Arts & Sciences Brown School McKelvey School Medicine Weekly Publications

WashU weekly Neuroscience publications

“Matrine inhibits itching by lowering the activity of calcium channel” (2018) Scientific Reports

Matrine inhibits itching by lowering the activity of calcium channel
(2018) Scientific Reports, 8 (1), art. no. 11328, . 

Geng, X.a , Shi, H.a , Ye, F.a , Du, H.b , Qian, L.a , Gu, L.a , Wu, G.a , Zhu, C.a , Yang, Y.a , Wang, C.a , Zhou, Y.a , Yu, G.a , Liu, Q.c , Dong, X.d e , Yu, L.a , Tang, Z.a

a State Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, China
b MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing, China
c Department of Anesthesiology and the Center for the Study of Itch, Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St Louis, MO, United States
d The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, School of Medicine, Johns Hopkins University, Baltimore, MD, United States
e Howard Hughes Medical Institute, School of Medicine, Johns Hopkins University, Baltimore, MD, United States

Abstract
Sophorae Flavescentis Radix (SFR) is a medicinal herb with many functions that are involved in anti-inflammation, antinociception, and anticancer. SFR is also used to treat a variety of itching diseases. Matrine (MT) is one of the main constituents in SFR and also has the effect of relieving itching, but the antipruritic mechanism is still unclear. Here, we investigated the effect of MT on anti-pruritus. In acute and chronic itch models, MT significantly inhibited the scratching behavior not only in acute itching induced by histamine (His), chloroquine (CQ) and compound 48/80 with a dose-depended manner, but also in the chronic pruritus models of atopic dermatitis (AD) and acetone-ether-water (AEW) in mice. Furthermore, MT could be detected in the blood after intraperitoneal injection (i.p.) and subcutaneous injection (s.c.). Finally, electrophysiological and calcium imaging results showed that MT inhibited the excitatory synaptic transmission from dorsal root ganglion (DRG) to the dorsal horn of the spinal cord by suppressing the presynaptic N-type calcium channel. Taken together, we believe that MT is a novel drug candidate in treating pruritus diseases, especially for histamine-independent and chronic pruritus, which might be attributed to inhibition of the presynaptic N-type calcium channel. © 2018, The Author(s).

Document Type: Article
Source: Scopus
Access Type: Open Access

“Using temporal ICA to selectively remove global noise while preserving global signal in functional MRI data” (2018) NeuroImage

Using temporal ICA to selectively remove global noise while preserving global signal in functional MRI data
(2018) NeuroImage, 181, pp. 692-717. 

Glasser, M.F.a b , Coalson, T.S.a , Bijsterbosch, J.D.c , Harrison, S.J.c , Harms, M.P.d , Anticevic, A.e , Van Essen, D.C.a , Smith, S.M.c

a Department of Neuroscience, Washington University Medical School, Saint Louis, MO, United States
b St. Luke’s Hospital, Saint Louis, MO, United States
c Centre for Functional MRI of the Brain (FMRIB), Wellcome Centre for Integrative Neuroimaging, Nuffield Department of Clinical Neurosciences, University of Oxford. John Radcliffe Hospital, Headley Way, Oxford, United Kingdom
d Department of Psychiatry, Washington University Medical School, Saint Louis, MO, United States
e Department of Psychiatry, Yale University School of Medicine, 300 George Street, New Haven, CT, United States

Abstract
Temporal fluctuations in functional Magnetic Resonance Imaging (fMRI) have been profitably used to study brain activity and connectivity for over two decades. Unfortunately, fMRI data also contain structured temporal “noise” from a variety of sources, including subject motion, subject physiology, and the MRI equipment. Recently, methods have been developed to automatically and selectively remove spatially specific structured noise from fMRI data using spatial Independent Components Analysis (ICA) and machine learning classifiers. Spatial ICA is particularly effective at removing spatially specific structured noise from high temporal and spatial resolution fMRI data of the type acquired by the Human Connectome Project and similar studies. However, spatial ICA is mathematically, by design, unable to separate spatially widespread “global” structured noise from fMRI data (e.g., blood flow modulations from subject respiration). No methods currently exist to selectively and completely remove global structured noise while retaining the global signal from neural activity. This has left the field in a quandary—to do or not to do global signal regression—given that both choices have substantial downsides. Here we show that temporal ICA can selectively segregate and remove global structured noise while retaining global neural signal in both task-based and resting state fMRI data. We compare the results before and after temporal ICA cleanup to those from global signal regression and show that temporal ICA cleanup removes the global positive biases caused by global physiological noise without inducing the network-specific negative biases of global signal regression. We believe that temporal ICA cleanup provides a “best of both worlds” solution to the global signal and global noise dilemma and that temporal ICA itself unlocks interesting neurobiological insights from fMRI data. © 2018 Elsevier Inc.

Document Type: Article
Source: Scopus

“PDCB does not promote CNS autoimmunity in the context of genetic susceptibility but worsens its outcome” (2018) Journal of Neuroimmunology

PDCB does not promote CNS autoimmunity in the context of genetic susceptibility but worsens its outcome
(2018) Journal of Neuroimmunology, 323, pp. 53-55. 

Dubey, D.a b c , Hussain, R.Z.a , Miller-Little, W.A.a , Salter, A.d , Doelger, R.a , Stüve, O.a e

a Department of Neurology & Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, United States
b Department of Neurology, Mayo Clinic, Rochester, United States
c Department of Neurology, Brigham & Women’s Hospital and Massachusetts’s General Hospital, Boston, United States
d Division of Biostatistics, Washington University School of Medicine, St. Louis, United States
e Department of Neurology, VA North Texas Health Care System, Medical Service, Dallas, United States

Abstract
Background: Para-dichlorobenzene (PDCB) is an aromatic hydrocarbon contained in mothballs that is potentially neurotoxic. A potential pathogenic role of PDCB in MS pathogenesis has been suggested. Methods: To determine the ability of chronic PDCB ingestion to induce CNS autoimmunity in a genetically susceptible mammalian species, naive myelin oligodendrocyte glycoprotein peptide (MOGp)35–55 T cell receptor (TCR) transgenic mice (2D2) on the C57Bl/6 background were orally gavaged once daily with corn oil control, 125 mg/kg PDCB, or 250 mg/kg PDCB for 45 days. The incidence of spontaneous EAE is increased in this mouse strain. Results: Both PDCB treatment groups showed the same spontaneous incidence of EAE, an earlier disease onset, and a slight decrease in survival for 125 mg/kg PDCB mice compared to control mice. We were unable to detect any PDCB, or its metabolites 2,5-dichlorophenol, 2,5-dicholormethylsulfide, and 2,5-dichloromethylsulfone in the brain and spinal cord of control mice. In contrast, PDCB was readily detectable in both compartments in mice who received PDCB via oral gavage, with concentrations being significantly higher in the brain (p < 0.01). Levels of the metabolites 2,5-dichlorophenol and 2,5-dichloromethylsulfone were also significantly higher in brains compared to spinal cords. Conclusion: Our study refutes the hypothesis that PDCB or its metabolites trigger spontaneous T cell-mediated CNS autoimmunity in the setting of genetic susceptibility. A slight increase in mortality with PDCB exposure may be due systemic toxicity of hydrocarbons. © 2018

Document Type: Article
Source: Scopus

“Geometric classification of brain network dynamics via conic derivative discriminants” (2018) Journal of Neuroscience Methods

Geometric classification of brain network dynamics via conic derivative discriminants
(2018) Journal of Neuroscience Methods, 308, pp. 88-105. 

Singh, M.F.a b c , Braver, T.S.b , Ching, S.c d

a Department of Neuroscience, Washington University in St. Louis, St. Louis, MO, United States
b Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States
c Department of Electrical and Systems Engineering, Washington University in St. Louis, St. Louis, MO, United States
d Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Background: Over the past decade, pattern decoding techniques have granted neuroscientists improved anatomical specificity in mapping neural representations associated with function and cognition. Dynamical patterns are of particular interest, as evidenced by the proliferation and success of frequency domain methods that reveal structured spatiotemporal rhythmic brain activity. One drawback of such approaches, however, is the need to estimate spectral power, which limits the temporal resolution of classification. New method: We propose an alternative method that enables classification of dynamical patterns with high temporal fidelity. The key feature of the method is a conversion of time-series data into temporal derivatives. By doing so, dynamically-coded information may be revealed in terms of geometric patterns in the phase space of the derivative signal. Results: We derive a geometric classifier for this problem which simplifies into a straightforward calculation in terms of covariances. We demonstrate the relative advantages and disadvantages of the technique with simulated data and benchmark its performance with an EEG dataset of covert spatial attention. We reveal the timecourse of covert spatial attention and, by mapping the classifier weights anatomically, its retinotopic organization. Comparison with existing method: We especially highlight the ability of the method to provide strong group-level classification performance compared to existing benchmarks, while providing information that is complementary with classical spectral-based techniques. The robustness and sensitivity of the method to noise is also examined relative to spectral-based techniques. Conclusion: The proposed classification technique enables decoding of dynamic patterns with high temporal resolution, performs favorably to benchmark methods, and facilitates anatomical inference. © 2018

Author Keywords
Directional statistics;  Dynamical systems;  EEG;  Machine learning;  Neural dynamics;  Pattern classification

Document Type: Article
Source: Scopus

“Continuity and stability of preschool depression from childhood through adolescence and following the onset of puberty” (2018) Comprehensive Psychiatry

Continuity and stability of preschool depression from childhood through adolescence and following the onset of puberty
(2018) Comprehensive Psychiatry, 86, pp. 39-46. 

Gaffrey, M.S.a b , Tillman, R.a , Barch, D.M.a c , Luby, J.L.a

a Washington University, Department of Psychiatry, Saint Louis, MO, United States
b Duke University, Department of Psychology and Neuroscience, Durham, NC, United States
c Washington University, Department of Psychological and Brain Sciences, Saint Louis, MO, United States

Abstract
Background: A growing body of research now supports the validity, clinical significance, and long-term negative impact of depression occurring during the preschool period. However, the prospective continuity of depressive symptoms and risk for major depressive disorder (MDD) from childhood through adolescence for preschoolers experiencing this highly impairing disorder remains unexplored. Such information is likely to be critical for understanding the developmental continuity of preschool depression and whether it continues to be a salient risk factor for an MDD diagnosis following the transition into adolescence and the onset of biological changes associated with it (i.e., puberty). Methods: Subjects were participants in the Preschool Depression Study conducted at the Early Emotional Development Program at Washington University School of Medicine in St. Louis. Subjects and their parents completed baseline assessments that included comprehensive measures of psychopathology and development at baseline and up to 9 follow-up assessments between 2003 and 2017. N = 279 subjects had diagnostic and clinical data available for the preschool period and the early pubertal and/or later pubertal periods and were included in the analyses. There were N = 275 subjects assessed during the early pubertal period and N = 184 subjects assessed during the later pubertal period. Results: Preschool depression was a highly salient predictor of prepubertal and mid-to-post pubertal MDD. Across all modeled time points children with a history of preschool depression continued to demonstrate elevated levels of depressive symptoms from childhood through adolescence, suggesting a heightened trajectory of depressive symptoms relative to their same age peers. Conclusion: Findings from the current study suggest that children with a history of preschool depression follow a trajectory of depression severity elevated relative to their same age peers from childhood through adolescence but with a similar shape over time. They also support the homotypic continuity of preschool depression into adolescence and the onset of puberty. © 2018

Document Type: Article
Source: Scopus

“Statistical Characterization of Human Brain Deformation during Mild Angular Acceleration Measured in Vivo by Tagged Magnetic Resonance Imaging” (2018) Journal of Biomechanical Engineering

Statistical Characterization of Human Brain Deformation during Mild Angular Acceleration Measured in Vivo by Tagged Magnetic Resonance Imaging
(2018) Journal of Biomechanical Engineering, 140 (10), art. no. 101005, . 

Chan, D.D.a , Knutsen, A.K.b , Lu, Y.-C.b , Yang, S.H.b , Magrath, E.b , Wang, W.-T.b , Bayly, P.V.c , Butman, J.A.d , Pham, D.L.e

a Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY, United States
b Center for Neuroscience and Regenerative Medicine, Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, United States
c Department of Mechanical Engineering and Materials Science, Washington University at St. Louis, St. Louis, MO, United States
d Radiology and Imaging Sciences, National Institutes of Health Clinical Center, Bethesda, MD, United States
e Center for Neuroscience and Regenerative Medicine, Henry M. Jackson Foundation for the Advancement of Military Medicine, 10 Center Drive, Bethesda, MD, United States

Abstract
Understanding of in vivo brain biomechanical behavior is critical in the study of traumatic brain injury (TBI) mechanisms and prevention. Using tagged magnetic resonance imaging, we measured spatiotemporal brain deformations in 34 healthy human volunteers under mild angular accelerations of the head. Two-dimensional (2D) Lagrangian strains were examined throughout the brain in each subject. Strain metrics peaked shortly after contact with a padded stop, corresponding to the inertial response of the brain after head deceleration. Maximum shear strain of at least 3% was experienced at peak deformation by an area fraction (median6standard error) of 23.561.8% of cortical gray matter, 15.961.4% of white matter, and 4.061.5% of deep gray matter. Cortical gray matter strains were greater in the temporal cortex on the side of the initial contact with the padded stop and also in the contralateral temporal, frontal, and parietal cortex. These tissue-level deformations from a population of healthy volunteers provide the first in vivo measurements of full-volume brain deformation in response to known kinematics. Although strains differed in different tissue type and cortical lobes, no significant differences between male and female head accelerations or strain metrics were found. These cumulative results highlight important kinematic features of the brain’s mechanical response and can be used to facilitate the evaluation of computational simulations of TBI. Copyright © 2018 by ASME.

Author Keywords
Angular acceleration;  Brain biomechanics;  Computational models;  In vivo;  Magnetic resonance imaging

Document Type: Article
Source: Scopus

“Focused ultrasound combined with microbubble-mediated intranasal delivery of gold nanoclusters to the brain” (2018) Journal of Controlled Release

Focused ultrasound combined with microbubble-mediated intranasal delivery of gold nanoclusters to the brain
(2018) Journal of Controlled Release, 286, pp. 145-153. 

Ye, D.a , Zhang, X.b , Yue, Y.c , Raliya, R.d , Biswas, P.d , Taylor, S.e , Tai, Y.-C.b , Rubin, J.B.e f , Liu, Y.b , Chen, H.c g

a Department of Mechanical Engineering and Material Science, Washington University in St. Louis, Saint Louis, MO, United States
b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Biomedical Engineering, Washington University in St. Louis, Saint Louis, MO, United States
d Department of Energy, Environmental & Chemical Engineering, Washington University in St. Louis, Saint Louis, MO, United States
e Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
f Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
g Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, MO, United States

Abstract
Focused ultrasound combined with microbubble-mediated intranasal delivery (FUSIN) is a new brain drug delivery technique. FUSIN utilizes the nasal route for direct nose-to-brain drug administration, thereby bypassing the blood-brain barrier (BBB) and minimizing systemic exposure. It also uses FUS-induced microbubble cavitation to enhance transport of intranasally (IN) administered agents to the FUS-targeted brain location. Previous studies have provided proof-of-concept data showing the feasibility of FUSIN to deliver dextran and the brain-derived neurotrophic factor to the caudate putamen of mouse brains. The objective of this study was to evaluate the biodistribution of IN administered gold nanoclusters (AuNCs) and assess the feasibility and short-term safety of FUSIN for the delivery of AuNCs to the brainstem. Three experiments were performed. First, the whole-body biodistribution of IN administered 64Cu-alloyed AuNCs (64Cu-AuNCs) was assessed using in vivo positron emission tomography/computed tomography (PET/CT) and verified with ex vivo gamma counting. Control mice were intravenously (IV) injected with the 64Cu-AuNCs. Second, 64Cu-AuNCs and Texas red-labeled AuNCs (TR-AuNCs) were used separately to evaluate FUSIN delivery outcome in the brain. 64Cu-AuNCs or TR-AuNCs were administered to mice through the nasal route, followed by FUS sonication at the brainstem in the presence of systemically injected microbubbles. The spatial distribution of 64Cu-AuNCs and TR-AuNCs were examined by autoradiography and fluorescence microscopy of ex vivo brain slices, respectively. Third, histological analysis was performed to evaluate any potential histological damage to the nose and brain after FUSIN treatment. The experimental results revealed that IN administration induced significantly lower 64Cu-AuNCs accumulation in the blood, lungs, liver, spleen, kidney, and heart compared with IV injection. FUSIN enhanced the delivery of 64Cu-AuNCs and TR-AuNCs at the FUS-targeted brain region compared with IN delivery alone. No histological-level tissue damage was detected in the nose, trigeminal nerve, and brain. These results suggest that FUSIN is a promising technique for noninvasive, spatially targeted, and safe delivery of nanoparticles to the brain with minimal systemic exposure. © 2018 Elsevier B.V.

Author Keywords
Blood-brain barrier;  Brain drug delivery;  Brainstem;  Focused ultrasound;  Intranasal delivery;  Nanoparticle;  Positron emission tomography

Document Type: Article
Source: Scopus

“Potentiating Hsp104 activity via phosphomimetic mutations in the middle domain” (2018) FEMS Yeast Research

Potentiating Hsp104 activity via phosphomimetic mutations in the middle domain
(2018) FEMS Yeast Research, 18 (5), art. no. foy042, . 

Tariq, A.a c , Lin, J.a , Noll, M.M.a , Torrente, M.P.a , Mack, K.L.a b , Murillo, O.H.a , Jackrel, M.E.a d , Shorter, J.a b

a Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, United States
b Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
c Chemistry Department of Brooklyn College, Ph.D. Programs in Chemistry, Biochemistry and Biology, Graduate Center of the City University of New York, New York, NY, United States
d Department of Chemistry, Washington University, St. Louis, MO, United States

Abstract
Hsp104 is a hexameric AAA + ATPase and protein disaggregase found in yeast, which can be potentiated via mutations in its middle domain (MD) to counter toxic phase separation by TDP-43, FUS and a-synuclein connected to devastating neurodegenerative disorders. Subtle missense mutations in the Hsp104 MD can enhance activity, indicating that post-translational modification of specific MD residues might also potentiate Hsp104. Indeed, several serine and threonine residues throughout Hsp104 can be phosphorylated in vivo. Here, we introduce phosphomimetic aspartate or glutamate residues at these positions and assess Hsp104 activity. Remarkably, phosphomimetic T499D/E and S535D/E mutations in the MD enable Hsp104 to counter TDP-43, FUS and a-synuclein aggregation and toxicity in yeast, whereas T499A/V/I and S535A do not. Moreover, Hsp104T499E and Hsp104S535E exhibit enhanced ATPase activity and Hsp70-independent disaggregase activity in vitro. We suggest that phosphorylation of T499 or S535 may elicit enhanced Hsp104 disaggregase activity in a reversible and regulated manner. © FEMS 2018.

Author Keywords
ALS;  Disaggregase;  Hsp104;  Neurodegeneration;  PD;  TDP-43

Document Type: Article
Source: Scopus

“Focused Ultrasound Enabled Trans-Blood Brain Barrier Delivery of Gold Nanoclusters: Effect of Surface Charges and Quantification Using Positron Emission Tomography” (2018) Small

Focused Ultrasound Enabled Trans-Blood Brain Barrier Delivery of Gold Nanoclusters: Effect of Surface Charges and Quantification Using Positron Emission Tomography
(2018) Small, 14 (30), art. no. 1703115, . 

Sultan, D.a , Ye, D.b , Heo, G.S.a , Zhang, X.a , Luehmann, H.a , Yue, Y.c , Detering, L.a , Komarov, S.a , Taylor, S.d , Tai, Y.-C.a , Rubin, J.B.d , Chen, H.e , Liu, Y.a

a Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Mechanical Engineering and Material Science, Washington University in St. Louis, St. Louis, MO, United States
c Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
d Department of Pediatrics and Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
e Department of Biomedical Engineering and Department of Radiation Oncology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Focused ultrasound (FUS) technology is reported to enhance the delivery of 64Cu-integrated ultrasmall gold nanoclusters (64Cu-AuNCs) across the blood-brain barrier (BBB) as measured by positron emission tomography (PET). To better define the optimal physical properties for brain delivery, 64Cu-AuNCs with different surface charges are synthesized and characterized. In vivo biodistribution studies are performed to compare the individual organ uptake of each type of 64Cu-AuNCs. Quantitative PET imaging post-FUS treatment shows site-targeted brain penetration, retention, and diffusion of the negative, neutral, and positive 64Cu-AuNCs. Autoradiography is performed to compare the intrabrain distribution of these nanoclusters. PET Imaging demonstrates the effective BBB opening and successful delivery of 64Cu-AuNCs into the brain. Of the three 64Cu-AuNCs investigated, the neutrally charged nanostructure performs the best and is the candidate platform for future theranostic applications in neuro-oncology. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Author Keywords
brain;  focused ultrasound;  imaging;  nanoclusters;  positron emission tomography

Document Type: Article
Source: Scopus

“Human fibroblast and stem cell resource from the Dominantly Inherited Alzheimer Network” (2018) Alzheimer’s Research and Therapy

Human fibroblast and stem cell resource from the Dominantly Inherited Alzheimer Network
(2018) Alzheimer’s Research and Therapy, 10 (1), art. no. 69, . 

Karch, C.M.a , Hernández, D.b c , Wang, J.-C.d , Marsh, J.a , Hewitt, A.W.b c e , Hsu, S.a , Norton, J.a , Levitch, D.f , Donahue, T.f , Sigurdson, W.f , Ghetti, B.g , Farlow, M.h , Chhatwal, J.i , Berman, S.j , Cruchaga, C.a , Morris, J.C.f , Bateman, R.J.f , Pébay, A.b c , Goate, A.M.d

a Department of Psychiatry, Washington University School of Medicine, Campus-Box 8134, 660 South Euclid Avenue, St. Louis, MO, United States
b Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC, Australia
c Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, VIC, Australia
d Department of Neuroscience, Department of Genetics and Genomic Sciences, Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY, United States
e School of Medicine, Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia
f Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO, United States
g Department of Pathology and Laboratory Medicine, Indiana University, 635 Barnhill Drive, MS A 142, Indianapolis, IN, United States
h Department of Neurology, Indiana University, 635 Barnhill Drive, MS A 142, Indianapolis, IN, United States
i Massachusetts General Hospital, Athinoula A. Martinos Center for Biomedical Imaging, 149 13th Street, Charlestown, MA, United States
j Alzheimer Disease Research Center, University of Pittsburgh School of Medicine, 4-West Montefiore University Hospital, 200 Lothrop Street, Pittsburgh, PA, United States

Abstract
Background: Mutations in amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) cause autosomal dominant forms of Alzheimer disease (ADAD). More than 280 pathogenic mutations have been reported in APP, PSEN1, and PSEN2. However, understanding of the basic biological mechanisms that drive the disease are limited. The Dominantly Inherited Alzheimer Network (DIAN) is an international observational study of APP, PSEN1, and PSEN2 mutation carriers with the goal of determining the sequence of changes in presymptomatic mutation carriers who are destined to develop Alzheimer disease. Results: We generated a library of 98 dermal fibroblast lines from 42 ADAD families enrolled in DIAN. We have reprogrammed a subset of the DIAN fibroblast lines into patient-specific induced pluripotent stem cell (iPSC) lines. These cells were thoroughly characterized for pluripotency markers. Conclusions: This library represents a comprehensive resource that can be used for disease modeling and the development of novel therapeutics. © 2018 The Author(s).

Author Keywords
Amyloid precursor protein;  Dominantly Inherited Alzheimer Network;  Fibroblasts;  Induced pluripotent stem cells;  Presenilin 1;  Presenilin 2

Document Type: Article
Source: Scopus

“Improved adductor function after canine recurrent laryngeal nerve injury and repair using muscle progenitor cells” (2018) Laryngoscope

Improved adductor function after canine recurrent laryngeal nerve injury and repair using muscle progenitor cells
(2018) Laryngoscope, 128 (7), pp. E241-E246. 

Paniello, R.C.a , Brookes, S.b , Bhatt, N.K.a , Bijangi-Vishehsaraei, K.c , Zhang, H.b , Halum, S.b

a Department of Otolaryngology–Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO, United States
b Department of Otolaryngology–Head and Neck Surgery, Purdue University, Indianapolis, IN, United States
c Department of Otolaryngology–Head and Neck Surgery, Indiana University, Indianapolis, IN, United States

Abstract
Objective: Muscle progenitor cells (MPCs) can be isolated from muscle samples and grown to a critical mass in culture. They have been shown to survive and integrate when implanted into rat laryngeal muscles. In this study, the ability of MPC implants to enhance adductor function of reinnervated thyroarytenoid muscles was tested in a canine model. Study Design: Animal study. Methods: Sternocleidomastoid muscle samples were harvested from three canines. Muscle progenitor cells were isolated and cultured to 107 cells over 4 to 5 weeks, then implanted into right thyroarytenoid muscles after ipsilateral recurrent laryngeal nerve transection and repair. The left sides underwent the same nerve injury, but no cells were implanted. Laryngeal adductor force was measured pretreatment and again 6 months later, and the muscles were harvested for histology. Results: Muscle progenitor cells were successfully cultured from all dogs. Laryngeal adductor force measurements averaged 60% of their baseline pretreatment values in nonimplanted controls, 98% after implantation with MPCs, and 128% after implantation with motor endplate-enhanced MPCs. Histology confirmed that the implanted MPCs survived, became integrated into thyroarytenoid muscle fibers, and were in close contact with nerve endings, suggesting functional innervation. Conclusion: Muscle progenitor cells were shown to significantly enhance adductor function in this pilot canine study. Patient-specific MPC implantation could potentially be used to improve laryngeal function in patients with vocal fold paresis/paralysis, atrophy, and other conditions. Further experiments are planned. Level of Evidence: NA. Laryngoscope, 2017. © 2017 The American Laryngological, Rhinological and Otological Society, Inc.

Author Keywords
innervation;  Larynx;  paralysis;  recurrent laryngeal nerve;  stem cells

Document Type: Article
Source: Scopus

“Infantile exotropia and developmental delay” (2018) Journal of Pediatric Ophthalmology and Strabismus

Infantile exotropia and developmental delay
(2018) Journal of Pediatric Ophthalmology and Strabismus, 55 (4), pp. 225-228. 

Lueder, G.T., Galli, M.

Departments of Ophthalmology and Visual Sciences and Pediatrics, St. Louis Children’s Hospital, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Purpose: To evaluate a group of infants with this disorder to determine the long-term outcome of surgery and to assess the need for neurologic evaluations. Methods: This interventional case series reviewed the records of infants who underwent surgery for the treatment of exotropia with onset during the first year of life. The preoperative ophthalmic and systemic findings, treatment, and developmental and ophthalmic outcomes were reviewed. Surgery was considered successful if the horizontal deviation was less than 10 prism diopters (PD). Developmental assessments were obtained at each visit. Results: Twenty-six patients presented between age 2 and 10 months with exotropia ranging from 20 to 95 PD. Ten (38%) patients had a developmental delay that was recognized at the first visit, 9 of whom had a systemic diagnosis at that time; the other patients remained developmentally normal during a mean follow-up of 7 years. Age at surgery ranged from 4 to 18 months. Surgery was successful in 10 (38%) of 26 patients after 1 surgery and in an additional 13 (50%) of 26 patients after a second surgery. Conclusions: In this study, the need for more than 1 surgery was higher in infantile exotropia when compared to other forms of childhood strabismus, but most children achieved good alignment with one or two surgeries. Developmental delay is common in patients with infantile exotropia, but this was usually recognized at the time of the initial evaluation. In the current patients, routine neurologic screening or imaging of these otherwise developmentally normal infants was not required. © 2018 Healio.

Document Type: Article
Source: Scopus

“LONGO: An R package for interactive gene length dependent analysis for neuronal identity” (2018) Bioinformatics

LONGO: An R package for interactive gene length dependent analysis for neuronal identity
(2018) Bioinformatics, 34 (13), pp. i422-i428. 

McCoy, M.J.a , Paul, A.J.b , Victor, M.B.a , Richner, M.a c , Gabel, H.W.d , Gong, H.e , Yoo, A.S.a , Ahn, T.-H.b f

a Department of Developmental Biology, Washington University School of Medicine, Saint Louis, MO, United States
b Program in Bioinformatics and Computational Biology, Saint Louis University, Saint Louis, MO, United States
c Department of Molecular Biosciences, Northwestern University, Evanston, IL, United States
d Department of Neuroscience, Washington University School of Medicine, Saint Louis, MO, United States
e Department of Mathematics and Statistics, Saint Louis University, Saint Louis, MO, United States
f Department of Computer Science, Saint Louis University, Saint Louis, MO, United States

Abstract
Motivation: Reprogramming somatic cells into neurons holds great promise to model neuronal development and disease. The efficiency and success rate of neuronal reprogramming, however, may vary between different conversion platforms and cell types, thereby necessitating an unbiased, systematic approach to estimate neuronal identity of converted cells. Recent studies have demonstrated that long genes (>100 kb from transcription start to end) are highly enriched in neurons, which provides an opportunity to identify neurons based on the expression of these long genes. Results: We have developed a versatile R package, LONGO, to analyze gene expression based on gene length. We propose a systematic analysis of long gene expression (LGE) with a metric termed the long gene quotient (LQ) that quantifies LGE in RNA-seq or microarray data to validate neuronal identity at the single-cell and population levels. This unique feature of neurons provides an opportunity to utilize measurements of LGE in transcriptome data to quickly and easily distinguish neurons from non-neuronal cells. By combining this conceptual advancement and statistical tool in a user-friendly and interactive software package, we intend to encourage and simplify further investigation into LGE, particularly as it applies to validating and improving neuronal differentiation and reprogramming methodologies. © The Author(s) 2018. Published by Oxford University Press. All rights reserved.

Document Type: Conference Paper
Source: Scopus
Access Type: Open Access

“The presentation of the mind-brain problem in leading psychiatry journals” (2018) Revista Brasileira de Psiquiatria

The presentation of the mind-brain problem in leading psychiatry journals
(2018) Revista Brasileira de Psiquiatria, 40 (3), pp. 335-342. 

Moreira-Almeida, A.a , Araujo, S.F.b , Cloninger, C.R.c

a Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal de Juiz de Fora (UFJF), Juiz de Fora, MG, Brazil
b Departamento de Psicologia, UFJF, Juiz de Fora, MG, Brazil
c Washington University School of Medicine, St. Louis, MO, United States

Abstract
Objective: The mind-brain problem (MBP) has marked implications for psychiatry, but has been poorly discussed in the psychiatric literature. This paper evaluates the presentation of the MBP in the three leading general psychiatry journals during the last 20 years. Methods: Systematic review of articles on the MBP published in the three general psychiatry journals with the highest impact factor from 1995 to 2015. The content of these articles was analyzed and discussed in the light of contemporary debates on the MBP. Results: Twenty-three papers, usually written by prestigious authors, explicitly discussed the MBP and received many citations (mean = 130). The two main categories were critiques of dualism and defenses of physicalism (mind as a brain product). These papers revealed several misrepresentations of theoretical positions and lacked relevant contemporary literature. Without further discussion or evidence, they presented the MBP as solved, dualism as an old-fashioned or superstitious idea, and physicalism as the only rational and empirically confirmed option. Conclusion: The MBP has not been properly presented and discussed in the three leading psychiatric journals in the last 20 years. The few articles on the topic have been highly cited, but reveal misrepresentations and lack of careful philosophical discussion, as well as a strong bias against dualism and toward a materialist/physicalist approach to psychiatry. © 2018, Associacao Brasileira de Psiquiatria. All rights reserved.

Author Keywords
Body-mind relations;  Neuropsychiatry;  Neurosciences;  Philosophy;  Psychiatry

Document Type: Article
Source: Scopus

“De novo mutation screening in childhood-onset cerebellar atrophy identifies gain-of-function mutations in the CACNA1G calcium channel gene” (2018) Brain

De novo mutation screening in childhood-onset cerebellar atrophy identifies gain-of-function mutations in the CACNA1G calcium channel gene
(2018) Brain, 141 (7), pp. 1998-2013. 

Chemin, J.a b , Siquier-Pernet, K.c d , Nicouleau, M.c d , Barcia, G.c d , Ahmad, A.a b , Medina-Cano, D.c d , Hanein, S.e , Altin, N.c d , Hubert, L.e , Bole-Feysot, C.f , Fourage, C.g h , Nitschké, P.g , Thevenon, J.i , Rio, M.d h , Blanc, P.d h , Vidal, C.e , Bahi-Buisson, N.c j k , Desguerre, I.c k , Munnich, A.c h , Lyonnet, S.c h j , Boddaert, N.c l m , Fassi, E.n , Shinawi, M.n , Zimmerman, H.o , Amiel, J.c h j , Faivre, L.i , Colleaux, L.c d , Lory, P.a b , Cantagrel, V.c d

a IGF, CNRS, INSERM, University of Montpellier, 141, rue de la Cardonille, Montpellier, France
b LabEx Ion Channel Science and Therapeutics, Montpellier, France
c Paris Descartes – Sorbonne Paris Cité University, Imagine Institute, Lab 323- B3, 24, Bd du Montparnasse, Paris, France
d Laboratory of Developmental Brain Disorders, INSERM UMR, Paris, France
e Translational Genetics, INSERM UMR, Imagine Institute, Paris, France
f Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Genomic Core Facility, Paris, France
g Paris-Descartes Sorbonne Paris-Cité University, Imagine Institute, Bioinformatics Core Facility, Paris, France
h Service de Génétique, Necker Enfants Malades University Hospital, APHP, Paris, France
i Centre de Genetique et Centre de Reference Anomalies du Developpement et Syndromes Malformatifs, Hôpital d’Enfants, CHU Dijon, Dijon, France
j Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR1163, Paris, France
k Service de Neurologie Pédiatrique, Necker Enfants Malades University Hospital, APHP, Paris, France
l Pediatric Radiology Department, Necker Enfants Malades University Hospital, APHP, Paris, France
m Image – Institut Imagine, INSERM UMR1163, INSERM U1000, Université Paris Descartes, Hôpital Necker Enfants Malades, Paris, France
n Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
o Division of Genetics, Department of Pediatrics, University of Mississippi Medical Center, 2500N State St, Jackson, MS, United States

Abstract
Cerebellar atrophy is a key neuroradiological finding usually associated with cerebellar ataxia and cognitive development defect in children. Unlike the adult forms, early onset cerebellar atrophies are classically described as mostly autosomal recessive conditions and the exact contribution of de novo mutations to this phenotype has not been assessed. In contrast, recent studies pinpoint the high prevalence of pathogenic de novo mutations in other developmental disorders such as intellectual disability, autism spectrum disorders and epilepsy. Here, we investigated a cohort of 47 patients with early onset cerebellar atrophy and/or hypoplasia using a custom gene panel as well as whole exome sequencing. De novo mutations were identified in 35% of patients while 27% had mutations inherited in an autosomal recessive manner. Understanding if these de novo events act through a loss or a gain of function effect is critical for treatment considerations. To gain a better insight into the disease mechanisms causing these cerebellar defects, we focused on CACNA1G, a gene not yet associated with the early-onset form. This gene encodes the Ca v 3.1 subunit of T-type calcium channels highly expressed in Purkinje neurons and deep cerebellar nuclei. We identified four patients with de novo CACNA1G mutations. They all display severe motor and cognitive impairment, cerebellar atrophy as well as variable features such as facial dysmorphisms, digital anomalies, microcephaly and epilepsy. Three subjects share a recurrent c.2881G>A/p.Ala961Thr variant while the fourth patient has the c.4591A>G/p.Met1531Val variant. Both mutations drastically impaired channel inactivation properties with significantly slower kinetics ( 1/45 times) and negatively shifted potential for half-inactivation (>10 mV). In addition, these two mutations increase neuronal firing in a cerebellar nuclear neuron model and promote a larger window current fully inhibited by TTA-P2, a selective T-type channel blocker. This study highlights the prevalence of de novo mutations in early-onset cerebellar atrophy and demonstrates that A961T and M1531V are gain of function mutations. Moreover, it reveals that aberrant activity of Ca v 3.1 channels can markedly alter brain development and suggests that this condition could be amenable to treatment. © The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain.

Author Keywords
Ca v 3.1;  CACNA1G;  cerebellar atrophy;  de novo mutation;  voltage-gated calcium channel

Document Type: Article
Source: Scopus

“Classification of producer characteristics in primate long calls using neural networks” (2018) Journal of the Acoustical Society of America

Classification of producer characteristics in primate long calls using neural networks
(2018) Journal of the Acoustical Society of America, 144 (1), pp. 344-353. 

Robakis, E.a , Watsa, M.b , Erkenswick, G.b

a Washington University in Saint Louis, One Brookings Drive, St. Louis, MO, United States
b Field Projects International, 7331 Murdoch Avenue, St. Louis, MO, United States

Abstract
Primate long calls are high-amplitude vocalizations that can be critical in maintaining intragroup contact and intergroup spacing, and can encode abundant information about a call’s producer, such as age, sex, and individual identity. Long calls of the wild emperor (Saguinus imperator) and saddleback (Leontocebus weddelli) tamarins were tested for these identity signals using artificial neural networks, machine-learning models that reduce subjectivity in vocalization classification. To assess whether modelling could be streamlined by using only factors which were responsible for the majority of variation within networks, each series of networks was re-trained after implementing two methods of feature selection. First, networks were trained and run using only the subset of variables whose weights accounted for ≥50% of each original network’s variation, as identified by the networks themselves. In the second, only variables implemented by decision trees in predicting outcomes were used. Networks predicted dependent variables above chance (≥58.7% for sex, ≥69.2 for age class, and ≥38.8% for seven to eight individuals), but classification accuracy was not markedly improved by feature selection. Findings are discussed with regard to implications for future studies on identity signaling in vocalizations and streamlining of data analysis. © 2018 Acoustical Society of America.

Document Type: Article
Source: Scopus

“Transcranial magnetic stimulation in the treatment of peripartum bipolar depression: A case report” (2018) Revista Brasileira de Psiquiatria

Transcranial magnetic stimulation in the treatment of peripartum bipolar depression: A case report
(2018) Revista Brasileira de Psiquiatria, 40 (3), pp. 344-345. 

Xiong, W.a , Lopez, R.b , Cristancho, P.c

a Department of Psychiatry, New York University, New York, NY, United States
b Facultad de Medicina, Universidad Adventista del Plata, Entre Ríos, Argentina
c Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, United States

Document Type: Letter
Source: Scopus

“Short delay in initiation of radiotherapy for patients with glioblastoma-effect of concurrent chemotherapy: A secondary analysis from the NRG Oncology/Radiation Therapy Oncology Group database” (2018) Neuro-Oncology

Short delay in initiation of radiotherapy for patients with glioblastoma-effect of concurrent chemotherapy: A secondary analysis from the NRG Oncology/Radiation Therapy Oncology Group database
(2018) Neuro-Oncology, 20 (7), pp. 966-974. Cited 1 time.

Blumenthal, D.T.a , Won, M.b , Mehta, M.P.c , Gilbert, M.R.d , Brown, P.D.e f , Bokstein, F.a , Brachman, D.G.g , Werner-Wasik, M.h , Hunter, G.K.i , Valeinis, E.j , Hopkins, K.k , Souhami, L.l , Howard, S.P.m , Lieberman, F.S.n , Shrieve, D.C.o , Wendland, M.M.p , Robinson, C.G.q , Zhang, P.b , Corn, B.W.a

a Tel Aviv Sourasky Medical Center, 6 Weizmann St., Tel Aviv, Israel
b NRG Oncology Statistics and Data Management Center, Philadelphia, PA, United States
c Baptist Hospital of Miami, Miami, FL, United States
d National Institutes of Health Clinical Center, Bethesda, MD, United States
e University of Texas-MD Anderson Cancer Center, Houston, TX, United States
f Mayo Clinic, Rochester, MN, United States
g Saint Joseph’s Hospital and Medical Center ACCRUALS for Arizona Oncology Services Foundation, Phoenix, Arizona, United States
h Thomas Jefferson University Hospital, Philadelphia, PA, United States
i Intermountain Medical Center, Murray, UA, United States
j Paulus Stradins Clinical University Hospital-EORTC, Riga, Latvia
k Bristol Oncology Center-EORTC, Bristol, United Kingdom
l McGill University, Montreal, Quebec, Canada
m University of Wisconsin Hospital, Madison, WI, United States
n UPMC-Shadyside Hospital, Pittsburgh, PA, United States
o University of Utah Health Science Center, Salt Lake City, UA, United States
p Willamette Valley Cancer Institute, Eugene, OR, United States
q Washington University, St Louis, MI, United States

Abstract
Background We previously reported the unexpected finding of significantly improved survival for newly diagnosed glioblastoma in patients when radiation therapy (RT) was initiated later (>4 wk post-op) compared with earlier (≤2 wk post-op). In that analysis, data were analyzed from 2855 patients from 16 NRG Oncology/Radiotherapy Oncology Group (RTOG) trials conducted prior to the era of concurrent temozolomide (TMZ) with RT. We now report on 1395 newly diagnosed glioblastomas from 2 studies, treated with RT and concurrent TMZ followed by adjuvant TMZ. Our hypothesis was that concurrent TMZ has a synergistic/radiosensitizing mechanism, making RT timing less significant. Methods Data from patients treated with TMZ-based chemoradiation from NRG Oncology/RTOG 0525 and 0825 were analyzed. An analysis comparable to our prior study was performed to determine whether there was still an impact on survival by delaying RT. Overall survival (OS) was investigated using the Kaplan-Meier method and Cox proportional hazards model. Early progression (during time of diagnosis to 30 days after RT completion) was analyzed using the chi-square test. Results Given the small number of patients who started RT early following surgery, comparisons were made between >4 and ≤4 weeks delay of radiation from time of operation. There was no statistically significant difference in OS (hazard ratio = 0.93; P = 0.29; 95% CI: 0.80-1.07) after adjusting for known prognostic factors (recursive partitioning analysis and O 6 -methylguanine-DNA methyltransferase methylation status). Similarly, the rate of early progression did not differ significantly (P = 0.63). Conclusions We did not observe a significant prognostic influence of delaying radiation when given concurrently with TMZ for newly diagnosed glioblastoma. The effects of early (1-3 wk post-op) or late (>5 wk) initiation of radiation tested in our prior study could not be replicated. © The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
chemoradiation;  delay;  glioblastoma;  survival;  temozolomide

Document Type: Article
Source: Scopus

“Multiple-Choice Testing in Education: Are the Best Practices for Assessment Also Good for Learning?” (2018) Journal of Applied Research in Memory and Cognition

Multiple-Choice Testing in Education: Are the Best Practices for Assessment Also Good for Learning?
(2018) Journal of Applied Research in Memory and Cognition, . Article in Press. 

Butler, A.C.

Washington University in St. Louis, United States

Abstract
Multiple-choice tests are arguably the most popular type of assessment in education, and much research has been dedicated to determining best practices for using them to measure learning. The act of taking a test also causes learning, and numerous studies have investigated how best to use multiple-choice tests to improve long-term retention and produce deeper understanding. In this review article, I explore whether the best practices for assessment align with the best practices for learning. Although consensus between these two literatures is not a foregone conclusion, there is substantial agreement in how best to construct and use multiple-choice tests for these two disparate purposes. The overall recommendation from both literatures is to create questions that are simple in format (e.g., avoid use of complex item types), challenge students but allow them to succeed often, and target specific cognitive processes that correspond to learning objectives. © 2018 Society for Applied Research in Memory and Cognition

Author Keywords
Assessment;  Learning;  Multiple-choice;  Testing

Document Type: Article in Press
Source: Scopus

“Influence of Parental Alcohol Dependence Symptoms and Parenting on Adolescent Risky Drinking and Conduct Problems: A Family Systems Perspective” (2018) Alcoholism: Clinical and Experimental Research

Influence of Parental Alcohol Dependence Symptoms and Parenting on Adolescent Risky Drinking and Conduct Problems: A Family Systems Perspective
(2018) Alcoholism: Clinical and Experimental Research, . Article in Press. 

Su, J.a , Kuo, S.I.-C.a , Aliev, F.b c , Guy, M.C.d , Derlan, C.L.a , Edenberg, H.J.e , Nurnberger, J.I.f , Kramer, J.R.g , Bucholz, K.K.h , Salvatore, J.E.a i , Dick, D.M.a b

a Department of Psychology Virginia Commonwealth University Richmond, Virginia
b College Behavioral and Emotional Health Institute Virginia Commonwealth University Richmond, Virginia
c Faculty of Business Karabuk University Karabuk Turkey
d Department of African American Studies Virginia Commonwealth University Richmond, Virginia
e Department of Biochemistry and Molecular Biology Indiana University Bloomington, Indiana
f Department of Psychiatry Indiana University Bloomington, Indiana
g Department of Psychiatry University of Iowa Iowa City, Iowa
h Department of Psychiatry Washington University in St. Louis St. Louis, Missouri
i Virginia Institute for Psychiatric and Behavioral Genetics Virginia Commonwealth University Richmond, Virginia

Abstract
Background: Parental alcohol problems are associated with adverse adolescent outcomes such as risky drinking and conduct problems. Important questions remain about the unique roles of fathers’ and mothers’ alcohol problems and differences and/or similarities in pathways of risk across ethnicity and gender. In this study, we used a family systems approach to consider spillover and crossover effects of fathers’ and mothers’ alcohol problems (number of alcohol dependence symptoms [ADS]) and parenting behaviors in relation to adolescents’ risky drinking and conduct problems. Methods: The sample included 1,282 adolescents (aged 12 to 17) and their parents from the Collaborative Study on the Genetics of Alcoholism. Parents completed the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA), and adolescents completed an adolescent version of SSAGA. Data were analyzed using multivariate structural equation modeling. Results: Fathers’ ADS count was associated with higher adolescent risky drinking and conduct problems indirectly via disruption to fathers’ and mothers’ positive parenting behaviors, whereas mothers’ ADS count was not associated with adolescents’ risky drinking and conduct problems directly or indirectly via positive parenting behaviors. No differences in these associations were found across ethnic background and offspring gender. Conclusions: Findings highlight the importance of considering the unique roles of fathers’ and mothers’ ADS in influencing family processes and adolescent outcomes. © 2018 Research Society on Alcoholism.

Author Keywords
Alcohol Dependence;  Conduct Problems;  Externalizing;  Parenting;  Risky Drinking

Document Type: Article in Press
Source: Scopus

“Exome sequencing of 85 Williams-Beuren syndrome cases rules out coding variation as a major contributor to remaining variance in social behavior” (2018) Molecular Genetics and Genomic Medicine

Exome sequencing of 85 Williams-Beuren syndrome cases rules out coding variation as a major contributor to remaining variance in social behavior
(2018) Molecular Genetics and Genomic Medicine, . Article in Press. 

Kopp, N.D.a , Parrish, P.C.R.b , Lugo, M.b c , Dougherty, J.D.a d , Kozel, B.A.b c

a Department of Genetics Washington University School of Medicine St. Louis, Missouri
b National Heart Lung and Blood Institute National Institutes of Health Bethesda, Maryland
c Department of Pediatrics Washington University School of Medicine St. Louis, Missouri
d Department of Psychiatry Washington University School of Medicine St. Louis, Missouri

Abstract
Background: Large, multigenic deletions at chromosome 7q11.23 result in a highly penetrant constellation of physical and behavioral symptoms known as Williams-Beuren syndrome (WS). Of particular interest is the unusual social-cognitive profile evidenced by deficits in social cognition and communication reminiscent of autism spectrum disorders (ASD) that are juxtaposed with normal or even relatively enhanced social motivation. Interestingly, duplications in the same region also result in ASD-like phenotypes as well as social phobias. Thus, the region clearly regulates human social motivation and behavior, yet the relevant gene(s) have not been definitively identified. Method: Here, we deeply phenotyped 85 individuals with WS and used exome sequencing to analyze common and rare variation for association with the remaining variance in social behavior as assessed by the Social Responsiveness Scale. Results: We replicated the previously reported unusual juxtaposition of behavioral symptoms in this new patient collection, but we did not find any new alleles of large effect in the targeted analysis of the remaining copy of genes in the Williams syndrome critical region. However, we report on two nominally significant SNPs in two genes that have been implicated in the cognitive and social phenotypes of Williams syndrome, BAZ1B and GTF2IRD1. Secondary discovery driven explorations focusing on known ASD genes and an exome wide scan do not highlight any variants of a large effect. Conclusions: Whole exome sequencing of 85 individuals with WS did not support the hypothesis that there are variants of large effect within the remaining Williams syndrome critical region that contribute to the social phenotype. This deeply phenotyped and genotyped patient cohort with a defined mutation provides the opportunity for similar analyses focusing on noncoding variation and/or other phenotypic domains. © 2018 Wiley Periodicals, Inc.

Author Keywords
Autism spectrum disorder;  Exome variation;  Social responsiveness scale;  Williams-Beuren syndrome

Document Type: Article in Press
Source: Scopus
Access Type: Open Access

“A Systematic Review and Meta-analysis of Ketamine as an Alternative to Opioids for Acute Pain in the Emergency Department” (2018) Academic Emergency Medicine

A Systematic Review and Meta-analysis of Ketamine as an Alternative to Opioids for Acute Pain in the Emergency Department
(2018) Academic Emergency Medicine, . Article in Press. 

Karlow, N.c , Schlaepfer, C.H.c , Stoll, C.R.T.a , Doering, M.c , Carpenter, C.R.b , Colditz, G.A.a , Motov, S.d , Miller, J.e , Schwarz, E.S.b

a Division of Public Health Sciences Washington University School of Medicine St. Louis, MO
b Division of Emergency Medicine Washington University School of Medicine St. Louis, MO
c Washington University School of Medicine St. Louis, MO
d Maimonides Medical Center Brooklyn, NY
e Department of Emergency Medicine Bergan Mercy Medical Center Omaha, NE

Abstract
Background: Opioids are commonly prescribed in the emergency department (ED) for the treatment of acute pain. Analgesic alternatives are being explored in response to an epidemic of opioid misuse. Low-dose ketamine (LDK) is one opioid alternative for the treatment of acute pain in the ED. Objectives: This systematic review and meta-analysis sought to quantify whether LDK is an effective and safe opioid alternative for acute pain reduction in adults in the ED setting. (PROSPERO Registration Number CRD42017065303). Methods: This was a systematic review of randomized controlled trials comparing intravenous opioids to LDK for relief of acute pain in the ED. Studies where the control group initially received opioids prior to ketamine were excluded. A research librarian designed the electronic search strategy. Changes in visual analog scale or numeric rating scale pain scales were analyzed to determine the relative effects of LDK and opioids in the treatment of acute pain. Results: Three studies met the criteria for inclusion in this meta-analysis. Compared to pain scale reduction with morphine, ketamine was not inferior (relative reduction = 0.42, 95% confidence interval = -0.70 to 1.54). No severe adverse events were reported in any study, but higher rates of nonsevere adverse events were observed with ketamine. Conclusions: Ketamine is noninferior to morphine for the control of acute pain, indicating that ketamine can be considered as an alternative to opioids for ED short-term pain control. © 2018 Society for Academic Emergency Medicine.

Document Type: Article in Press
Source: Scopus

“Effects of Flashcards on Learning Authentic Materials: The Role of Detailed Versus Conceptual Flashcards and Individual Differences in Structure-Building Ability” (2018) Journal of Applied Research in Memory and Cognition

Effects of Flashcards on Learning Authentic Materials: The Role of Detailed Versus Conceptual Flashcards and Individual Differences in Structure-Building Ability
(2018) Journal of Applied Research in Memory and Cognition, . Article in Press. 

Lin, C., McDaniel, M.A., Miyatsu, T.

Washington University in St. Louis, United States

Abstract
Little research has examined the fruitfulness of flashcards for improving learning outcomes of authentic classroom material. In Experiment 1, across different content areas flashcards did not significantly increase performance on a final test relative to the free-study condition. Experiment 2 investigated whether providing conceptual flashcards would aid participants’ learning relative to detailed flashcards (the kind generated most frequently by participants). Conceptual flashcards produced superior short-answer test performance than detailed flashcards for less able learners (low structure builders) but not for more able learners (high structure builders). The limited benefits of flashcards appear to reflect several factors: the current sample of students generally recruited effective study strategies (in the free-study condition) and the preponderance of detailed flashcards in both textbook provided materials and student-generated flashcards. Consistent with the material-appropriate processing framework, detailed but not conceptual flashcards would be redundant with encoding normally invited by didactic materials. © 2018 Society for Applied Research in Memory and Cognition

Author Keywords
Flashcards;  Material appropriate processing;  Structure building;  Study strategies

Document Type: Article in Press
Source: Scopus

“The role of Twist1 in mutant huntingtin–induced transcriptional alterations and neurotoxicity” (2018) Journal of Biological Chemistry

The role of Twist1 in mutant huntingtin–induced transcriptional alterations and neurotoxicity
(2018) Journal of Biological Chemistry, 293 (30), pp. 11850-11866.

Pan, Y.a , Zhu, Y.a , Yang, W.b c , Tycksen, E.b , Liu, S.d , Palucki, J.a , Zhu, L.a , Sasaki, Y.c , Sharma, M.K.e , Kim, A.H.a c d f g h , Zhang, B.d f , Yano, H.a c f g h  

a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
b Genome Technology Access Center, Washington University School of Medicine, St. Louis, MO, United States
c Department of Genetics, 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 Center for Biomedical Informatics, Washington University School of Medicine, St. Louis, MO, United States
f Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, United States
g Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
h Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by an abnormal expansion of polyglutamine repeats in the huntingtin protein (Htt). Transcriptional dysregulation is an early event in the course of HD progression and is thought to contribute to disease pathogenesis, but how mutant Htt causes transcriptional alterations and subsequent cell death in neurons is not well understood. RNA-Seq analysis revealed that expression of a mutant Htt fragment in primary cortical neurons leads to robust gene expression changes before neuronal death. Basic helix-loop-helix transcription factor Twist1, which is essential for embryogenesis and is normally expressed at low levels in mature neurons, was substantially up-regulated in mutant Htt–expressing neurons in culture and in the brains of HD mouse models. Knockdown of Twist1 by RNAi in mutant Htt–expressing primary cortical neurons reversed the altered expression of a subset of genes involved in neuronal function and, importantly, abrogated neurotoxicity. Using brain-derived neurotrophic factor (Bdnf), which is known to be involved in HD pathogenesis, as a model gene, we found that Twist1 knockdown could reverse mutant Htt–induced DNA hypermethylation at the Bdnf regulatory region and reactivate Bdnf expression. Together, these results suggest that Twist1 is an important upstream mediator of mutant Htt–induced neuronal death and may in part operate through epigenetic mechanisms. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Document Type: Article
Source: Scopus

“Neuroprotective role of retinal SIRT3 against acute photo-stress” (2017) npj Aging and Mechanisms of Disease

Neuroprotective role of retinal SIRT3 against acute photo-stress
(2017) npj Aging and Mechanisms of Disease, 3 (1), art. no. 19, . 

Ban, N.a b c , Ozawa, Y.a b , Osada, H.a , Lin, J.B.c d , Toda, E.a , Watanabe, M.e , Yuki, K.a b , Kubota, S.a b , Apte, R.S.c d f , Tsubota, K.b

a Laboratory of Retinal Cell Biology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
b Department of Ophthalmology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
c Department of Ophthalmology and Visual Sciences, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
d Neuroscience Program, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
e Graduate School of Media and Governance, Faculty of Environment and Information Studies, Keio University, 5322 Endo, Fujisawa, Kanagawa, Japan
f Department of Developmental Biology, Washington University in St. Louis School of Medicine, St. Louis, MO, United States

Abstract
SIRT3 is a key regulator of mitochondrial reactive oxygen species as well as mitochondrial function. The retina is one of the highest energy-demanding tissues, in which the regulation of reactive oxygen species is critical to prevent retinal neurodegeneration. Although previous reports have demonstrated that SIRT3 is highly expressed in the retina and important in neuroprotection, function of SIRT3 in regulating reactive oxygen species in the retina is largely unknown. In this study, we investigated the role of retinal SIRT3 in a light-induced retinal degeneration model using SIRT3 knockout mice. We demonstrate that SIRT3 deficiency causes acute reactive oxygen species accumulation and endoplasmic reticulum stress in the retina after the light exposure, which leads to increased photoreceptor death, retinal thinning, and decreased retinal function. Using a photoreceptor-derived cell line, we revealed that reactive oxygen species were the upstream initiators of endoplasmic reticulum stress. Under SIRT3 knockdown condition, we demonstrated that decreased superoxide dismutase 2 activity led to elevated intracellular reactive oxygen species. These studies have helped to elucidate the critical role of SIRT3 in photoreceptor neuronal survival, and suggest that SIRT3 might be a therapeutic target for oxidative stress-induced retinal disorders. © 2017, The Author(s).

Document Type: Article
Source: Scopus