In the News
Dr. Buxbaum discusses autism care in The Daily News feature The Daily Check Up.
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Dr. Buxbaum discusses treating autism in The Daily News feature The Daily Check Up.
Alzheimer's Disease, Autism, Behavior, Demyelination, Gene Regulation, Genetics, Genomics, Human Genetics and Genetic Disorders, Knockout Mice, Metastasis, Microarray, Molecular Biology, Myelination, Neurobiology, Protein Structure/Function, Schizophrenia, Signal Transduction, Stem Cells, Synapses, Synaptic Plasticity, Synaptogenesis, Transgenic Mice
Genetics and Genomic Sciences [GGS], Neuroscience [NEU]
BSc, Touro College
MSc, Weizmann Institute of Science
PhD, Weizmann Institute of Science
Laboratory of Molecular Neuropsychiatry
The laboratory of Molecular Neuropsychiatry studies human psychiatric and neurological diseases using the methods of genetics, genomics, cell and molecular biology and animal models. Current laboratory focus includes autism, schizophrenia and Alzheimer's disease.
In autism, we are using techniques of molecular genetics to identify, and ultimately characterize, genes that contribute to autism susceptibility. Using population-based gene mapping studies (including linkage and association studies), we have identified a region on chromosome 2 that appears to harbor an autism susceptibility gene. In that region, we have identified an aspartate-glutamate carrier (AGC1) that appears to contribute to autism susceptibility. We are characterizing AGC1 functionally using cell and animal models, while continuing to study it genetically. We are also working with a large consortium to identify additional autism susceptibility genes. These studies implicate neuronal cell adhesion molecules and synaptic proteins in autism and we are developing mouse models that can recapitulate aspects of the disorders.
In schizophrenia, we are following up on microarray studies that implicate oligodendrocyte abnormalities and offer the first cell based explanation for the disease. Microarray studies carried out at Mount Sinai demonstrated a reduction in schizophrenia of genes associated with oligodendrocytes. This finding has been replicated in multiple independent laboratories. These observations, coupled with more recent observations identifying neuregulin as a susceptibility gene for schizophrenia, have led us to postulate an oligodendrocyte etiology to schizophrenia. We are making use of cell biological and animal model to follow up on this initial observation. We are also testing these genes for genetic association with schizophrenia.
In Alzheimer's disease, we are interested in the biological functions of the Alzheimer amyloid protein precursor (APP) as it apparently regulates transcription via a signal transduction process. We are looking at this process to identify which genes are regulated by APP. Moreover, we are interested in characterizing the function of the protein calsenin, and related calsenin-like protein (CALP), as they may be involved in the cleavage of APP and hence modulate the accumulation of the amyloid Abeta protein, which is pathological in Alzheimer's disease.
Trainees have the opportunity to join these projects and participate in the molecular analysis of these common neurological diseases, using state-of-the-art biochemical, molecular and cell biological techniques. RNA profiling and other genome-based techniques are also used to identify changes ingene and protein expression in the brains of individuals with these disorders.
Kajiwara Y, McKenzie A, Dorr N, Gama Sosa MA, Elder G, Schmeidler J, Dickstein DL, Bozdagi O, Zhang B, Buxbaum JD. The human-specific CASP4 gene contributes to Alzheimer-related synaptic and behavioral deficits. Human molecular genetics 2016 Aug;.
Daskalakis NP, Cohen H, Nievergelt CM, Baker DG, Buxbaum JD, Russo SJ, Yehuda R. New translational perspectives for blood-based biomarkers of PTSD: From glucocorticoid to immune mediators of stress susceptibility. Experimental neurology 2016 Jul;.
Mehta D, Tropf FC, Gratten J, Bakshi A, Zhu Z, Bacanu SA, Hemani G, Magnusson PK, Barban N, Esko T, Metspalu A, Snieder H, Mowry BJ, Kendler KS, Yang J, Visscher PM, McGrath JJ, Mills MC, Wray NR, Lee SH, Andreassen OA, Bramon E, Bruggeman R, Buxbaum JD, Cairns MJ, Cantor RM, Cloninger CR, Cohen D, Crespo-Facorro B, Darvasi A, DeLisi LE, Dinan T, Djurovic S, Donohoe G, Drapeau E, Escott-Price V, Freimer NB, Georgieva L, de Haan L, Henskens FA, Joa I, Julià A, Khrunin A, Lerer B, Limborska S, Loughland CM, Macek M, Magnusson PK, Marsal S, McCarley RW, McIntosh AM, McQuillin A, Melegh B, Michie PT, Morris DW, Murphy KC, Myin-Germeys I, Olincy A, Van Os J, Pantelis C, Posthuma D, Quested D, Schall U, Scott RJ, Seidman LJ, Toncheva D, Tooney PA, Waddington J, Weinberger DR, Weiser M, Wu JQ. Evidence for Genetic Overlap Between Schizophrenia and Age at First Birth in Women. JAMA psychiatry 2016 Mar;.
Wang AT, Lim T, Jamison J, Bush L, Soorya LV, Tavassoli T, Siper PM, Buxbaum JD, Kolevzon A. Neural selectivity for communicative auditory signals in Phelan-McDermid syndrome. Journal of neurodevelopmental disorders 2016 Feb; 8.
Scheckel C, Drapeau E, Frias MA, Park CY, Fak J, Zucker-Scharff I, Kou Y, Haroutunian V, Ma'ayan A, Buxbaum JD, Darnell RB. Regulatory consequences of neuronal ELAV-like protein binding to coding and non-coding RNAs in human brain. eLife 2016 Feb; 5.
Hsiao K, Harony-Nicolas H, Buxbaum JD, Bozdagi-Gunal O, Benson DL. Cyfip1 Regulates Presynaptic Activity during Development. The Journal of neuroscience : the official journal of the Society for Neuroscience 2016 Feb; 36(5).
Ionita-Laza I, McCallum K, Xu B, Buxbaum JD. A spectral approach integrating functional genomic annotations for coding and noncoding variants. Nature genetics 2016 Jan;.
Tavassoli T, Bellesheim K, Tommerdahl M, Holden JM, Kolevzon A, Buxbaum JD. Altered tactile processing in children with autism spectrum disorder. Autism research : official journal of the International Society for Autism Research 2015 Nov;.
Sanders SJ, He X, Willsey AJ, Ercan-Sencicek AG, Samocha KE, Cicek AE, Murtha MT, Bal VH, Bishop SL, Dong S, Goldberg AP, Jinlu C, Keaney JF, Klei L, Mandell JD, Moreno-De-Luca D, Poultney CS, Robinson EB, Smith L, Solli-Nowlan T, Su MY, Teran NA, Walker MF, Werling DM, Beaudet AL, Cantor RM, Fombonne E, Geschwind DH, Grice DE, Lord C, Lowe JK, Mane SM, Martin DM, Morrow EM, Talkowski ME, Sutcliffe JS, Walsh CA, Yu TW, Ledbetter DH, Martin CL, Cook EH, Buxbaum JD, Daly MJ, Devlin B, Roeder K, State MW. Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci. Neuron 2015 Sep; 87(6).
Ghani M, Reitz C, Cheng R, Vardarajan BN, Jun G, Sato C, Naj A, Rajbhandary R, Wang LS, Valladares O, Lin CF, Larson EB, Graff-Radford NR, Evans D, De Jager PL, Crane PK, Buxbaum JD, Murrell JR, Raj T, Ertekin-Taner N, Logue M, Baldwin CT, Green RC, Barnes LL, Cantwell LB, Fallin MD, Go RC, Griffith PA, Obisesan TO, Manly JJ, Lunetta KL, Kamboh MI, Lopez OL, Bennett DA, Hendrie H, Hall KS, Goate AM, Byrd GS, Kukull WA, Foroud TM, Haines JL, Farrer LA, Pericak-Vance MA, Lee JH, Schellenberg GD, St George-Hyslop P, Mayeux R, Rogaeva E. Association of Long Runs of Homozygosity With Alzheimer Disease Among African American Individuals. JAMA neurology 2015 Sep;.
Harony-Nicolas H, De Rubeis S, Kolevzon A, Buxbaum JD. Phelan McDermid Syndrome: From Genetic Discoveries to Animal Models and Treatment. Journal of child neurology 2015 Sep;.
Tavassoli T, Bellesheim K, Siper PM, Wang AT, Halpern D, Gorenstein M, Grodberg D, Kolevzon A, Buxbaum JD. Measuring Sensory Reactivity in Autism Spectrum Disorder: Application and Simplification of a Clinician-Administered Sensory Observation Scale. Journal of autism and developmental disorders 2015 Sep;.
Grodberg D, Siper P, Jamison J, Buxbaum JD, Kolevzon A. A Simplified Diagnostic Observational Assessment of Autism Spectrum Disorder in Early Childhood. Autism research : official journal of the International Society for Autism Research 2015 Aug;.
Aachoui Y, Kajiwara Y, Leaf IA, Mao D, Ting JP, Coers J, Aderem A, Buxbaum JD, Miao EA. Canonical Inflammasomes Drive IFN-γ to Prime Caspase-11 in Defense against a Cytosol-Invasive Bacterium. Cell host & microbe 2015 Aug;.
De Rubeis S, Buxbaum JD. Genetics and genomics of autism spectrum disorder: Embracing complexity. Human molecular genetics 2015 Jul;.
Uppal N, Puri R, Yuk F, Janssen WG, Bozdagi-Gunal O, Harony-Nicolas H, Dickstein DL, Buxbaum JD, Hof PR. Ultrastructural analyses in the hippocampus CA1 field in Shank3-deficient mice. Molecular autism 2015 Jun; 6.
Hohman TJ, Cooke-Bailey JN, Reitz C, Jun G, Naj A, Beecham GW, Liu Z, Carney RM, Vance JM, Cuccaro ML, Rajbhandary R, Vardarajan BN, Wang LS, Valladares O, Lin CF, Larson EB, Graff-Radford NR, Evans D, De Jager PL, Crane PK, Buxbaum JD, Murrell JR, Raj T, Ertekin-Taner N, Logue MW, Baldwin CT, Green RC, Barnes LL, Cantwell LB, Fallin MD, Go RC, Griffith P, Obisesan TO, Manly JJ, Lunetta KL, Kamboh MI, Lopez OL, Bennett DA, Hardy J, Hendrie HC, Hall KS, Goate AM, Lang R, Byrd GS, Kukull WA, Foroud TM, Farrer LA, Martin ER, Pericak-Vance MA, Schellenberg GD, Mayeux R, Haines JL, Thornton-Wells TA. Global and local ancestry in African-Americans: Implications for Alzheimer's disease risk. Alzheimer's & dementia : the journal of the Alzheimer's Association 2015 Jun;.
De Rubeis S, Buxbaum JD. Recent advances in the genetics of autism spectrum disorder. Current neurology and neuroscience reports 2015 Jun; 15(6).
Duffney LJ, Zhong P, Wei J, Matas E, Cheng J, Qin L, Ma K, Dietz DM, Kajiwara Y, Buxbaum JD, Yan Z. Autism-like Deficits in Shank3-Deficient Mice Are Rescued by Targeting Actin Regulators. Cell reports 2015 May;.
Lai MC, Baron-Cohen S, Buxbaum JD. Understanding autism in the light of sex/gender. Molecular autism 2015 May; 6.
Buxbaum JD. DSM-5 and Psychiatric Genetics - Round Hole, Meet Square Peg. Biological psychiatry 2015 May; 77(9).
Kozol RA, Cukier HN, Zou B, Mayo V, De Rubeis S, Cai G, Griswold AJ, Whitehead PL, Haines JL, Gilbert JR, Cuccaro ML, Martin ER, Baker JD, Buxbaum JD, Pericak-Vance MA, Dallman JE. Two knockdown models of the autism genes SYNGAP1 and SHANK3 in zebrafish produce similar behavioral phenotypes associated with embryonic disruptions of brain morphogenesis. Human molecular genetics 2015 Apr;.
Landrigan PJ, Baker DB. The National Children's Study--end or new beginning?. The New England journal of medicine 2015 Apr; 372(16).
Cochoy DM, Kolevzon A, Kajiwara Y, Schoen M, Pascual-Lucas M, Lurie S, Buxbaum JD, Boeckers TM, Schmeisser MJ. Phenotypic and functional analysis of SHANK3 stop mutations identified in individuals with ASD and/or ID. Molecular autism 2015 Apr; 6.
Jun G, Ibrahim-Verbaas CA, Vronskaya M, Lambert JC, Chung J, Naj AC, Kunkle BW, Wang LS, Bis JC, Bellenguez C, Harold D, Lunetta KL, Destefano AL, Grenier-Boley B, Sims R, Beecham GW, Smith AV, Chouraki V, Hamilton-Nelson KL, Ikram MA, Fievet N, Denning N, Martin ER, Schmidt H, Kamatani Y, Dunstan ML, Valladares O, Laza AR, Zelenika D, Ramirez A, Foroud TM, Choi SH, Boland A, Becker T, Kukull WA, van der Lee SJ, Pasquier F, Cruchaga C, Beekly D, Fitzpatrick AL, Hanon O, Gill M, Barber R, Gudnason V, Campion D, Love S, Bennett DA, Amin N, Berr C, Tsolaki M, Buxbaum JD, Lopez OL, Deramecourt V, Fox NC, Cantwell LB, Tárraga L, Dufouil C, Hardy J, Crane PK, Eiriksdottir G, Hannequin D, Clarke R, Evans D, Mosley TH, Letenneur L, Brayne C, Maier W, De Jager P, Emilsson V, Dartigues JF, Hampel H, Kamboh MI, de Bruijn RF, Tzourio C, Pastor P, Larson EB, Rotter JI, O'Donovan MC, Montine TJ, Nalls MA, Mead S, Reiman EM, Jonsson PV, Holmes C, St George-Hyslop PH, Boada M, Passmore P, Wendland JR, Schmidt R, Morgan K, Winslow AR, Powell JF, Carasquillo M, Younkin SG, Jakobsdóttir J, Kauwe JS, Wilhelmsen KC, Rujescu D, Nöthen MM, Hofman A, Jones L, Haines JL, Psaty BM, Van Broeckhoven C, Holmans P, Launer LJ, Mayeux R, Lathrop M, Goate AM, Escott-Price V, Seshadri S, Pericak-Vance MA, Amouyel P, Williams J, van Duijn CM, Schellenberg GD, Farrer LA. A novel Alzheimer disease locus located near the gene encoding tau protein. Molecular psychiatry 2015 Mar;.
Soorya LV, Siper PM, Beck T, Soffes S, Halpern D, Gorenstein M, Kolevzon A, Buxbaum J, Wang AT. Randomized comparative trial of a social cognitive skills group for children with autism spectrum disorder. Journal of the American Academy of Child and Adolescent Psychiatry 2015 Mar; 54(3).
Browne HA, Hansen SN, Buxbaum JD, Gair SL, Nissen JB, Nikolajsen KH, Schendel DE, Reichenberg A, Parner ET, Grice DE. Familial Clustering of Tic Disorders and Obsessive-Compulsive Disorder. JAMA psychiatry 2015 Feb;.
Wang LS, Naj AC, Graham RR, Crane PK, Kunkle BW, Cruchaga C, Murcia JD, Cannon-Albright L, Baldwin CT, Zetterberg H, Blennow K, Kukull WA, Faber KM, Schupf N, Norton MC, Tschanz JT, Munger RG, Corcoran CD, Rogaeva E, Lin CF, Dombroski BA, Cantwell LB, Partch A, Valladares O, Hakonarson H, St George-Hyslop P, Green RC, Goate AM, Foroud TM, Carney RM, Larson EB, Behrens TW, Kauwe JS, Haines JL, Farrer LA, Pericak-Vance MA, Mayeux R, Schellenberg GD, Albert MS, Albin RL, Apostolova LG, Arnold SE, Barber R, Barmada MM, Barnes LL, Beach TG, Becker JT, Beecham GW, Beekly D, Bennett DA, Bigio EH, Bird TD, Blacker D, Boeve BF, Bowen JD, Boxer A, Burke JR, Buxbaum JD, Cairns NJ, Cao C, Carlson CS, Carroll SL, Chui HC, Clark DG, Cribbs DH, Crocco EA, DeCarli C, DeKosky ST, Demirci FY, Dick M, Dickson DW, Duara R, Ertekin-Taner N, Fallon KB, Farlow MR, Ferris S, Frosch MP, Galasko DR, Ganguli M, Gearing M, Geschwind DH, Ghetti B, Gilbert JR, Glass JD, Graff-Radford NR, Growdon JH, Hamilton RL, Hamilton-Nelson KL, Harrell LE, Head E, Honig LS, Hulette CM, Hyman BT, Jarvik GP, Jicha GA, Jin LW, Jun G, Kamboh MI, Karydas A, Kaye JA, Kim R, Koo EH, Kowall NW, Kramer JH, Kramer P, LaFerla FM, Lah JJ, Leverenz JB, Levey AI, Li G, Lieberman AP, Lopez OL, Lunetta KL, Lyketsos CG, Mack WJ, Marson DC, Martin ER, Martiniuk F, Mash DC, Masliah E, McCormick WC, McCurry SM, McDavid AN, McKee AC, Mesulam MM, Miller BL, Miller CA, Miller JW, Montine TJ, Morris JC, Murrell JR, Olichney JM, Parisi JE, Perry W, Peskind E, Petersen RC, Pierce A, Poon WW, Potter H, Quinn JF, Raj A, Raskind M, Reiman EM, Reisberg B, Reitz C, Ringman JM, Roberson ED, Rosen HJ, Rosenberg RN, Sano M, Saykin AJ, Schneider JA, Schneider LS, Seeley WW, Smith AG, Sonnen JA, Spina S, Stern RA, Tanzi RE, Thornton-Wells TA, Trojanowski JQ, Troncoso JC, Tsuang DW, Van Deerlin VM, Van Eldik LJ, Vardarajan BN, Vinters HV, Vonsattel JP, Weintraub S, Welsh-Bohmer KA, Williamson J, Wishnek S, Woltjer RL, Wright CB, Younkin SG, Yu CE, Yu L. Rarity of the Alzheimer Disease-Protective APP A673T Variant in the United States. JAMA neurology 2015 Feb; 72(2).
Beecham GW, Dickson DW, Scott WK, Martin ER, Schellenberg G, Nuytemans K, Larson EB, Buxbaum JD, Trojanowski JQ, Van Deerlin VM, Hurtig HI, Mash DC, Beach TG, Troncoso JC, Pletnikova O, Frosch MP, Ghetti B, Foroud TM, Honig LS, Marder K, Vonsattel JP, Goldman SM, Vinters HV, Ross OA, Wszolek ZK, Wang L, Dykxhoorn DM, Pericak-Vance MA, Montine TJ, Leverenz JB, Dawson TM, Vance JM. PARK10 is a major locus for sporadic neuropathologically confirmed Parkinson disease. Neurology 2015 Feb;.
Ionita-Laza I, Capanu M, De Rubeis S, McCallum K, Buxbaum JD. Identification of Rare Causal Variants in Sequence-Based Studies: Methods and Applications to VPS13B, a Gene Involved in Cohen Syndrome and Autism. PLoS genetics 2014 Dec; 10(12).
Kolevzon A, Bush L, Wang AT, Halpern D, Frank Y, Grodberg D, Rapaport R, Tavassoli T, Chaplin W, Soorya L, Buxbaum JD. A pilot controlled trial of insulin-like growth factor-1 in children with Phelan-McDermid syndrome. Molecular autism 2014 Dec; 5(1).
De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Ercument Cicek A, Kou Y, Liu L, Fromer M, Walker S, Singh T, Klei L, Kosmicki J, Fu SC, Aleksic B, Biscaldi M, Bolton PF, Brownfeld JM, Cai J, Campbell NG, Carracedo A, Chahrour MH, Chiocchetti AG, Coon H, Crawford EL, Crooks L, Curran SR, Dawson G, Duketis E, Fernandez BA, Gallagher L, Geller E, Guter SJ, Sean Hill R, Ionita-Laza I, Jimenez Gonzalez P, Kilpinen H, Klauck SM, Kolevzon A, Lee I, Lei J, Lehtimäki T, Lin CF, Ma'ayan A, Marshall CR, McInnes AL, Neale B, Owen MJ, Ozaki N, Parellada M, Parr JR, Purcell S, Puura K, Rajagopalan D, Rehnström K, Reichenberg A, Sabo A, Sachse M, Sanders SJ, Schafer C, Schulte-Rüther M, Skuse D, Stevens C, Szatmari P, Tammimies K, Valladares O, Voran A, Wang LS, Weiss LA, Jeremy Willsey A, Yu TW, Yuen RK, Cook EH, Freitag CM, Gill M, Hultman CM, Lehner T, Palotie A, Schellenberg GD, Sklar P, State MW, Sutcliffe JS, Walsh CA, Scherer SW, Zwick ME, Barrett JC, Cutler DJ, Roeder K, Devlin B, Daly MJ, Buxbaum JD. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 2014 Nov; 515(7526).
Elder ga, Ragnauth a, Dorr n, Franciosi s, Schmeidler j, Haroutunian v, Buxbaum jd. Increased locomotor activity in mice lacking the low-density lipoprotein receptor. Behav Brain Rsrch 2008; 191.
Gotham k, Risi s, Dawson g, Tager-Flusberg h, Joseph r, Carter a, Hepburn s, McMahon w, Rodier p, Hyman sl, Sigman m, Rogers s, Landa r, Spence ma, Osann k, Flodman p, Volkmar f, Hollander e, Buxbaum j, Pickles a, Lord c. A replication of the Autism Diagnostic Observation Schedule (ADOS) revised algorithms. J Am Acad Child Adolesc Psychiatry 2008; 47.
Ramoz n, Cai g, Reichert jg, Silverman jm, Buxbaum jd. An analysis of candidate autism loci on chromosome 2q24-q33: Evidence for association to the STK39 gene. Neuropsychiatr Genet 2008;.
Ikin af, Causevic m, Pedrini s, Benson ls, Buxbaum jd, Suzuki t, Lovestone s, Higashiyama s, Mustelin t, Burgoyne rd, Gandy s. Evidence against roles for phorbol binding protein Munc13-1, ADAM adaptor Eve-1, or vesicle trafficking phosphoproteins Munc18 or NSF in phorbol/PKC-activated Alzheimer APP ectodomain shedding. Mol Neurodegener 2007;.
Lepagnol-Bestel am, Maussion g, Boda b, Cardona a, Iwayama y, Delezoide al, Moalic jm, Muller d, Dean b, Yoshikawa t, Gorwood p, Buxbaum jd, Ramoz n, Simonneau m. SLC25A12 expression is associated with neurite outgrowth and is upregulated in the prefrontal cortex of autistic subjects. Mol. Psych 2008; 13.
Elder ga, Cho jy, English df, Franciosi s, Schmeidler j, Gama Sosa ma, De Gasperi r, Fisher ea, Mathews pm, Haroutunian v, Buxbaum jd. Elevated plasma cholesterol does not affect brain AB in mice lacking the low-density lipoprotein receptor. J. Neurochem 2007; 102.
Buxbaum jd, Georgieva l, Young jj, Plescia c, Kajiwara y, Jiang y, Moskvina v, Norton n, Peirce t, Williams h, Craddock nj, Carroll l, Corfas g, Davis kl, Owen mj, Harroch s, Sakurai t, O'Donovan mc. Molecular dissection of NRG1-ERBB4 signalling implicates PTPRZ1 as a potential schizophrenia susceptibility gene. Mol. Psych 2008; 13.
Ikin af, Sabo sl, Lanier lm, Buxbaum jd. A macromolecular complex involving the amyloid precursor protein (APP) and the cytosolic adapter FE65 is a negative regulator of axon branching. Mol. Cell. Neurosci 2007; 35.
Buxbaum jd, Cai g, Chaste p, Nygren g, Goldsmith j, Reichert j, Anckarsater h, Rastam m, Smith cj, Silverman jm, Hollander e, Leboyer m, Gillberg c, Verloes a, Betancur c. Mutation screening of the PTEN gene in patients with autism spectrum disorders and macrocephaly. Neuropsych. Genet 2007; 144.
T. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat. Genet 2007; 39.
Physicians and scientists on the faculty of the Icahn School of Medicine at Mount Sinai often interact with pharmaceutical, device and biotechnology companies to improve patient care, develop new therapies and achieve scientific breakthroughs. In order to promote an ethical and transparent environment for conducting research, providing clinical care and teaching, Mount Sinai requires that salaried faculty inform the School of their relationships with such companies.
Below are financial relationships with industry reported by Dr. Buxbaum during 2015 and/or 2016. Please note that this information may differ from information posted on corporate sites due to timing or classification differences.
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