WashU weekly Neuroscience publications

Development of vestibular behaviors in zebrafish
(2018) Current Opinion in Neurobiology, 53, pp. 83-89. 

Bagnall, M.W.^a , Schoppik, D.^b

^a Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
^b Departments of Otolaryngology, Neuroscience & Physiology, the Neuroscience Institute, New York University School of Medicine, New York, NY, United States

Abstract
Most animals orient their bodies with respect to gravity to facilitate locomotion and perception. The neural circuits responsible for these orienting movements have long served as a model to address fundamental questions in systems neuroscience. Though postural control is vital, we know little about development of either balance reflexes or the neural circuitry that produces them. Recent work in a genetically and optically accessible vertebrate, the larval zebrafish, has begun to reveal the mechanisms by which such vestibular behaviors and circuits come to function. Here we highlight recent work that leverages the particular advantages of the larval zebrafish to illuminate mechanisms of postural development, the role of sensation for balance circuit development, and the organization of developing vestibular circuits. Further, we frame open questions regarding the developmental mechanisms for functional circuit assembly and maturation where studying the zebrafish vestibular system is likely to open new frontiers. © 2018 Elsevier Ltd

Document Type: Review
Source: Scopus

Collective Narcissism: Americans Exaggerate the Role of Their Home State in Appraising U.S. History
(2018) Psychological Science, . Article in Press. 

Putnam, A.L.^a , Ross, M.Q.^a , Soter, L.K.^a , Roediger, H.L., III^b

^a Department of Psychology, Carleton College
^b Department of Psychology, Washington University in St. Louis

Abstract
Collective narcissism—a phenomenon in which individuals show excessively high regard for their own group—is ubiquitous in studies of small groups. We examined how Americans from the 50 U.S. states (N = 2,898) remembered U.S. history by asking them, “In terms of percentage, what do you think was your home state’s contribution to the history of the United States?” The mean state estimates ranged from 9% (Iowa) to 41% (Virginia), with the total contribution for all states equaling 907%, indicating strong collective narcissism. In comparison, ratings provided by nonresidents for states were much lower (but still high). Surprisingly, asking people questions about U.S. history before they made their judgment did not lower estimates. We argue that this ethnocentric bias is due to ego protection, selective memory retrieval processes involving the availability heuristic, and poor statistical reasoning. This study shows that biases that influence individual remembering also influence collective remembering. © 2018, The Author(s) 2018.

Author Keywords
and preregistered;  availability bias;  collective memory;  egocentrism;  judgment;  narcissism;  open data;  open materials

Document Type: Article in Press
Source: Scopus

Muscle MRI in patients with dysferlinopathy: Pattern recognition and implications for clinical trials
(2018) Journal of Neurology, Neurosurgery and Psychiatry, . Article in Press. 

Diaz-Manera, J.^{a b} , Fernandez-Torron, R.^{c d} , Llauger, J.^e , James, M.K.^d , Mayhew, A.^d , Smith, F.E.^f , Moore, U.R.^d , Blamire, A.M.^f , Carlier, P.G.^g , Rufibach, L.^h , Mittal, P.^h , Eagle, M.^d , Jacobs, M.^{i j} , Hodgson, T.^f , Wallace, D.^f , Ward, L.^f , Smith, M.^k , Stramare, R.^l , Rampado, A.^l , Sato, N.^m , Tamaru, T.^m , Harwick, B.ⁿ , Rico Gala, S.^o , Turk, S.^g , Coppenrath, E.M.^p , Foster, G.^q , Bendahan, D.^{r s} , Le Fur, Y.^s , Fricke, S.T.^t , Otero, H.^t , Foster, S.L.^{u v} , Peduto, A.^{u v} , Sawyer, A.M.^w , Hilsden, H.^d , Lochmuller, H.^d , Grieben, U.^x , Spuler, S.^x , Tesi Rocha, C.^y , Day, J.W.^y , Jones, K.J.^z , Bharucha-Goebel, D.X.^{aa ab} , Salort-Campana, E.^ac , Harms, M.^ad , Pestronk, A.^ad , Krause, S.^ae , Schreiber-Katz, O.^ae , Walter, M.C.^ae , Paradas, C.^af , Hogrel, J.-Y.^ag , Stojkovic, T.^ag , Takeda, S.^ah , Mori-Yoshimura, M.^ah , Bravver, E.^ai , Sparks, S.^ai , Bello, L.^aj , Semplicini, C.^aj , Pegoraro, E.^aj , Mendell, J.R.^ak , Bushby, K.^d , Straub, V.^d

^a Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Barcelona, Spain
^b Neuromuscular Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
^c Neuromuscular Area, Biodonostia Health Research Institute, Neurology Service, Donostia University Hospital, Donostia-San-Sebastian, Spain
^d John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Newcastle-Upon-Tyne, United Kingdom
^e Radiology Department, Universitat Autònoma de Barcelona, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
^f Magnetic Resonance Centre, Institute for Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, United Kingdom
^g AIM and CEA NMR Laboratory, Institute of Myology, Pitié-Salpêtrière University Hospital, Paris, France
^h Jain Foundation, Seattle, WA, United States
ⁱ Center for Translational Science, Division of Biostatistics and Study Methodology, Children’s National Health System, Washington, DC, United States
^j Department of Pediatrics, Epidemiology and Biostatistics, George Washington University, Washington, DC, United States
^k Department of Radiology, Nationwide Children’s Hospital, Columbus, OH, United States
^l Radiology Unit, Department of Medicine, University of Padova, Padova, Italy
^m Department of Radiology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan
ⁿ Department of Radiology, CMC Mercy Charlotte, Carolinas Healthcare System Neurosciences Institute, Charlotte, NC, United States
^o Department of Radiology, Hospital U. Virgen de Valme, Sevilla, Spain
^p Department of Clinical Radiology, Ludwig-Maximilians-University, Munich, Germany
^q Center for Clinical Imaging Research CCIR, Washington University, St. Louis, MO, United States
^r Centre de Résonance, Magnétique Biologique et Médicale, Marseille, France
^s Aix-Marseille Université, Marseille, France
^t Department of Diagnostic Imaging and Radiology, Children’s National Health System, Washington, DC, United States
^u Department of Radiology, Westmead Hospital, Westmead, NSW, Australia
^v Faculty of Health Sciences, University of Sydney, Sydney, Australia
^w Lucas Center for Imaging, Stanford University, School of Medicine, Stanford, CA, United States
^x Charite Muscle Research Unit, Experimental and Clinical Research Center, A Joint Co-operation of the Charité Medical Faculty, Max Delbrück Center for Molecular Medicine, Berlin, Germany
^y Department of Neurology and Neurological Sciences, Stanford University, School of Medicine, Stanford, CA, United States
^z Institute for Neuroscience and Muscle Research, Children’s Hospital at Westmead, University of Sydney, Sydney, NSW, Australia
^aa Department of Neurology, Children’s National Health System, Washington, DC, United States
^ab National Institutes of Health (NINDS), Bethesda, MD, United States
^ac Neuromuscular and ALS Center, La Timone Hospital, Aix-Marseille Université, Marseille, France
^ad Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
^ae Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University of Munich, Munich, Germany
^af Neuromuscular Unit, Department of Neurology, Hospital U. Virgen Del Rocío, Instituto de Biomedicina de Sevilla, Sevilla, Spain
^ag Institut de Myologie, AP-HP, G.H. Pitié-Salpêtrière, Île-de-France, Paris, France
^ah Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo Kodaira, Japan
^ai Neurosciences Institute, Carolinas Healthcare System, Charlotte, NC, United States
^aj Department of Neurosciences, University of Padova, Padova, Italy
^ak Nationwide Children’s Hospital, Columbus, OH, United States

Abstract
Background and objective: Dysferlinopathies are a group of muscle disorders caused by mutations in the DYSF gene. Previous muscle imaging studies describe a selective pattern of muscle involvement in smaller patient cohorts, but a large imaging study across the entire spectrum of the dysferlinopathies had not been performed and previous imaging findings were not correlated with functional tests. Methods: We present cross-sectional T1-weighted muscle MRI data from 182 patients with genetically confirmed dysferlinopathies. We have analysed the pattern of muscles involved in the disease using hierarchical analysis and presented it as heatmaps. Results of the MRI scans have been correlated with relevant functional tests for each region of the body analysed. Results: In 181 of the 182 patients scanned, we observed muscle pathology on T1-weighted images, with the gastrocnemius medialis and the soleus being the most commonly affected muscles. A similar pattern of involvement was identified in most patients regardless of their clinical presentation. Increased muscle pathology on MRI correlated positively with disease duration and functional impairment. Conclusions: The information generated by this study is of high diagnostic value and important for clinical trial development. We have been able to describe a pattern that can be considered as characteristic of dysferlinopathy. We have defined the natural history of the disease from a radiological point of view. These results enabled the identification of the most relevant regions of interest for quantitative MRI in longitudinal studies, such as clinical trials. Clinical trial registration: NCT01676077. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved.

Author Keywords
dysferlinopathy;  muscle MRI;  muscular dystrophy;  outcome measures

Document Type: Article in Press
Source: Scopus

A Molecular Grammar Governing the Driving Forces for Phase Separation of Prion-like RNA Binding Proteins
(2018) Cell, . Article in Press. 

Wang, J.^a , Choi, J.-M.^b , Holehouse, A.S.^b , Lee, H.O.^a , Zhang, X.^a , Jahnel, M.^a , Maharana, S.^a , Lemaitre, R.^a , Pozniakovsky, A.^a , Drechsel, D.^c , Poser, I.^a , Pappu, R.V.^b , Alberti, S.^a , Hyman, A.A.^a

^a Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
^b Department of Biomedical Engineering and Center for Biological Systems Engineering, Washington University in St. Louis, St. Louis, MO, United States
^c Research Institute of Molecular Pathology, Campus-Vienna-Biocenter 1, Vienna, Austria

Abstract
Proteins such as FUS phase separate to form liquid-like condensates that can harden into less dynamic structures. However, how these properties emerge from the collective interactions of many amino acids remains largely unknown. Here, we use extensive mutagenesis to identify a sequence-encoded molecular grammar underlying the driving forces of phase separation of proteins in the FUS family and test aspects of this grammar in cells. Phase separation is primarily governed by multivalent interactions among tyrosine residues from prion-like domains and arginine residues from RNA-binding domains, which are modulated by negatively charged residues. Glycine residues enhance the fluidity, whereas glutamine and serine residues promote hardening. We develop a model to show that the measured saturation concentrations of phase separation are inversely proportional to the product of the numbers of arginine and tyrosine residues. These results suggest it is possible to predict phase-separation properties based on amino acid sequences. © 2018 Elsevier Inc.

The phase-separation behavior of FUS family proteins can be predicted by the prevalence and position of specific amino acids.

Author Keywords
cation-π;  FUS;  intrinsically disordered;  low complexity;  membraneless compartments;  phase separation;  PLD;  prion-like;  prion-like RNA binding proteins;  saturation concentration

Document Type: Article in Press
Source: Scopus

In Search of an Identity for Amyloid Plaques
(2018) Trends in Neurosciences, . Article in Press. 

Huynh, T.-P.V.^{a b} , Holtzman, D.M.^b

^a Medical Scientist Training Program (MSTP), Washington University School of Medicine, St. Louis, MO, United States
^b 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
In 1984, biochemists George Glenner and Caine Wong, in search of ‘a unique amyloid fibril precursor protein in the serum’ of Alzheimer disease (AD) patients, successfully isolated and sequenced the first 24 amino acids of a ‘cerebrovascular amyloid fibril protein β’ that we now know as the amyloid-β (Aβ) peptide. This landmark paper laid the foundation for extensive research in the following decades that ultimately established the role of β-amyloidosis as a player in the pathogenesis of AD. © 2018 Elsevier Ltd

Author Keywords
Alzheimer disease;  amyloid plaques;  amyloid precursor protein;  amyloid-β

Document Type: Article in Press
Source: Scopus

Neural correlates of global and specific cognitive deficits in schizophrenia
(2018) Schizophrenia Research, . Article in Press. 

Jirsaraie, R.J.^a , Sheffield, J.M.^b , Barch, D.M.^{b c}

^a Department of Psychology, University of Colorado Denver, 1250 14th Street, Denver, CO, United States
^b Department of Psychological & Brain Science, Washington University, Box 1125, One Brookings Drive, St. Louis, MO, United States
^c Department of Psychiatry, Washington University, Box 1125, One Brookings Drive, St. Louis, MO, United States

Abstract
Cognitive deficits are a core feature of schizophrenia, but the neural mechanisms that contribute to these characteristics are not fully understood. This study investigated whether volume of the dorsal lateral prefrontal cortex (DLPFC), inferior frontal gyrus (IFG), hippocampus, and white matter were associated with impairment in specific cognitive domains, including executive functioning, working memory, verbal memory, verbal fluency, processing speed, versus global functioning. The multi-site data used in this study was collected from the Bipolar and Schizophrenia Network on Intermediate Phenotypes (B-SNIP), and consisted of 206 healthy controls and 247 individuals with either schizophrenia or schizoaffective disorder. The neuroimaging data was segmented based on the Destrieux atlas in FreeSurfer. Linear regression analyses revealed that global cognition, executive functioning, working memory, and processing speed were associated with all brain structures, except the DLPFC was only associated with executive fucntion. When controlling for the global cognitive deficit, executive function was trending significance with white matter, but continued to be associated with the DLPFC and IFG, as did the association between processing speed and the hippocampus. These findings suggest that volumes of the DLPFC, IFG, hippocampus, and white matter are associated with the global cognitive impairment seen in schizophrenia, but some brain structures may also be specifically related to domain-specific deficits (primarily executive function) over-and-beyond the global cognitive deficit. © 2018 Elsevier B.V.

Author Keywords
Brain volume;  Cognitive deficits;  Dorsolateral prefrontal cortex;  Hippocampus;  Structural MRI;  White matter

Document Type: Article in Press
Source: Scopus

Epidermal Growth Factor Receptor Extracellular Domain Mutations in Glioblastoma Present Opportunities for Clinical Imaging and Therapeutic Development
(2018) Cancer Cell, 34 (1), pp. 163-177.e7. 

Binder, Z.A.^{a b} , Thorne, A.H.^c , Bakas, S.^{b d} , Wileyto, E.P.^e , Bilello, M.^{b d} , Akbari, H.^{b d} , Rathore, S.^{b d} , Ha, S.M.^{b d} , Zhang, L.^a , Ferguson, C.J.^f , Dahiya, S.^f , Bi, W.L.^g , Reardon, D.A.^h , Idbaih, A.ⁱ , Felsberg, J.^j , Hentschel, B.^k , Weller, M.^l , Bagley, S.J.^m , Morrissette, J.J.D.ⁿ , Nasrallah, M.P.^o , Ma, J.^c , Zanca, C.^c , Scott, A.M.^p , Orellana, L.^{q r} , Davatzikos, C.^{b d} , Furnari, F.B.^c , O’Rourke, D.M.^{a b m}

^a Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^b Center for Biomedical Image Computing and Analytics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^c Ludwig Institute for Cancer Research, La Jolla, San Diego, United States
^d Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^e Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^f Division of Neuropathology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
^g Center for Skull Base and Pituitary Surgery, Department of Neurosurgery, Brigham and Woman’s Hospital, Harvard Medical Center, Boston, MA, United States
^h Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
ⁱ Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpitaux Universitaires Pitié Salpêtrière – Charles Foix, Service de Neurologie 2-Mazarin, Paris, France
^j Institute of Neuropathology, Heinrich Heine University, Medical Faculty, Moorenstrasse 5, Duesseldorf, Germany
^k Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Medical Faculty, Härtelstrasse 16, Leipzig, Germany
^l Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland
^m Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, United States
ⁿ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^o Division of Neuropathology, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^p Olivia Newton-John Cancer Research Institute, La Trobe University, Melbourne, Australia
^q Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden
^r Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden

Abstract
We explored the clinical and pathological impact of epidermal growth factor receptor (EGFR) extracellular domain missense mutations. Retrospective assessment of 260 de novo glioblastoma patients revealed a significant reduction in overall survival of patients having tumors with EGFR mutations at alanine 289 (EGFRA289D/T/V). Quantitative multi-parametric magnetic resonance imaging analyses indicated increased tumor invasion for EGFRA289D/T/V mutants, corroborated in mice bearing intracranial tumors expressing EGFRA289V and dependent on ERK-mediated expression of matrix metalloproteinase-1. EGFRA289V tumor growth was attenuated with an antibody against a cryptic epitope, based on in silico simulation. The findings of this study indicate a highly invasive phenotype associated with the EGFRA289V mutation in glioblastoma, postulating EGFRA289V as a molecular marker for responsiveness to therapy with EGFR-targeting antibodies. © 2018 Elsevier Inc.

Binder et al. show that glioblastoma (GBM) expressing EGFR A289 mutants exhibit invasive features and are associated with shorter survival in patients and mice. GBM cells expressing EGFRA289V increase ERK-dependent MMP1 expression but are sensitive to an EGFR monoclonal antibody being clinically developed.

Author Keywords
A289D/T/V;  EGFR;  EGFR oncogenes;  EGFR targeted therapy;  GBM;  glioblastoma;  glioma;  radiogenomics;  radiomics;  survival

Document Type: Article
Source: Scopus

Purkinje cell cytoplasmic antibody type i (anti-Yo): Predictive of gastrointestinal adenocarcinomas in men
(2017) Journal of Neurology, Neurosurgery and Psychiatry, . Article in Press. 

Linnoila, J.^a , Guo, Y.^b , Gadoth, A.^{a b} , Raghunathan, A.^b , Parks, B.^c , McKeon, A.^{a b} , Lucchinetti, C.F.^a , Lennon, V.A.^{a b d} , Pittock, S.J.^{a b}

^a Department of Neurology, Mayo Clinic, Rochester, MN, United States
^b Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
^c Department of Neurology, Washington University, St Louis, MO, United States
^d Department of Immunology, Mayo Clinic, Rochester, MN, United States

Author Keywords
anti-yo;  araneoplastic neurological autoimmunity

Document Type: Article in Press
Source: Scopus