treatment type were assessed with multivariable regression. The association of drug-related poisoning admissions with days covered with buprenorphine or naltrexone prescriptions vs days without prescriptions was assessed among MOUD initiators. Odds ratios from within-person fixed effects models were estimated as a function of MOUD and stratified by cooccurring SUDs. Results: Among 179280 individuals with OUD (mean [SD] age, 33.2 [11.0] years; 90196 [50.5%] men), 102930 (57.4%) received psychosocial treatment without MOUD. Across 47488 individuals with cooccurring SUDs, 33449 (70.4%) did not receive MOUD, whereas across 131792 individuals without cooccurring SUDs, 69481 (52.7%) did not receive MOUD. Cooccurring SUD was associated with decreased odds of initiating buprenorphine (risk ratio [RR], 0.55 [95% CI, 0.54-0.56]) but increased odds of initiating naltrexone (extended release: RR, 1.12 [95% CI, 1.05-1.20]; oral: RR, 1.95 [95% CI, 1.86-2.03]). Among 12485 individuals initiating MOUD who experienced at least 1 drug-related poisoning during insurance enrollment, buprenorphine treatment days were associated with decreased poisonings compared with days without MOUD for individuals with cooccurring SUD (odds ratio [OR], 0.56 [95% CI, 0.48-0.65]) and individuals without cooccurring SUD (OR, 0.57 [95% CI, 0.53-0.63]), with comparable associations observed for extended-release naltrexone. No protective association was observed for oral naltrexone. Conclusions and Relevance: These findings suggest that individuals with OUD and polysubstance use were less likely to initiate buprenorphine and naltrexone than individuals without polysubstance use. Among individuals initiating MOUD, polysubstance use was associated with decreased buprenorphine and increased naltrexone initiation, despite buprenorphine’s protective associations against drug-related poisoning.. © 2022 American Medical Association. All rights reserved.

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Do Recall and Recognition Lead to Different Retrieval Experiences? (2022) American Journal of Psychology, 135 (1), pp. 33-43.

Uner, O.^a , Roediger, H.L., III^b 

^a Indiana University, United States
^b Washington University in St. Louis, United States

Abstract
The relation between recall and recognition has been debated in various contexts, and researchers have asked whether these tasks lie on a single continuum depending on the type of retrieval cues or whether they represent distinctly different processes. In the current experiment, we considered the continuity hypothesis, which states that recall and recognition are different only in cue information available, and we asked whether retrieval experience during various tests can further inform the nature of this relationship. Participants studied lists of 5-letter words and were tested with either no overt cues (free recall) or with the first 2 letters, first 3 letters, first 4 letters, or all 5 letters (recognition) of a word as retrieval cues. We used the remember/know/ guess paradigm and asked participants to report their retrieval experience to infer the underlying experiences of recollection and familiarity. Accuracy increased continuously as the number of letter cues increased. This continuity was reflected in experiences of recollection, but familiarity increased nonlinearly across cue conditions. Our results show some support for the continuity hypothesis; however, recall and recognition do differ in that recall relies more heavily on recollection, whereas recognition relies on both recollection and familiarity © 2022. by the Board of Trustees of the University of Illinois

Author Keywords
Familiarity;  Recall;  Recognition;  Recollection;  Remember/know

Funding details
James S. McDonnell FoundationJSMF

Document Type: Article
Publication Stage: Final
Source: Scopus

Comparison of sonication patterns and microbubble administration strategies for focused ultrasound-mediated large-volume drug delivery
(2022) IEEE Transactions on Biomedical Engineering, . 

Gong, Y.^a , Ye, D.^b , Chien, C.^b , Yue, Y.^b , Chen, H.^c

^a Department of Biomedical Engineering, Washington University in St Louis, 7548 St Louis, Missouri, United States
^b Biomedical Engineering, Washington University in St Louis, 7548 St Louis, Missouri, United States
^c Radiation Oncology, Washington University in St Louis, 7548 St Louis, Missouri, United States, 63130-4899

Abstract
Objective: Diffuse intrinsic pontine glioma (DIPG) is the most common and deadliest brainstem tumor in children. Focused ultrasound combined with microbubble-mediated BBB opening (FUS-BBBO) is a promising technique for overcoming the frequently intact blood-brain barrier (BBB) in DIPG to enhance therapeutic drug delivery to the brainstem. Since DIPG is highly diffusive, large-volume FUS-BBBO is needed to cover the entire tumor region. The objective of this study was to determine the optimal treatment strategy to achieve efficient and homogeneous large-volume BBBO at the brainstem for the delivery of an immune checkpoint inhibitor, anti-PD-L1 antibody (aPD-L1). Methods: Two critical parameters for large-volume FUS-BBBO, multi-point sonication pattern (interleaved vs. serial) and microbubble injection method (bolus vs. infusion), were evaluated by treating mice with four combinations of these two parameters. 2D Passive cavitation imaging (PCI) was performed for monitoring the large-volume sonication. Results: Interleaved sonication combined with bolus injection of microbubbles resulted in 1.29 to 2.06 folds higher efficiency than other strategies as evaluated by Evans blue extravasation. The average coefficient of variation of the Evans blue delivery was 0.66 for interleaved sonication with bolus injection, compared to 0.680.88 for all other strategies. Similar trend was also observed in the quantified total cavitation dose and coefficient of variance of the cavitation dose. This strategy was then applied to deliver fluorescently labeled aPD-L1 quantified using fluorescence imaging. A strong segmented linear correlation (R2=0.81) was found between the total cavitation dose and the total fluorescence intensity of aPD-L1 delivered at different sonication pressures (0.15 MPa, 0.30 MPa, and 0.45 MPa). Significance: Findings from this study suggest that efficient and homogeneous large-volume FUS-BBBO can be achieved by interleaved sonication combined with bolus injection of microbubbles, and the efficiency and homogeneity can be monitored by PCI. IEEE

Author Keywords
Blood-brain barrier;  Brainstem;  Brainstem drug delivery;  Drug delivery;  Focused ultrasound;  Immune checkpoint inhibitor;  Mice;  Monitoring;  Passive cavitation imaging;  Safety;  Tumors;  Ultrasonic imaging

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Large scale genotype- and phenotype-driven machine learning in Von Hippel-Lindau disease
(2022) Human Mutation, . 

Chiorean, A.^a , Farncombe, K.M.^b , Delong, S.^a , Andric, V.^a , Ansar, S.^a , Chan, C.^a , Clark, K.^c d , Danos, A.M.^c d , Gao, Y.^a , Giles, R.H.^e , Goldenberg, A.^f , Jani, P.^a , Krysiak, K.^c d , Kujan, L.^c d , Macpherson, S.^a , Maher, E.R.^g h , McCoy, L.G.^a , Salama, Y.^a , Saliba, J.^c d , Sheta, L.^c d , Griffith, M.^c d , Griffith, O.L.^c d , Erdman, L.^f , Ramani, A.^f , Kim, R.H.^i j k l

^a Department of Medicine, Division of Medical Oncology, University Health Network, Toronto, ON, Canada
^b Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
^c Department of Medicine, Division of Oncology, Washington University School of Medicine, Washington University, St. Louis, MO, United States
^d McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, United States
^e International Kidney Cancer Coalition, Duivendrecht-Amsterdam, Duivendrecht, Netherlands
^f Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
^g Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom
^h NIHR Cambridge Biomedical Research Centre, Cambridge Biomedical Campus, Cambridge, United Kingdom
ⁱ Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network and Sinai Health System, Toronto, ON, Canada
^j Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada
^k Ontario Institute for Cancer Research, Toronto, ON, Canada
^l Department of Medicine, University of Toronto, Toronto, ON, Canada

Abstract
Von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome where individuals are predisposed to tumor development in the brain, adrenal gland, kidney, and other organs. It is caused by pathogenic variants in the VHL tumor suppressor gene. Standardized disease information has been difficult to collect due to the rarity and diversity of VHL patients. Over 4100 unique articles published until October 2019 were screened for germline genotype–phenotype data. Patient data were translated into standardized descriptions using Human Genome Variation Society gene variant nomenclature and Human Phenotype Ontology terms and has been manually curated into an open-access knowledgebase called Clinical Interpretation of Variants in Cancer. In total, 634 unique VHL variants, 2882 patients, and 1991 families from 427 papers were captured. We identified relationship trends between phenotype and genotype data using classic statistical methods and spectral clustering unsupervised learning. Our analyses reveal earlier onset of pheochromocytoma/paraganglioma and retinal angiomas, phenotype co-occurrences and genotype–phenotype correlations including hotspots. It confirms existing VHL associations and can be used to identify new patterns and associations in VHL disease. Our database serves as an aggregate knowledge translation tool to facilitate sharing information about the pathogenicity of VHL variants. © 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.

Author Keywords
CIViC;  genotype–phenotype;  machine learning;  spectral clustering;  Von Hippel-Lindau

Funding details
U24CA237719
National Institutes of HealthNIHK22CA188163, R00HG007940
National Human Genome Research InstituteNHGRI
National Cancer InstituteNCIU01CA209936
National Center for Advancing Translational SciencesNCATS
Institute of Clinical and Translational SciencesICTSUL1TR002345
Children’s Discovery InstituteCDI
Washington University School of Medicine in St. LouisWUSM
St. Louis Children’s HospitalSLCH

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

RapidPlan hippocampal sparing whole brain model version 2—how far can we reduce the dose?
(2022) Medical Dosimetry, . 

Liu, H.^a b , Clark, R.^a , Magliari, A.^a , Foster, R.^c , Reynoso, F.^d , Schmidt, M.^d , Gondi, V.^c , Abraham, C.^d , Curry, H.^a , Kupelian, P.^a , Khuntia, D.^a , Beriwal, S.^a e

^a Varian Medical Systems Inc, Palo Alto, CA, United States
^b Medical College of Wisconsin, Department of Radiation Oncology, Wauwatosa, WI, United States
^c Northwestern Medicine Cancer Center Warrenville and Northwestern Medicine Proton Center, Warrenville, IL, United States
^d Washington University School of Medicine in St. Louis, Department of Radiation Oncology, MO, St. Louis
^e Allegheny Health Network Cancer Institute, Pittsburgh, PA, United States

Abstract
Whole-brain radiotherapy has been the standard palliative treatment for patients with brain metastases due to its effectiveness, availability, and ease of administration. Recent clinical trials have shown that limiting radiation dose to the hippocampus is associated with decreased cognitive toxicity. In this study, we updated an existing Knowledge Based Planning model to further reduce dose to the hippocampus and improve other dosimetric plan quality characteristics. Forty-two clinical cases were contoured according to guidelines. A new dosimetric scorecard was created as an objective measure for plan quality. The new Hippocampal Sparing Whole Brain Version 2 (HSWBv2) model adopted a complex recursive training process and was validated with five additional cases. HSWBv2 treatment plans were generated on the Varian HalcyonTM and TrueBeamTM systems and compared against plans generated from the existing (HSWBv1) model released in 2016. On the HalcyonTM platform, 42 cases were re-planned. Hippocampal D100% from HSWBv2 and HSWBv1 models had an average dose of 5.75 Gy and 6.46 Gy, respectively (p &lt; 0.001). HSWBv2 model also achieved a hippocampal Dmean of 7.49 Gy, vs 8.10 Gy in HSWBv1 model (p &lt; 0.001). Hippocampal D0.03CC from HSWBv2 model was 9.86 Gy, in contrast to 10.57 Gy in HSWBv1 (p &lt; 0.001). For PTV_3000, D98% and D2% from HSWBv2 model were 28.27 Gy and 31.81 Gy, respectively, compared to 28.08 Gy (p = 0.020) and 32.66 Gy from HSWBv1 (p &lt; 0.001). Among several other dosimetric quality improvements, there was a significant reduction in PTV_3000 V105% from 35.35% (HSWBv1) to 6.44% (HSWBv2) (p &lt; 0.001). On 5 additional validation cases, dosimetric improvements were also observed on TrueBeamTM. In comparison to published data, the HSWBv2 model achieved higher quality hippocampal avoidance whole brain radiation therapy treatment plans through further reductions in hippocampal dose while improving target coverage and dose conformity/homogeneity. HSWBv2 model is shared publicly. © 2022 The Authors

Author Keywords
Halcyon;  Hippocampal Avoidance Whole Brain Radiotherapy;  Knowledge Based Planning;  RapidPlan;  TrueBeam

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Heterozygous variants in CTR9, which encodes a major component of the PAF1 complex, are associated with a neurodevelopmental disorder
(2022) Genetics in Medicine, . 

Meuwissen, M.^a , Verstraeten, A.^a , Ranza, E.^b , Iwaszkiewicz, J.^c , Bastiaansen, M.^a , Mateiu, L.^a , Nemegeer, M.^a , Meester, J.A.N.^a , Afenjar, A.^d , Amaral, M.^e , Ballhausen, D.^f , Barnett, S.^g , Barth, M.^h , Asselbergh, B.^i j , Spaas, K.^i j , Heeman, B.^j k , Bassetti, J.^l , Blackburn, P.^m , Schaer, M.ⁿ , Blanc, X.^b , Zoete, V.^c o , Casas, K.^p , Courtin, T.^q , Doummar, D.^r , Guerry, F.^b , Keren, B.^q , Pappas, J.^s , Rabin, R.^s , Begtrup, A.^t , Shinawi, M.^u , Vulto-van Silfhout, A.T.^v , Kleefstra, T.^v , Wagner, M.^w x , Ziegler, A.^h , Schaefer, E.^y , Gerard, B.^z , De Bie, C.I.^aa , Holwerda, S.J.B.^aa , Abbot, M.A.^ab , Antonarakis, S.E.^b , Loeys, B.^a v

^a Center for Medical Genetics, Faculty of Medicine and Health Sciences, Antwerp University Hospital, University of Antwerp, Edegem, Belgium
^b Medigenome, Swiss Institute of Genomic Medicine, Geneva, Switzerland
^c Molecular Modeling Group, Swiss Institute of Bioinformatics, Lausanne, Switzerland
^d Centre de Référence Malformations et Maladies Congénitales du Cervelet et Déficiences Intellectuelles de Causes Rares, Département de Génétique et Embryologie Médicale, Hôpital Trousseau, Sorbonne Université, AP-HP, Paris, France
^e HudsonAlpha Institute for Biotechnology, Huntsville, AL, United States
^f Pediatric Metabolic Unit, Pediatrics, Woman-Mother-Child Department, University of Lausanne and University Hospital of Lausanne, Lausanne, Switzerland
^g Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
^h Biochemistry and Genetics Department, University Hospital of Angers, Angers, France
ⁱ Neuromics Support Facility, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium
^j Department of Biomedical Sciences, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Antwerp, Belgium
^k Applied and Translational Neurogenomics, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium
^l Division of Medical Genetics, Department of Pediatrics, Weill Cornell Medicine, New York, NY, United States
^m Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, United States
ⁿ Autism Brain & Behavior Laboratory, Department Psychiatry, Faculty of Medicine, University of Geneva, Geneva, Switzerland
^o Ludwig Institute for Cancer Research, Department of Fundamental Oncology, Faculty of Biology and Medicine, Lausanne University, Lausanne, Epalinges, Switzerland
^p Medical Genetics, Sanford Broadway Clinic, ND, Fargo
^q Department of Genetics, AP-HP, La Pitié-Salpêtrière Hospital, Sorbonne Université, Paris
^r Neuropédiatrie, AP-HP, Hôpital d’enfants Armand Trousseau, Sorbonne Université, Paris
^s NYU Langone Medical Center, New York, NY, United States
^t GeneDx, Gaithersburg, MD, United States
^u Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine in St. Louis, MO, St. Louis
^v Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
^w Institute of Human Genetics, Technical University München, Munich, Germany
^x Institute for Neurogenomics, Helmholtz Zentrum München, Neuherberg, Germany
^y Service de Génétique Médicale, Institut de Génétique Médicale d’Alsace, Hopitaux Universitaires de Strasbourg, Strasbourg, France
^z Laboratoires de Diagnostic Génétique, Institut de Génétique Médicale d’Alsace, Hopitaux Universitaires de Strasbourg, Strasbourg, France
^aa Department of Clinical Genetics, University Medical Center Utrecht, Utrecht, Netherlands
^ab Medical Genetics, Department of Pediatrics, University of Massachusetts Medical School-Baystate, Springfield, MA, United States

Abstract
Purpose: CTR9 is a subunit of the PAF1 complex (PAF1C) that plays a crucial role in transcription regulation by binding CTR9 to RNA polymerase II. It is involved in transcription-coupled histone modification through promoting H3K4 and H3K36 methylation. We describe the clinical and molecular studies in 13 probands, harboring likely pathogenic CTR9 missense variants, collected through GeneMatcher. Methods: Exome sequencing was performed in all individuals. CTR9 variants were assessed through 3-dimensional modeling of the activated human transcription complex Pol II-DSIF-PAF-SPT6 and the PAF1/CTR9 complex. H3K4/H3K36 methylation analysis, mitophagy assessment based on tetramethylrhodamine ethyl ester perchlorate immunofluorescence, and RNA-sequencing in skin fibroblasts from 4 patients was performed. Results: Common clinical findings were variable degrees of intellectual disability, hypotonia, joint hyperlaxity, speech delay, coordination problems, tremor, and autism spectrum disorder. Mild dysmorphism and cardiac anomalies were less frequent. For 11 CTR9 variants, de novo occurrence was shown. Three-dimensional modeling predicted a likely disruptive effect of the variants on local CTR9 structure and protein interaction. Additional studies in fibroblasts did not unveil the downstream functional consequences of the identified variants. Conclusion: We describe a neurodevelopmental disorder caused by (mainly) de novo variants in CTR9, likely affecting PAF1C function. © 2022 American College of Medical Genetics and Genomics

Author Keywords
Autism spectrum disorder;  CTR9;  Intellectual disability;  Neurodevelopmental disorder;  PAF1C

Funding details
2013T093
Marfan Foundation
European CommissionEC
European Research CouncilERC12X8520N, 769036, ERC-COG-2017-771945
Fonds Wetenschappelijk OnderzoekFWOG040221N, G042321N, G044720N
Universiteit Antwerpen40709, GOA 33933

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Ecological Momentary Assessment of Real-World Functional Behaviors in Individuals With Stroke: A Longitudinal Observational Study
(2022) Archives of Physical Medicine and Rehabilitation, . 

Bui, Q.^a , Kaufman, K.J.^b , Pham, V.^c , Lenze, E.J.^c , Lee, J.-M.^d , Mohr, D.C.^e f , Fong, M.W.M.^d g h , Metts, C.L.ⁱ , Tomazin, S.E.^b , Wong, A.W.K.^b g j

^a From the Division of Biostatistics, Washington University, School of Medicine, St Louis, Missouri, United States
^b Center for Rehabilitation Outcomes Research, Shirley Ryan AbilityLab, Chicago, Illinois, United States
^c Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri, United States
^d Department of Neurology, Washington University School of Medicine, St Louis, Missouri, United States
^e Center for Behavioral Intervention Technologies, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
^f Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
^g Department of Physical Medicine and Rehabilitation, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
^h Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, United States
ⁱ Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, United States
^j Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, United States

Abstract
Objective: To validate and characterize real-world functional behaviors in individuals after stroke. Design: Longitudinal observational study using ecological momentary assessment (EMA) as a real-time assessment of functional behaviors in natural contexts. Wilcoxon rank-sum tests, Fisher exact tests, and Spearman correlations were used to analyze data. Setting: Community. Participants: Individuals with mild to moderate stroke (N=212). Interventions: Not applicable. Main Outcome Measures: Individuals were assessed 5 times daily for 14 days with EMA surveys to determine what, with whom, and where individuals were doing activities and appraise mental, somatic, and cognitive symptoms. Individuals also completed standardized assessments during laboratory visits, including Lawton Instrumental Activities of Daily Living Scale, Activity Card Sort, Patient-Reported Outcome Measurement Information System, and Quality of Life in Neurological Disorders. Results: Most individuals (median age, 60 years; 55% male) were ischemic stroke (90%) and had mild stroke severity (median National Institutes of Health Stroke Scale, 2). A total of 14,140 EMA surveys were analyzed. Individuals were home 78% of the time; primarily participated in passive, unproductive activities (27%), especially watching television and resting; and participated least in physical activities (4%). EMA was sensitive to indicators of poststroke disability; unemployed individuals reported fewer vocational activities but more activities of daily living (ADL) and passive activities than employed counterparts. Users of mobility devices and individuals with cognitive problems spent significantly less time on vocational activities and more on ADL than nonusers and those without cognitive problems. Our data supported the validity of EMA methods in stroke, with small to moderate correlations of EMA with in-laboratory measures of daily functioning (r=−0.30 to 0.35, P<.05) and very large correlations between EMA and in-laboratory measures of symptoms, especially those measuring same constructs (r=−0.64 to 0.79, P<.0001). Conclusions: Our findings reveal that EMA tracked poststroke functioning precisely. EMA may be beneficial in examining poststroke functional recovery, in monitoring patients for home-based interventions, and for longitudinal research. © 2022 American Congress of Rehabilitation Medicine

Author Keywords
Ecological momentary assessment;  Rehabilitation;  Stroke;  Telemedicine

Funding details
P2CHD101899
National Institute of Neurological Disorders and StrokeNINDS
American Occupational Therapy FoundationAOTF
National Center for Medical Rehabilitation ResearchNCMRRK01HD095388
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Vicarious exposure to the criminal legal system among parents and siblings
(2022) Journal of Marriage and Family, . 

Boen, C.E.^a , Olson, H.^b , Lee, H.^c

^a Department of Sociology, Population Studies Center, Population Aging Research Center, Leonard Davis Institute, University of Pennsylvania, Philadelphia, PA, United States
^b Department of Sociology and Graduate Group in Demography, University of Pennsylvania, Philadelphia, PA, United States
^c Department of Sociology, Brown School of Social Work, Center for the Study of Race, Ethnicity, and Equity, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Objective: This study documents life course patterns of vicarious exposure to the criminal legal system among parents and siblings in the United States. Background: The criminal legal system shapes family outcomes in important ways. Still, life course patterns of vicarious exposure to the system—especially to lower-level contacts—among parents and siblings are not well documented. Method: Using longitudinal data from the Panel Study of Income Dynamics, Kaplan–Meier survival curves, and Cox regression models, we estimate cumulative risks of vicarious exposure to arrest, probation, and incarceration among parents (n = 3885 parents; 185,444 person-years) and siblings (n = 1875; 44,766 person-years) and examine disparities by race–ethnicity, gender, and education, and at their intersections. Results: Vicarious exposure to the system is common—but highly unequal—among parents and siblings. Racially minoritized parents and siblings had greater levels and earlier risks of exposure. For example, by age 50, an estimated one in five Black parents experienced having a child incarcerated, a risk about twice as high as White and 50% higher than Latinx parents. By age 26, an estimated 6 in 10 Black young people with brothers experienced having a brother arrested; more than 4 in 10 experienced a brother on probation; and more than 3 in 10 experienced brother incarceration. For many estimates, racialized inequities in risks of vicarious system exposure widened at higher levels of education. Conclusion: These findings provide essential context for understanding the role of the criminal legal system in maintaining and exacerbating family inequality. © 2022 National Council on Family Relations.

Author Keywords
criminal justice system;  incarceration;  longitudinal research;  parents;  race;  siblings

Funding details
National Science FoundationNSF1623684, SES 1157698
National Institutes of HealthNIHR01 AG040213, R01 HD069609, R24 HD044964, T32 HD007242
University of Pennsylvania
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Suicide attempts during adolescence: Testing the system dynamics of the interpersonal theory of suicide
(2022) Journal of Adolescence, . 

Chung, S.^a , Hovmand, P.^b , McBride, A.M.^c , Joiner, T.^d

^a Computational Social Scientist, Washington University in St. Louis, St Louis, MO, United States
^b Center for Community Health Integration, School of Medicine, and Biomedical Engineering, Case School of Engineering, Case Western Reserve University, Cleveland, OH, United States
^c Morris Endowed Dean and Graduate School of Social Work, University of Denver, Denver, CO, United States
^d Robert O. Lawton Distinguished of Psychology, Florida State University, Tallahassee, FL, United States

Abstract
Introduction: Despite increased efforts to prevent suicide, attempts to die by suicide are rising amongst youth in the United States. Testing causal theories that depict suicide attempts from an adolescent development perspective could bolster prevention and intervention efforts. This study using system dynamics modeling to appraise whether a prevalent theory of suicide, the Interpersonal Theory of Suicide, predicts suicide attempts across adolescence. Methods: A system dynamics computational simulation model was conceptualized based on the Interpersonal Theory of Suicide, as described by Joiner and Van Orden et al. This model was parameterized with representative longitudinal data on adolescents in the United States who attempted suicide across four waves from the National Longitudinal Survey of Adolescent and Adult Health. Results: Though able to predict exponential growth in suicide attempts for early adolescents, the Interpersonal Theory of Suicide, when specified as a dynamic theory, did not adequately predict the nonlinear changes in suicide attempts from adolescence into adulthood. The theory was amended with potential feedback loops from literature and tested for fit. Conclusions: The study builds on a field of emerging views that suicide dynamics should be tested to account for nonlinear feedback effects. Results suggest that the Interpersonal Theory of Suicide should be amended to include the effect of interventions after an attempt and the dynamic developmental processes during adolescence that affect suicide behaviors over time. © 2022 The Foundation for Professionals in Services for Adolescents.

Author Keywords
adolescents;  interpersonal theory of suicide;  suicide prevention;  system dynamics

Document Type: Article
Publication Stage: Article in Press
Source: Scopus