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Office of Neuroscience Research > Resources and Facilities > WUSTL Neuroscience Publications for the week

WUSTL Neuroscience Publications for the week

 

The publications below include authors at Washington University and were identified by Scopus search.  These are the most current publications.  For previous lists, visit the WUSTL Neuroscience publications archive.

August 7, 2017 

1) 

Benitez, B.A., Sands, M.S.
Primary fibroblasts from CSPα mutation carriers recapitulate hallmarks of the adult onset neuronal ceroid lipofuscinosis
(2017) Scientific Reports, 7 (1), art. no. 6332, . 

DOI: 10.1038/s41598-017-06710-1


a Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
b Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
c Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States


Abstract
Mutations in the co-chaperone protein, CSPα, cause an autosomal dominant, adult-neuronal ceroid lipofuscinosis (AD-ANCL). The current understanding of CSPα function exclusively at the synapse fails to explain the autophagy-lysosome pathway (ALP) dysfunction in cells from AD-ANCL patients. Here, we demonstrate unexpectedly that primary dermal fibroblasts from pre-symptomatic mutation carriers recapitulate in vitro features found in the brains of AD-ANCL patients including auto-fluorescent storage material (AFSM) accumulation, CSPα aggregates, increased levels of lysosomal proteins and lysosome enzyme activities. AFSM accumulation correlates with CSPα aggregation and both are susceptible to pharmacological modulation of ALP function. In addition, we demonstrate that endogenous CSPα is present in the lysosome-enriched fractions and co-localizes with lysosome markers in soma, neurites and synaptic boutons. Overexpression of CSPα wild-type (WT) decreases lysotracker signal, secreted lysosomal enzymes and SNAP23-mediated lysosome exocytosis. CSPα WT, mutant and aggregated CSPα are degraded mainly by the ALP but this disease-causing mutation exhibits a faster rate of degradation. Co-expression of both WT and mutant CSPα cause a block in the fusion of autophagosomes/lysosomes. Our data suggest that aggregation-dependent perturbation of ALP function is a relevant pathogenic mechanism for AD-ANCL and supports the use of AFSM or CSPα aggregation as biomarkers for drug screening purposes. © 2017 The Author(s).


Document Type: Article
Source: Scopus

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2) 

Monosov, I.E.
Anterior cingulate is a source of valence-specific information about value and uncertainty
(2017) Nature Communications, 8 (1), art. no. 134, . 

DOI: 10.1038/s41467-017-00072-y


Departments of Neuroscience and Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States


Abstract
Anterior cingulate cortex (ACC) is thought to control a wide range of reward, punishment, and uncertainty-related behaviors. However, how it does so is unclear. Here, in a Pavlovian procedure in which monkeys displayed a diverse repertoire of reward-related, punishment-related, and uncertainty-related behaviors, we show that many ACC-neurons represent expected value and uncertainty in a valence-specific manner, signaling value or uncertainty predictions about either rewards or punishments. Other ACC-neurons signal prediction information about rewards and punishments by displaying excitation to both (rather than excitation to one and inhibition to the other). This diversity in valence representations may support the role of ACC in many behavioral states that are either enhanced by reward and punishment (e.g., vigilance) or specific to either reward or punishment (e.g., approach and avoidance). Also, this first demonstration of punishment-uncertainty signals in the brain suggests that ACC could be a target for the treatment of uncertainty-related disorders of mood. © 2017 The Author(s).


Document Type: Article
Source: Scopus

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3) 

Keefer, K.M., Stein, K.C., True, H.L.
Heterologous prion-forming proteins interact to cross-seed aggregation in Saccharomyces cerevisiae
(2017) Scientific Reports, 7 (1), art. no. 5853, . 

DOI: 10.1038/s41598-017-05829-5


a Department of Cell Biology and Physiology, Washington University, School of Medicine, St. Louis, MO, United States
b Department of Biology, Stanford University, Stanford, CA, United States


Abstract
The early stages of protein misfolding remain incompletely understood, as most mammalian proteinopathies are only detected after irreversible protein aggregates have formed. Cross-seeding, where one aggregated protein templates the misfolding of a heterologous protein, is one mechanism proposed to stimulate protein aggregation and facilitate disease pathogenesis. Here, we demonstrate the existence of cross-seeding as a crucial step in the formation of the yeast prion [PSI +], formed by the translation termination factor Sup35. We provide evidence for the genetic and physical interaction of the prion protein Rnq1 with Sup35 as a predominant mechanism leading to self-propagating Sup35 aggregation. We identify interacting sites within Rnq1 and Sup35 and determine the effects of breaking and restoring a crucial interaction. Altogether, our results demonstrate that single-residue disruption can drastically reduce the effects of cross-seeding, a finding that has important implications for human protein misfolding disorders. © 2017 The Author(s).


Document Type: Article
Source: Scopus

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4) 

Hassanpour, M.S., Eggebrecht, A.T., Peelle, J.E., Culvera, J.P.
Mapping effective connectivity within cortical networks with diffuse optical tomography
(2017) Neurophotonics, 4 (4), art. no. 041402, . 

DOI: 10.1117/1.NPh.4.4.041402


a Washington University in St. Louis, Department of Physics, St. Louis, MO, United States
b Washington University in St. Louis, Department of Radiology, St. Louis, MO, United States
c Washington University in St. Louis, Department of Otolaryngology, St. Louis, MO, United States
d Washington University in St. Louis, Department of Biomedical Engineering, St. Louis, MO, United States


Abstract
Understanding how cortical networks interact in response to task demands is important both for providing insight into the brain's processing architecture and for managing neurological diseases and mental disorders. High-density diffuse optical tomography (HD-DOT) is a neuroimaging technique that offers the significant advantages of having a naturalistic, acoustically controllable environment and being compatible with metal implants, neither of which is possible with functional magnetic resonance imaging. We used HD-DOT to study the effective connectivity and assess the modulatory effects of speech intelligibility and syntactic complexity on functional connections within the cortical speech network. To accomplish this, we extend the use of a generalized psychophysiological interaction (PPI) analysis framework. In particular, we apply PPI methods to event-related HD-DOT recordings of cortical oxyhemoglobin activity during auditory sentence processing. We evaluate multiple approaches for selecting cortical regions of interest and for modeling interactions among these regions. Our results show that using subject-based regions has minimal effect on group-level connectivity maps. We also demonstrate that incorporating an interaction model based on estimated neural activity results in significantly stronger effective connectivity. Taken together our findings support the use of HD-DOT with PPI methods for noninvasively studying task-related modulations of functional connectivity. © 2017 The Authors.


Author Keywords
Diffuse optical tomography;  Effective connectivity;  Psychophysiological interaction;  Speech comprehension


Document Type: Article
Source: Scopus

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5) 

Bailey, R.R.
Promoting physical activity and nutrition in people with stroke
(2017) American Journal of Occupational Therapy, 71 (5), art. no. 7105360010, . 

DOI: 10.5014/ajot.2017.021378


Washington University School of Medicine in St. Louis, St. Louis, MO, United States


Abstract
The prevalence of cardiovascular disease, diabetes, and obesity is high in people with stroke. Risk factors for these conditions include hypertension, high cholesterol, and physical inactivity. These risk factors are common in people with stroke and often go unmanaged. Engagement in healthy behaviors is important for managing and preventing these risk factors and comorbid conditions. More specifically, physical activity and nutrition are key health behaviors for the management and maintenance of health in people with stroke. These health behaviors, by their very nature, are also occupations; thus, they are influenced by client factors, performance skills and patterns, and environments and contexts. This article discusses physical activity and nutrition within the context of the Occupational Therapy Practice Framework: Domain and Process and proposes potential roles for occupational therapy practitioners and researchers in developing, testing, and providing physical activity and nutrition interventions for people with stroke.


Document Type: Article
Source: Scopus

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6) 

Smallfield, S.
Supporting adults with Alzheimer's disease and related major neurocognitive disorders and their caregivers: Effective occupational therapy interventions
(2017) American Journal of Occupational Therapy, 71 (5), art. no. 7105170010, . 

DOI: 10.5014/ajot.2017.715002


Occupational Therapy and Medicine, Washington University in St. Louis, St. Louis, MO, United States


Abstract
Occupational therapy practitioners play a significant role in supporting adults with Alzheimer's disease and related major neurocognitive disorders, as well as their caregivers, through all phases of the disease process. This editorial highlights the systematic reviews completed in collaboration with the American Occupational Therapy Association's Evidence-Based Practice Project that summarize the evidence for the effectiveness of interventions within the scope of occupational therapy practice for this population. Readers are encouraged to translate and integrate this updated knowledge into everyday practice.


Document Type: Review
Source: Scopus

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7) 

Hirbe, A.C., Gutmann, D.H.
The management of neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors: challenges, progress, and future prospects
(2017) Expert Opinion on Orphan Drugs, 5 (8), pp. 623-631. 

DOI: 10.1080/21678707.2017.1348294


a Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
b Department of Neurology, Washington University, St. Louis, MO, United States


Abstract
Introduction: The most common malignancy affecting adults with the neurofibromatosis type 1 (NF1) cancer predisposition syndrome is the malignant peripheral nerve sheath tumor (MPNST), a highly aggressive sarcoma that typically develops from a pre-existing benign plexiform neurofibroma. These tumors are difficult to treat, with limited therapeutic options and poor patient responses, leading to unacceptably high mortality rates. Despite advances in our understanding of the pathogenesis of these tumors, the overall prognosis for these cancers remains dismal. Areas covered: This paper reviews the cellular and molecular etiologies underlying MPNST development and progression, the diagnostic workup of patients with these malignancies, and the current and investigational treatment options. Areas of controversy in which further research is needed will be highlighted. Expert opinion: MPNSTs remain a therapeutic challenge. Multidisciplinary care at a high volume sarcoma center is essential for optimal outcomes. Further work is needed to develop targeted combinational therapies for these tumors. © 2017 Informa UK Limited, trading as Taylor & Francis Group.


Author Keywords
Atypical neurofibromas;  malignant peripheral nerve sheath tumors neurofibromatosis;  plexiform neurofibromas


Document Type: Review
Source: Scopus

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8) 

Spolverato, G., Bagante, F., Aldrighetti, L., Poultsides, G., Bauer, T.W., Field, R.C., Marques, H.P., Weiss, M., Maithel, S.K., Pawlik, T.M.
Neuroendocrine Liver Metastasis: Prognostic Implications of Primary Tumor Site on Patients Undergoing Curative Intent Liver Surgery
(2017) Journal of Gastrointestinal Surgery, pp. 1-9. Article in Press. 

DOI: 10.1007/s11605-017-3491-1


a Department of Surgery, University of Verona, Verona, Italy
b Scientific Institute San Raffaele, Milan, Italy
c Stanford University, Stanford, CA, United States
d University of Virginia, Charlottesville, VA, United States
e School of Medicine, Washington University, St Louis, MO, United States
f Curry Cabral Hospital, Lisbon, Portugal
g Johns Hopkins Hospital, Baltimore, MD, United States
h Emory University, Atlanta, GA, United States
i Department of Surgery, The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States


Abstract
Background: Neuroendocrine tumors typically arise from pancreatic (PNET) vs. gastrointestinal or thoracic origins (non-PNET). The impact of primary tumor site on long-term prognosis following resection of neuroendocrine liver metastasis (NELM) remains poorly defined. The objective of the current study was to define the association of primary tumor location on prognosis of patients undergoing curative intent liver resection for NELM. Methods: Between 1990 and 2014, 421 patients who underwent resection of NELM were identified from a multi-institutional database. Clinicopathological characteristics, operative details, and outcomes were stratified and analyzed by location of the primary tumor (PNET vs. non-PNET). A propensity score-matched analysis was utilized to assess the impact of primary tumor location on long-term survival. Results: Among the 421 patients, 197 (46.8%) patients had NELM from a PNET primary while 224 (53.2%) had a non-PNET primary (small bowel, n = 145; rectal, n = 10; bronchial, n = 22; other, n = 47). There were no differences in tumor burden and tumor site, while presence of extrahepatic disease was more common among patients with non-PNET NELM (extrahepatic disease, PNET NELM, n = 11 27.5% vs. non-PNET NELM, n = 29 72.5%; p = 0.010). Patients with PNET NELM were more likely to have non-functional disease compared with patients who had non-PNET NELM (non-functional, PNET NELM, n = 117 54.9% vs. non-PNET NELM, n = 96 45.1%; p = 0.011). On the final pathological specimen of the resected NELM, patients with PNET NELM were more likely to have a moderately differentiated tumor (59.3%), while patients with non-PNET NELM were more likely to have a poorly differentiated tumor (67.8%) (p = 0.005). Patients with PNET NELM had a worse 5-year DFS and 5-year OS compared with patients who had non-PNET NELM (DFS, PNET 36.2% vs. non-PNET 55.2%; p = 0.001 and OS, PNET 79.5% vs. non-PNET 83.4%; p = 0.008). After propensity score matching, both 5-year DFS and 5-year OS of the PNET and non-PNET groups were comparable (DFS, PNET 46.2% vs. non-PNET 55.9%; p = 0.22 and OS, PNET 81.5% vs. non-PNET 84.3%; p = 0.19). Conclusion: PNET patients more often present with non-functional NELM and moderately differentiated tumors. On propensity-matched analysis, factors such as extrahepatic disease and tumor grade, but not primary tumor location, were associated with prognosis of patients undergoing curative intent liver surgery for NELM. © 2017 The Society for Surgery of the Alimentary Tract


Author Keywords
NELM;  Neuroendocrine liver metastasis;  Pancreatic neuroendocrine tumor;  PNET;  Surgery


Document Type: Article in Press
Source: Scopus

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9) 

Riggs, W.J., Roche, J.P., Giardina, C.K., Harris, M.S., Bastian, Z.J., Fontenot, T.E., Buchman, C.A., Brown, K.D., Adunka, O.F., Fitzpatrick, D.C.
Intraoperative electrocochleographic characteristics of auditory neuropathy spectrum disorder in cochlear implant subjects
(2017) Frontiers in Neuroscience, 11 (JUL), art. no. 416, . 

DOI: 10.3389/fnins.2017.00416


a Department of Otolaryngology/Head and Neck Surgery, Ohio State University College of Medicine, Columbus, OH, United States
b Lab Department of Otolaryngology/Head and Neck Surgery, University of Wisconsin School of Medicine, Madison, WI, United States
c Department of Otolaryngology/Head and Neck Surgery, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, United States
d Department of Otolaryngology/Head and Neck Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO, United States


Abstract
Auditory neuropathy spectrum disorder (ANSD) is characterized by an apparent discrepancy between measures of cochlear and neural function based on auditory brainstem response (ABR) testing. Clinical indicators of ANSD are a present cochlear microphonic (CM) with small or absent wave V. Many identified ANSD patients have speech impairment severe enough that cochlear implantation (CI) is indicated. To better understand the cochleae identified with ANSD that lead to a CI, we performed intraoperative round window electrocochleography (ECochG) to tone bursts in children (n = 167) and adults (n = 163). Magnitudes of the responses to tones of different frequencies were summed to measure the "total response" (ECochG-TR), a metric often dominated by hair cell activity, and auditory nerve activity was estimated visually from the compound action potential (CAP) and auditory nerve neurophonic (ANN) as a ranked "Nerve Score". Subjects identified as ANSD (45 ears in children, 3 in adults) had higher values of ECochG-TR than adult and pediatric subjects also receiving CIs not identified as ANSD. However, nerve scores of the ANSD group were similar to the other cohorts, although dominated by the ANN to low frequencies more than in the non-ANSD groups. To high frequencies, the common morphology of ANSD cases was a large CM and summating potential, and small or absent CAP. Common morphologies in other groups were either only a CM, or a combination of CM and CAP. These results indicate that responses to high frequencies, derived primarily from hair cells, are the main source of the CM used to evaluate ANSD in the clinical setting. However, the clinical tests do not capture the wide range of neural activity seen to low frequency sounds. © 2017 Riggs, Roche, Giardina, Harris, Bastian, Fontenot, Buchman, Brown, Adunka and Fitzpatrick.


Author Keywords
Auditory neuropathy spectrum disorder;  Cochlear implants;  Cochlear microphonic;  Electrocochleography;  Intraoperative;  Pediatrics


Document Type: Article
Source: Scopus

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10) 

Barry, D.M., Yu, Y.-Q., Hao, Y., Liu, X.-T., Chen, Z.-F.
Response to comment on “Molecular and neural basis of contagious itch behavior in mice”
(2017) Science, 357 (6347), art. no. eaan5000, . 

DOI: 10.1126/science.aan5000


a Center for the Study of Itch, Washington University, School of Medicine, St. Louis, MO, United States
b Department of Anesthesiology, Washington University, School of Medicine, St. Louis, MO, United States
c Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, United States
d Department of Developmental Biology, Washington University, School of Medicine, St. Louis, MO, United States
e Institute for Biomedical Sciences of Pain, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
f Department of Pediatrics, Tongji Hospital, Tongji Medical College, HuaZhong University of Science and Technology, Wuhan, Hubei, China
g Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, State Key Laboratory of Respiratory Disease, Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China


Document Type: Note
Source: Scopus

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11) 

Gendron, T.F., C9ORF72 Neurofilament Study Group, Daughrity, L.M., Heckman, M.G., Diehl, N.N., Wuu, J., Miller, T.M., Pastor, P., Trojanowski, J.Q., Grossman, M., Berry, J.D., Hu, W.T., Ratti, A., Benatar, M., Silani, V., Glass, J.D., Floeter, M.K., Jeromin, A., Boylan, K.B., Petrucelli, L.
Phosphorylated neurofilament heavy chain: A biomarker of survival for C9ORF72-associated amyotrophic lateral sclerosis
(2017) Annals of Neurology, 82 (1), pp. 139-146. 

DOI: 10.1002/ana.24980


a Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
b Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL, United States
c Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, FL, United States
d Department of Neurology, University of Miami, Miami, FL, United States
e Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
f Department of Neurology, University Hospital Mútua de Terrassa, and Research Foundation Mútua de Terrassa, University of Barcelona, Terrassa, Barcelona, Spain
g Centers for Networked Biomedical Research (CIBERNED), Madrid, Spain
h Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
i Department of Neurology and Penn Frontotemporal Degeneration Center, University of Pennsylvania, Philadelphia, PA, United States
j Neurological Clinical Research Institute, Massachusetts General Hospital, Boston, MA, United States
k Department of Neurology, Emory University School of Medicine, Atlanta, GA, United States
l Department of Neurology–Stroke Unit and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy
m Department of Pathophysiology and Transplantation, “Dino Ferrari” Centre, University of Milan, Milan, Italy
n Department of Pathology, Emory University School of Medicine, Atlanta, GA, United States
o Motor Neuron Disorders Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
p Iron Horse Diagnostics, Scottsdale, AZ, United States
q Department of Neurology, Mayo Clinic, Jacksonville, FL, United States


Abstract
As potential treatments for C9ORF72-associated amyotrophic lateral sclerosis (c9ALS) approach clinical trials, the identification of prognostic biomarkers for c9ALS becomes a priority. We show that levels of phosphorylated neurofilament heavy chain (pNFH) in cerebrospinal fluid (CSF) predict disease status and survival in c9ALS patients, and are largely stable over time. Moreover, c9ALS patients exhibit higher pNFH levels, more rapid disease progression, and shorter survival after disease onset than ALS patients without C9ORF72 expansions. These data support the use of CSF pNFH as a prognostic biomarker for clinical trials, which will increase the likelihood of successfully developing a treatment for c9ALS. Ann Neurol 2017;82:139–146. © 2017 The Authors Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association


Document Type: Article
Source: Scopus

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12) 

Santosa, K.B., Fattah, A., Gavilán, J., Hadlock, T.A., Snyder-Warwick, A.K.
Photographic standards for patients with facial palsy and recommendations by members of the sir charles bell society
(2017) JAMA Facial Plastic Surgery, 19 (4), pp. 275-281. 

DOI: 10.1001/jamafacial.2016.1883


a Division of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine, St Louis, MO, United States
b Facial Nerve Programme, Regional Paediatric Burns and Plastic Surgery Service, Alder Hey Children's National Health Service Foundation Trust, Liverpool, United Kingdom
c Department of Otorhinolaryngology, La Paz University Hospital, Madrid, Spain
d Facial Nerve Center, Division of Facial and Plastic and Reconstructive Surgery, Department of Otology and Laryngology, Harvard Medical School and Massachusetts Eye and Ear, Boston, United States
e Facial Nerve Institute, Division of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine, 660 S Euclid Ave, Campus Box 8238, St Louis, MO, United States


Abstract
IMPORTANCE There is no widely accepted assessment tool or common language used by clinicians caring for patients with facial palsy, making exchange of information challenging. Standardized photographymay represent such a language and is imperative for precise exchange of information and comparison of outcomes in this special patient population. OBJECTIVES To review the literature to evaluate the use of facial photography in the management of patients with facial palsy and to examine the use of photography in documenting facial nerve function among members of the Sir Charles Bell Society-a group of medical professionals dedicated to care of patients with facial palsy. DESIGN, SETTING, AND PARTICIPANTS A literature searchwas performed to review photographic standards in patients with facial palsy. In addition, a cross-sectional survey of members of the Sir Charles Bell Society was conducted to examine use of medical photography in documenting facial nerve function. The literature search and analysis was performed in August and September 2015, and the survey was conducted in August and September 2013. MAIN OUTCOMES AND MEASURES The literature review searched EMBASE, CINAHL, and MEDLINE databases from inception of each database through September 2015. Additional studieswere identified by scanning references from relevant studies. Only English-language articleswere eligible for inclusion. Articles that discussed patients with facial palsy and outlined photographic guidelines for this patient populationwere included in the study. The surveywas disseminated to the Sir Charles Bell Society members in electronic form. It consisted of 10 questions related to facial grading scales, patient-reported outcome measures, other psychological assessment tools, and photographic and videographic recordings. RESULTS In total, 393 articles were identified in the literature search, 7 of which fit the inclusion criteria. Six of the 7 articles discussed or proposed views specific to patients with facial palsy. However, none of the articles specifically focused on photographic standards for the population with facial palsy. Eighty-three of 151 members (55%) of the Sir Charles Bell Society responded to the survey. All survey respondents used photographic documentation, but there was variability in which facial expressions were used. Eighty-two percent (68 of 83) used some form of videography. From these data, we propose a set of minimum photographic standards for patients with facial palsy, including the following 10 static views: at rest or repose, small closed-mouth smile, large smile showing teeth, elevation of eyebrows, closure of eyes gently, closure of eyes tightly, puckering of lips, showing bottom teeth, snarling or wrinkling of the nose, and nasal base view. CONCLUSIONS AND RELEVANCE There is no consensus on photographic standardization to report outcomes for patients with facial palsy. Minimum photographic standards for facial paralysis publications are proposed. Videography of the dynamic movements of these views should also be recorded. © 2017 American Medical Association. All rights reserved.


Document Type: Review
Source: Scopus

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13) 

Zhang, D.J., Allon, G., Van Mieghem, J.A.
Does social interaction improve learning outcomes? Evidence from field experiments on massive open online courses
(2017) Manufacturing and Service Operations Management, 19 (3), pp. 347-367. 

DOI: 10.1287/msom.2016.0615


a Olin Business School, Washington University in St. Louis, St. Louis, MO, United States
b Wharton School, University of Pennsylvania, Philadelphia, PA, United States
c Kellogg School of Management, Northwestern University, Evanston, IL, United States


Abstract
This paper studies how service providers can design social interaction among participants and quantify the causal impact of that interaction on service quality. We focus on education and analyze whether encouraging social interaction among students improves learning outcomes in massive open online courses (MOOCs), which are a new service delivery channel with universal access at reduced, if not zero, cost. We analyze three randomized experiments in a MOOC with more than 30,317 students from 183 countries. Two experiments study large-group interaction by encouraging a random subset of students to visit the course discussion board. The majority of students treated in these experiments had higher social engagement, higher quiz completion rates, and higher course grades. Using these treatments as instrumental variables, we estimate that one additional board visit causally increases the probability that a student finishes the quiz in the subsequent week by up to 4:3%. The third experiment studies small-group interaction by encouraging a random subset of students to conduct one-onone synchronous discussions. Students who followed through and actually conducted pairwise discussions increased their quiz completion rates and quiz scores by 10% in the subsequent week. Combining results from these three experiments, we provide recommendations for designing social interaction mechanisms to improve service quality. © 2017 INFORMS.


Author Keywords
Education;  Field experiments;  Massive open online courses (MOOCs);  Service operations;  Social interaction


Document Type: Article
Source: Scopus

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14) 

Su, Y., Vlassenko, A.G., Couture, L.E., Benzinger, T.L., Snyder, A.Z., Derdeyn, C.P., Raichle, M.E.
Quantitative hemodynamic PET imaging using image-derived arterial input function and a PET/MR hybrid scanner
(2017) Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 37 (4), pp. 1435-1446. Cited 1 time.

DOI: 10.1177/0271678X16656200


a 1 Mallinckrodt Institute of Radiology, Washington University School of Medicine, USA
b 2 Department Neurosurgery, Washington University School of Medicine, USA
c 3 Department of Radiology, University of Iowa, USA
d 4 Department of Neurology, Washington University School of Medicine, USA


Abstract
Positron emission tomography (PET) with 15O-tracers is commonly used to measure brain hemodynamic parameters such as cerebral blood flow, cerebral blood volume, and cerebral metabolic rate of oxygen. Conventionally, the absolute quantification of these parameters requires an arterial input function that is obtained invasively by sampling blood from an artery. In this work, we developed and validated an image-derived arterial input function technique that avoids the unreliable and burdensome arterial sampling procedure for full quantitative 15O-PET imaging. We then compared hemodynamic PET imaging performed on a PET/MR hybrid scanner against a conventional PET only scanner. We demonstrated the proposed imaging-based technique was able to generate brain hemodynamic parameter measurements in strong agreement with the traditional arterial sampling based approach. We also demonstrated that quantitative 15O-PET imaging can be successfully implemented on a PET/MR hybrid scanner.


Author Keywords
Arterial input function;  cerebral blood flow;  cerebral metabolic rate of oxygen;  positron emission tomography


Document Type: Article
Source: Scopus

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15) 

Cicero, T.J., Ellis, M.S.
Understanding the demand side of the prescription opioid epidemic: Does the initial source of opioids matter?
(2017) Drug and Alcohol Dependence, 173, pp. S4-S10. 

DOI: 10.1016/j.drugalcdep.2016.03.014


Washington University in St. Louis, Department of Psychiatry, Campus Box 8134, 660 S. Euclid Avenue, St. Louis, MO, United States


Abstract
Background These studies were carried out to examine whether the onset and progression of an opioid substance use disorder (SUD) differed in those who first used opioids to get “high” compared to those who received a prescription from a doctor to relieve pain (Non-Rx vs. Rx groups, respectively). Methods A subset of patients (N = 214) from an ongoing larger study of patients entering one of 125 drug treatment programs for opioid use disorder across the country agreed to give up their anonymity and participate in structured and open-ended online interviews examining drug abuse patterns. Results With the exception that the Non-Rx group began their opioid abuse at a younger age than the Rx group and more quickly evolved from initial exposure to regular opioid abuse, there were relatively few differences in the characteristics, patterns and trajectories of opioid abuse. The vast majority of patients in both groups, most of whom had serious, antecedent psychiatric disorders, indicated that they used opioids to self-medicate psychological problems (67–73%) and/or stated that opioids provided a means to “escape” from the stresses of everyday life (79–85%). As the SUD progressed, for many individuals any “positive” attributes of opioids waned and avoidance of withdrawal became the overriding concern, often serving as the impetus for treatment. Conclusions Our results suggest that self-treatment of co-morbid psychiatric disturbances is a powerful motivating force to initiate and sustain abuse of opioids and that the initial source of drugs—a prescription or experimentation—is largely irrelevant in the progression to a SUD. © 2016 The Authors


Author Keywords
Epidemiology;  Iatrogenic abuse;  Opioid abuse;  Opioids;  Pharmacoepidemiology;  Psychiatric epidemiology


Document Type: Article
Source: Scopus

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16) 

Yi, J.J., Paranjape, S.R., Walker, M.P., Choudhury, R., Wolter, J.M., Fragola, G., Emanuele, M.J., Major, M.B., Zylka, M.J.
The autism-linked UBE3A T485A mutant E3 ubiquitin ligase activates the Wnt/β-catenin pathway by inhibiting the proteasome
(2017) Journal of Biological Chemistry, 292 (30), pp. 12503-12515. 

DOI: 10.1074/jbc.M117.788448


a Department of Neuroscience, Washington University School of Medicine, Saint Louis, MO, United States
b Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC, United States
c UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC, United States
d Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, NC, United States
e Department of Pharmacology, University of North Carolina, Chapel Hill, NC, United States
f Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, United States


Abstract
UBE3A is a HECT domain E3 ubiquitin ligase whose dysfunction is linked to autism, Angelman syndrome, and cancer. Recently, we characterized a de novo autism-linked UBE3A mutant (UBE3AT485A) that disrupts phosphorylation control of UBE3A activity. Through quantitative proteomics and reporter assays, we found that the UBE3AT485A protein ubiquitinates multiple proteasome subunits, reduces proteasome subunit abundance and activity, stabilizes nuclear β-catenin, and stimulates canonical Wnt signaling more effectively than wild-type UBE3A. We also found that UBE3AT485A activates Wnt signaling to a greater extent in cells with low levels of ongoing Wnt signaling, suggesting that cells with low basal Wnt activity are particularly vulnerable to UBE3AT485A mutation. Ligase-dead UBE3A did not stimulate Wnt pathway activation. Overexpression of several proteasome subunits reversed the effect of UBE3AT485A on Wnt signaling. We also observed that subunits that interact with UBE3A and affect Wnt signaling are located along one side of the 19S regulatory particle, indicating a previously unrecognized spatial organization to the proteasome. Altogether, our findings indicate that UBE3A regulates Wnt signaling in a cell context-dependent manner and that an autism-linked mutation exacerbates these signaling effects. Our study has broad implications for human disorders associated with UBE3A gain or loss of function and suggests that dysfunctional UBE3A might affect additional proteins and pathways that are sensitive to proteasome activity. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.


Document Type: Article
Source: Scopus

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17) 

Couture, F., Jansen, A.M., Taghert, P., Brix, K.
EJCB - Molecular basis of protein fates in the secretory and endocytic pathways, and beyond
(2017) European Journal of Cell Biology, . Article in Press. 

DOI: 10.1016/j.ejcb.2017.06.006


a University of Sherbrooke, 3001, 12e avenue Nord, Sherbrooke, Québec, J1H 5N4, Canada
b Kongshaven 22B, 2500 Valby, Denmark
c Washington University Medical School, 660 S Euclid Avenue, St Louis MO 63110, USA
d Jacobs University Bremen gGmbH, Campus Ring 1, 28759 Bremen, Germany


Document Type: Article in Press
Source: Scopus

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18) 

Gordon, E.M., Laumann, T.O., Gilmore, A.W., Newbold, D.J., Greene, D.J., Berg, J.J., Ortega, M., Hoyt-Drazen, C., Gratton, C., Sun, H., Hampton, J.M., Coalson, R.S., Nguyen, A.L., McDermott, K.B., Shimony, J.S., Snyder, A.Z., Schlaggar, B.L., Petersen, S.E., Nelson, S.M., Dosenbach, N.U.F.
Precision Functional Mapping of Individual Human Brains
(2017) Neuron, . Article in Press. 

DOI: 10.1016/j.neuron.2017.07.011


a VISN 17 Center of Excellence for Research on Returning War Veterans, Waco, TX, 76711, USA
b Center for Vital Longevity, School of Behavioral and Brain Sciences, University of Texas at Dallas, Dallas, TX, 75235, USA
c Department of Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA
d Laboratory of Brain and Cognition, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, 20892, USA
e Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA
f Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, 63110, USA
g Department of Psychology, New York University, New York, NY 10003, USA
h Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO, 63110, USA
i Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, 63130, USA
j Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, 63110, USA
k Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, 63110, USA
l Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, 63130, USA
m Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, 63110, USA
n Department of Psychology and Neuroscience, Baylor University, Waco, TX 76789, USA


Abstract
Human functional MRI (fMRI) research primarily focuses on analyzing data averaged across groups, which limits the detail, specificity, and clinical utility of fMRI resting-state functional connectivity (RSFC) and task-activation maps. To push our understanding of functional brain organization to the level of individual humans, we assembled a novel MRI dataset containing 5 hr of RSFC data, 6 hr of task fMRI, multiple structural MRIs, and neuropsychological tests from each of ten adults. Using these data, we generated ten high-fidelity, individual-specific functional connectomes. This individual-connectome approach revealed several new types of spatial and organizational variability in brain networks, including unique network features and topologies that corresponded with structural and task-derived brain features. We are releasing this highly sampled, individual-focused dataset as a resource for neuroscientists, and we propose precision individual connectomics as a model for future work examining the organization of healthy and diseased individual human brains. Gordon et al. demonstrate advantages of conducting whole-brain fMRI research in individual humans using large amounts of per-individual data, which greatly increases reliability and specificity. This work illustrates new approaches for fMRI-based neuroscience that allow detailed characterization of individual brain organization. © 2017 Elsevier Inc.


Author Keywords
Brain networks;  FMRI;  Functional connectivity;  Individual variability;  Myelin mapping


Document Type: Article in Press
Source: Scopus

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19) 

TCW, J., Wang, M., Pimenova, A.A., Bowles, K.R., Hartley, B.J., Lacin, E., Machlovi, S.I., Abdelaal, R., Karch, C.M., Phatnani, H., Slesinger, P.A., Zhang, B., Goate, A.M., Brennand, K.J.
An Efficient Platform for Astrocyte Differentiation from Human Induced Pluripotent Stem Cells
(2017) Stem Cell Reports, . Article in Press. 

DOI: 10.1016/j.stemcr.2017.06.018


a Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA
b Ronald M. Loeb Center for Alzheimer's disease, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA
c Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA
d Department of Genetics and Genomic Sciences, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029, USA
e New York Genome Center, 101 Avenue of the Americas, New York, NY 10013, USA
f Department of Psychiatry, Washington University in St. Louis, St. Louis, MO 63130, USA


Abstract
Growing evidence implicates the importance of glia, particularly astrocytes, in neurological and psychiatric diseases. Here, we describe a rapid and robust method for the differentiation of highly pure populations of replicative astrocytes from human induced pluripotent stem cells (hiPSCs), via a neural progenitor cell (NPC) intermediate. We evaluated this protocol across 42 NPC lines (derived from 30 individuals). Transcriptomic analysis demonstrated that hiPSC-astrocytes from four individuals are highly similar to primary human fetal astrocytes and characteristic of a non-reactive state. hiPSC-astrocytes respond to inflammatory stimulants, display phagocytic capacity, and enhance microglial phagocytosis. hiPSC-astrocytes also possess spontaneous calcium transient activity. Our protocol is a reproducible, straightforward (single medium), and rapid (<30 days) method to generate populations of hiPSC-astrocytes that can be used for neuron-astrocyte and microglia-astrocyte co-cultures for the study of neuropsychiatric disorders. Brennand, Goate, and colleagues report a rapid and robust method for the differentiation of highly pure populations of replicative astrocytes from human induced pluripotent stem cells (hiPSCs) via a neural progenitor cell (NPC) intermediate. hiPSC-astrocytes resemble primary human fetal astrocytes, have a transcriptional signature consistent with a non-reactive state, respond to inflammatory stimulants, and enhance microglial phagocytosis. © 2017 The Author(s).


Author Keywords
Astrocyte;  Human induced pluripotent stem cell;  IPSC


Document Type: Article in Press
Source: Scopus

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20) 

Agrawal, A., Nelson, E.C., Bucholz, K.K., Tillman, R., Grucza, R.A., Statham, D.J., Madden, P.A.F., Martin, N.G., Heath, A.C., Lynskey, M.T.
Major depressive disorder, suicidal thoughts and behaviours, and cannabis involvement in discordant twins: A retrospective cohort study
(2017) The Lancet Psychiatry, . Article in Press. 

DOI: 10.1016/S2215-0366(17)30280-8


a Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA
b QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
c University of the Sunshine Coast, Sippy Downs, QLD, Australia
d National Addictions Centre, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK


Abstract
Background: Early and frequent cannabis use are associated with an increased likelihood of major depressive disorder (MDD) as well as suicidal thoughts and behaviours. We identify associations between aspects of cannabis use, MDD, and suicidal thoughts and behaviours and examine whether such associations persist after accounting for those predisposing factors, including genetic liability and early family environment, that are shared by identical twins who are discordant for cannabis exposure. Any residual association in such identical pairs might be indicative of individual-specific pathways that might be of a causal nature. Methods: We did a logistic regression analysis of cannabis use from retrospective data on same-sex male and female twin pairs drawn from 3 studies that had recruited twins from the Australian Twin Registry, 1992-93 (sample 1), 1996-2000 (sample 2), and 2005-09 (sample 3). We studied associations between early use and frequent use of cannabis and MDD, suicidal ideation (ever and persistent), and suicide plan and attempt in the full sample as well as in pairs of monozygotic and dizygotic twins that were discordant for each measure of cannabis involvement at a single timepoint. Significant monozygotic associations were further adjusted for covariates, such as early alcohol or nicotine use, early dysphoric or anhedonic mood, conduct disorder, and childhood sexual abuse. Interactions between each cannabis measure and sex, sample or study effects, and birth year category were also examined as covariates. Findings: In 13 986 twins (6181 monozygotic and 7805 dizygotic), cannabis use ranged from 1345 (30·4%) of 4432 people in sample 1 to 2275 (69·0%) of 3299 in sample 3. Mean age of first cannabis use ranged from 17·9 years (SD 3·3) in sample 3 to 21·1 years (5·2) in sample 1, and frequent use (≥100 times) was reported by 214 (15·9%) of 1345 users in sample 1 and 499 (21·9%) of 2275 in sample 3. The prevalence of suicidal ideation ranged from 1102 (24·9%) of 4432 people in sample 1 to 1644 (26·3%) of 6255 people in sample 2 and 865 (26·2%) of 3299 people in sample 3. Prevalence of MDD ranged from 901 (20·3%) people in sample 1 to 1773 (28·3%) in sample 2. The monozygotic twin who used cannabis frequently was more likely to report MDD (odds ratio 1·98, 95% CI 1·11-3·53) and suicidal ideation (2·47, 1·19-5·10) compared with their identical twin who had used cannabis less frequently, even after adjustment for covariates. For early cannabis use, the monozygotic point estimate was not significant but could be equated to the significant dizygotic estimate, suggesting a possible association with suicidal ideation. Interpretation: The increased likelihood of MDD and suicidal ideation in frequent cannabis users cannot be solely attributed to common predisposing factors. Funding: National Institute on Drug Abuse, National Institutes of Health, Australian National Health and Medical Research Council. © 2017 Elsevier Ltd.


Document Type: Article in Press
Source: Scopus

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21) 

Chitnis, T., Graves, J., Weinstock-Guttman, B., Belman, A., Olsen, C., Misra, M., Aaen, G., Benson, L., Candee, M., Gorman, M., Greenberg, B., Krupp, L., Lotze, T., Mar, S., Ness, J., Rose, J., Rubin, J., Schreiner, T., Tillema, J., Waldman, A., Rodriguez, M., Casper, C., Waubant, E.
Distinct effects of obesity and puberty on risk and age at onset of pediatric MS
(2016) Annals of Clinical and Translational Neurology, 3 (12), pp. 897-907. 

DOI: 10.1002/acn3.365


a Partners Pediatric Multiple Sclerosis Center, Massachusetts General Hospital for Children, Boston, MA, United States
b Department of Neurology, University of California, San Francisco, CA, United States
c Pediatric Multiple Sclerosis Center, Jacobs Neurological Institute, SUNY Buffalo, NY, United States
d Lourie Center for Pediatric MS, Stony Brook Children's Hospital, Stonybrook, NY, United States
e Department of Pediatrics, University of Utah, Salt Lake City, UT, United States
f Department of Pediatric Endocrinology, Massachusetts General Hospital for Children, Boston, MA, United States
g Pediatric MS Center at Loma Linda University Children's Hospital, Loma Linda, CA, United States
h Boston Children's Hospital, Boston, MA, United States
i University of Utah/Primary Children's Hospital, Salt Lake City, UT, United States
j Department of Neurology, UT Southwestern, Dallas, TX, United States
k Blue Bird Circle Multiple Sclerosis Center, Baylor College of Medicine, Houston, TX, United States
l Pediatric Onset Demyelinating Diseases and Autoimmune Encephalitis Center, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, MO, United States
m University of Alabama Center for Pediatric Onset Demyelinating Disease, Children's Hospital of Alabama, Birmingham, AL, United States
n Department of Neurology, University of Utah, Salt Lake City, UT, United States
o Department of Pediatric Neurology, Northwestern Feinberg School of Medicine, Chicago, IL, United States
p Children's Hospital Colorado, University of Colorado, Denver, CO, United States
q Mayo Clinic's Pediatric MS Center, Rochester, MN, United States
r Department of Neurology, University of Pennsylvania, Philadelphia, PA, United States
s Department of Pediatrics, Benioff Children's Hospital, University of California, San Francisco, CA, United States


Abstract
Objective: The aim of this study was to examine the relative contributions of body mass index (BMI) and pubertal measures for risk and age of onset of pediatric MS. Methods: Case–control study of 254 (63% female) MS cases (onset<18 years of age) and 420 (49% female) controls conducted at 14 U.S. Pediatric MS Centers. Sex- and age-stratified BMI percentiles were calculated using CDC growth charts from height and weight measured at enrollment for controls, and within 1 year of onset for MS cases. Sex-stratified associations between MS risk and age at symptom onset with both BMI and pubertal factors were estimated controlling for race and ethnicity. Results: Only 11% of girls and 15% of boys were prepubertal (Tanner stage I) at MS onset. 80% of girls had onset of MS after menarche. BMI percentiles were higher in MS cases versus controls (girls: P < 0.001; boys: P = 0.018). BMI was associated with odds of MS in multivariate models in postpubertal girls (OR = 1.60, 95% confidence interval [CI]: 1.12, 2.27, P = 0.009) and boys (OR = 1.43, 95% CI: 1.08, 1.88, P = 0.011). In girls with MS onset after menarche, higher BMI was associated with younger age at first symptoms (P = 0.031). Younger menarche was associated with stronger effects of BMI through mediation and interaction analysis. In pubertal/postpubertal boys, 89% of whom were obese/overweight, earlier sexual maturity was associated with earlier onset of MS (P < 0.001). Interpretation: Higher BMI in early adolescence is a risk factor for MS in girls and boys. Earlier age at sexual maturity contributes to earlier age at MS onset, particularly in association with obesity. © 2016 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.


Document Type: Article
Source: Scopus