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2. Genomic data resources of the Brain Somatic Mosaicism Network for neuropsychiatric diseases.

Author

Garrison, McKinzie, Jang, Yeongjun, Bae, Taejeong, Cherskov, Adriana, Emery, Sarah, Fasching, Liana, Jones, Attila, Moldovan, John, Molitor, Cindy, Pochareddy, Sirisha, Peters, Mette, Shin, Joo, Wang, Yifan, Yang, Xiaoxu, Akbarian, Schahram, Chess, Andrew, Gage, Fred, Gleeson, Joseph, Kidd, Jeffrey, McConnell, Michael, Mills, Ryan, Moran, John, Park, Peter, Sestan, Nenad, Urban, Alexander, Vaccarino, Flora, Walsh, Christopher, Weinberger, Daniel, Wheelan, Sarah, and Abyzov, Alexej

Subjects
Humans, Autism Spectrum Disorder, Mosaicism, Genome, Brain, Genomics
Abstract

Somatic mosaicism is defined as an occurrence of two or more populations of cells having genomic sequences differing at given loci in an individual who is derived from a single zygote. It is a characteristic of multicellular organisms that plays a crucial role in normal development and disease. To study the nature and extent of somatic mosaicism in autism spectrum disorder, bipolar disorder, focal cortical dysplasia, schizophrenia, and Tourette syndrome, a multi-institutional consortium called the Brain Somatic Mosaicism Network (BSMN) was formed through the National Institute of Mental Health (NIMH). In addition to genomic data of affected and neurotypical brains, the BSMN also developed and validated a best practices somatic single nucleotide variant calling workflow through the analysis of reference brain tissue. These resources, which include >400 terabytes of data from 1087 subjects, are now available to the research community via the NIMH Data Archive (NDA) and are described here.

Published
2023

3. BRAT1-related disorders: phenotypic spectrum and phenotype-genotype correlations from 97 patients.

Author

Engel, Camille, Valence, Stéphanie, Delplancq, Geoffroy, Maroofian, Reza, Accogli, Andrea, Agolini, Emanuele, Alkuraya, Fowzan, Baglioni, Valentina, Bagnasco, Irene, Becmeur-Lefebvre, Mathilde, Bertini, Enrico, Borggraefe, Ingo, Brischoux-Boucher, Elise, Bruel, Ange-Line, Brusco, Alfredo, Bubshait, Dalal, Cabrol, Christelle, Cilio, Maria, Cornet, Marie-Coralie, Coubes, Christine, Danhaive, Olivier, Delague, Valérie, Denommé-Pichon, Anne-Sophie, Di Giacomo, Marilena, Doco-Fenzy, Martine, Engels, Hartmut, Cremer, Kirsten, Gérard, Marion, Gleeson, Joseph, Heron, Delphine, Goffeney, Joanna, Guimier, Anne, Harms, Frederike, Houlden, Henry, Iacomino, Michele, Kaiyrzhanov, Rauan, Kamien, Benjamin, Karimiani, Ehsan, Kraus, Dror, Kuentz, Paul, Kutsche, Kerstin, Lederer, Damien, Massingham, Lauren, Mignot, Cyril, Morris-Rosendahl, Déborah, Nagarajan, Lakshmi, Odent, Sylvie, Ormières, Clothilde, Partlow, Jennifer, Pasquier, Laurent, Penney, Lynette, Philippe, Christophe, Piccolo, Gianluca, Poulton, Cathryn, Putoux, Audrey, Rio, Marlène, Rougeot, Christelle, Salpietro, Vincenzo, Scheffer, Ingrid, Schneider, Amy, Srivastava, Siddharth, Straussberg, Rachel, Striano, Pasquale, Valente, Enza, Venot, Perrine, Villard, Laurent, Vitobello, Antonio, Wagner, Johanna, Wagner, Matias, Zaki, Maha, Zara, Federizo, Lesca, Gaetan, Yassaee, Vahid, Miryounesi, Mohammad, Hashemi-Gorji, Farzad, Beiraghi, Mehran, Ashrafzadeh, Farah, Galehdari, Hamid, Walsh, Christopher, Novelli, Antonio, Tacke, Moritz, Sadykova, Dinara, Maidyrov, Yerdan, Koneev, Kairgali, Shashkin, Chingiz, Capra, Valeria, Zamani, Mina, Van Maldergem, Lionel, Burglen, Lydie, and Piard, Juliette

Subjects
Humans, Nuclear Proteins, Epilepsy, Phenotype, Genotype, Genetic Association Studies, Neurodegenerative Diseases, Atrophy
Abstract

BRAT1 biallelic variants are associated with rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL), and neurodevelopmental disorder associating cerebellar atrophy with or without seizures syndrome (NEDCAS). To date, forty individuals have been reported in the literature. We collected clinical and molecular data from 57 additional cases allowing us to study a large cohort of 97 individuals and draw phenotype-genotype correlations. Fifty-nine individuals presented with BRAT1-related RMFSL phenotype. Most of them had no psychomotor acquisition (100%), epilepsy (100%), microcephaly (91%), limb rigidity (93%), and died prematurely (93%). Thirty-eight individuals presented a non-lethal phenotype of BRAT1-related NEDCAS phenotype. Seventy-six percent of the patients in this group were able to walk and 68% were able to say at least a few words. Most of them had cerebellar ataxia (82%), axial hypotonia (79%) and cerebellar atrophy (100%). Genotype-phenotype correlations in our cohort revealed that biallelic nonsense, frameshift or inframe deletion/insertion variants result in the severe BRAT1-related RMFSL phenotype (46/46; 100%). In contrast, genotypes with at least one missense were more likely associated with NEDCAS (28/34; 82%). The phenotype of patients carrying splice variants was variable: 41% presented with RMFSL (7/17) and 59% with NEDCAS (10/17).

Published
2023

6. Rare variation in noncoding regions with evolutionary signatures contributes to autism spectrum disorder risk

Author

Shin, Taehwan, Song, Janet HT, Kosicki, Michael, Kenny, Connor, Beck, Samantha G, Kelley, Lily, Qian, Xuyu, Bonacina, Julieta, Papandile, Frances, Antony, Irene, Gonzalez, Dilenny, Scotellaro, Julia, Bushinsky, Evan M, Andersen, Rebecca E, Maury, Eduardo, Pennacchio, Len A, Doan, Ryan N, and Walsh, Christopher A

Subjects
Biological Sciences, Genetics, Intellectual and Developmental Disabilities (IDD), Brain Disorders, Mental Health, Human Genome, Autism, Clinical Research, Underpinning research, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Aetiology, Mental health, Human Accelerated Regions, IL1RAPL1, SIM1, Vista Enhancers, autism spectrum disorder, caMPRA, consanguineous families, conserved neural enhancers, noncoding regions, recessive variants
Abstract

Little is known about the role of noncoding regions in the etiology of autism spectrum disorder (ASD). We examined three classes of noncoding regions: Human Accelerated Regions (HARs), which show signatures of positive selection in humans; experimentally validated neural Vista Enhancers (VEs); and conserved regions predicted to act as neural enhancers (CNEs). Targeted and whole genome analysis of >16,600 samples and >4900 ASD probands revealed that likely recessive, rare, inherited variants in HARs, VEs, and CNEs substantially contribute to ASD risk in probands whose parents share ancestry, which enriches for recessive contributions, but modestly, if at all, in simplex family structures. We identified multiple patient variants in HARs near IL1RAPL1 and in a VE near SIM1 and showed that they change enhancer activity. Our results implicate both human-evolved and evolutionarily conserved noncoding regions in ASD risk and suggest potential mechanisms of how changes in regulatory regions can modulate social behavior.

Published
2023

8. CCE Estimation of High-Dimensional Panel Data Models with Interactive Fixed Effects

Author

Vogt, Michael, Walsh, Christopher, and Linton, Oliver

Subjects
Economics - Econometrics
Abstract

Interactive fixed effects are a popular means to model unobserved heterogeneity in panel data. Models with interactive fixed effects are well studied in the low-dimensional case where the number of parameters to be estimated is small. However, they are largely unexplored in the high-dimensional case where the number of parameters is large, potentially much larger than the sample size itself. In this paper, we develop new econometric methods for the estimation of high-dimensional panel data models with interactive fixed effects. Our estimator is based on similar ideas as the very popular common correlated effects (CCE) estimator which is frequently used in the low-dimensional case. We thus call our estimator a high-dimensional CCE estimator. We derive theory for the estimator both in the large-T-case, where the time series length T tends to infinity, and in the small-T-case, where T is a fixed natural number. The theoretical analysis of the paper is complemented by a simulation study which evaluates the finite sample performance of the estimator.

Published
2022

9. Ensuring accurate stain reproduction in deep generative networks for virtual immunohistochemistry

Author

Walsh, Christopher D., Edwards, Joanne, and Insall, Robert H.

Subjects
Electrical Engineering and Systems Science - Image and Video Processing, Computer Science - Computer Vision and Pattern Recognition, Quantitative Biology - Quantitative Methods, I.4.3, I.4.5
Abstract

Immunohistochemistry is a valuable diagnostic tool for cancer pathology. However, it requires specialist labs and equipment, is time-intensive, and is difficult to reproduce. Consequently, a long term aim is to provide a digital method of recreating physical immunohistochemical stains. Generative Adversarial Networks have become exceedingly advanced at mapping one image type to another and have shown promise at inferring immunostains from haematoxylin and eosin. However, they have a substantial weakness when used with pathology images as they can fabricate structures that are not present in the original data. CycleGANs can mitigate invented tissue structures in pathology image mapping but have a related disposition to generate areas of inaccurate staining. In this paper, we describe a modification to the loss function of a CycleGAN to improve its mapping ability for pathology images by enforcing realistic stain replication while retaining tissue structure. Our approach improves upon others by considering structure and staining during model training. We evaluated our network using the Fr\'echet Inception distance, coupled with a new technique that we propose to appraise the accuracy of virtual immunohistochemistry. This assesses the overlap between each stain component in the inferred and ground truth images through colour deconvolution, thresholding and the Sorensen-Dice coefficient. Our modified loss function resulted in a Dice coefficient for the virtual stain of 0.78 compared with the real AE1/AE3 slide. This was superior to the unaltered CycleGAN's score of 0.74. Additionally, our loss function improved the Fr\'echet Inception distance for the reconstruction to 74.54 from 76.47. We, therefore, describe an advance in virtual restaining that can extend to other immunostains and tumour types and deliver reproducible, fast and readily accessible immunohistochemistry worldwide., Comment: Eighteen pages, six figures

Published
2022

10. Loss of non-motor kinesin KIF26A causes congenital brain malformations via dysregulated neuronal migration and axonal growth as well as apoptosis.

Author

Qian, Xuyu, DeGennaro, Ellen, Talukdar, Maya, Akula, Shyam, Lai, Abbe, Shao, Diane, Gonzalez, Dilenny, Marciano, Jack, Smith, Richard, Hylton, Norma, Yang, Edward, Bazan, J, Barrett, Lee, Yeh, Rebecca, Hill, R, Beck, Samantha, Otani, Aoi, Angad, Jolly, Mitani, Tadahiro, Posey, Jennifer, Pehlivan, Davut, Calame, Daniel, Aydin, Hatip, Yesilbas, Osman, Parks, Kendall, England, Eleina, Im, Kiho, Taranath, Ajay, Scott, Hamish, Barnett, Christopher, Arts, Peer, Sherr, Elliott, Lupski, James, Walsh, Christopher, and Argilli, Emanuela

Subjects
apoptosis, cerebral cortex, congenital brain malformation, corpus callosum, development, genetics, kinesin, migration, organoid, Humans, Animals, Mice, Kinesins, Neurons, Focal Adhesion Protein-Tyrosine Kinases, Apoptosis, Brain
Abstract

Kinesins are canonical molecular motors but can also function as modulators of intracellular signaling. KIF26A, an unconventional kinesin that lacks motor activity, inhibits growth-factor-receptor-bound protein 2 (GRB2)- and focal adhesion kinase (FAK)-dependent signal transduction, but its functions in the brain have not been characterized. We report a patient cohort with biallelic loss-of-function variants in KIF26A, exhibiting a spectrum of congenital brain malformations. In the developing brain, KIF26A is preferentially expressed during early- and mid-gestation in excitatory neurons. Combining mice and human iPSC-derived organoid models, we discovered that loss of KIF26A causes excitatory neuron-specific defects in radial migration, localization, dendritic and axonal growth, and apoptosis, offering a convincing explanation of the disease etiology in patients. Single-cell RNA sequencing in KIF26A knockout organoids revealed transcriptional changes in MAPK, MYC, and E2F pathways. Our findings illustrate the pathogenesis of KIF26A loss-of-function variants and identify the surprising versatility of this non-motor kinesin.

Published
2022

11. Role of self-generated magnetic fields in the inertial fusion ignition threshold

Author

Sadler, James D., Walsh, Christopher A., Zhou, Ye, and Li, Hui

Subjects
Physics - Plasma Physics
Abstract

Magnetic fields spontaneously grow at unstable interfaces around hot-spot asymmetries during inertial confinement fusion implosions. Although difficult to measure, theoretical considerations and numerical simulations predict field strengths exceeding 5kT in current national ignition facility experiments. Magnetic confinement of electrons then reduces the hot-spot heat loss by >5%. We demonstrate this via magnetic post-processing of two-dimensional xRAGE hydrodynamic simulation data at bang time. We then derive a model for the self-magnetization, finding that it varies with the square of the stagnation temperature and inversely with the areal density. The self-magnetized Lawson analysis then gives a slightly reduced ignition threshold. Time dependent hot-spot energy balance models corroborate this finding, with the magnetic field quadrupling the fusion yield for near threshold parameters. The inclusion of magnetized multi-dimensional fluid instabilities could further alter the ignition threshold, and will be the subject of future work.

Published
2022
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12. Analysis of somatic mutations in 131 human brains reveals aging-associated hypermutability

Author

Bae, Taejeong, Fasching, Liana, Wang, Yifan, Shin, Joo Heon, Suvakov, Milovan, Jang, Yeongjun, Norton, Scott, Dias, Caroline, Mariani, Jessica, Jourdon, Alexandre, Wu, Feinan, Panda, Arijit, Pattni, Reenal, Chahine, Yasmine, Yeh, Rebecca, Roberts, Rosalinda C, Huttner, Anita, Kleinman, Joel E, Hyde, Thomas M, Straub, Richard E, Walsh, Christopher A, Urban, Alexander E, Leckman, James F, Weinberger, Daniel R, Vaccarino, Flora M, Abyzov, Alexej, Park, Peter J, Sestan, Nenad, Weinberger, Daniel, Moran, John V, Gage, Fred H, Gleeson, Joseph, Mathern, Gary, Courchesne, Eric, Roy, Subhojit, Chess, Andrew J, Akbarian, Schahram, Bizzotto, Sara, Coulter, Michael, D’Gama, Alissa, Ganz, Javier, Hill, Robert, Huang, August Yue, Khoshkhoo, Sattar, Kim, Sonia, Lee, Alice, Lodato, Michael, Maury, Eduardo A, Miller, Michael, Borges-Monroy, Rebeca, Rodin, Rachel, Zhou, Zinan, Bohrson, Craig, Chu, Chong, Cortes-Ciriano, Isidro, Dou, Yanmei, Galor, Alon, Gulhan, Doga, Kwon, Minseok, Luquette, Joe, Sherman, Maxwell, Viswanadham, Vinay, Jones, Attila, Rosenbluh, Chaggai, Cho, Sean, Langmead, Ben, Thorpe, Jeremy, Erwin, Jennifer, Jaffe, Andrew, McConnell, Michael, Narurkar, Rujuta, Paquola, Apua, Shin, Jooheon, Straub, Richard, Molitor, Cindy, Peters, Mette, Linker, Sara, Reed, Patrick, Wang, Meiyan, Urban, Alexander, Zhou, Bo, Zhu, Xiaowei, Serres Amero, Aitor, Juan, David, Lobon, Irene, Marques-Bonet, Tomas, Solis Moruno, Manuel, Garcia Perez, Raquel, Povolotskaya, Inna, Soriano, Eduardo, Antaki, Danny, and Averbuj, Dan

Subjects
Biotechnology, Brain Disorders, Intellectual and Developmental Disabilities (IDD), Genetics, Autism, Pediatric, Mental Health, Human Genome, Underpinning research, 2.1 Biological and endogenous factors, Aetiology, 1.1 Normal biological development and functioning, Mental health, Aging, Autistic Disorder, Brain, Enhancer Elements, Genetic, Gene Expression Regulation, Humans, Mutagenesis, Mutation, Protein Binding, Transcription Factors, Whole Genome Sequencing, Brain Somatic Mosaicism Network§, General Science & Technology
Abstract

We analyzed 131 human brains (44 neurotypical, 19 with Tourette syndrome, 9 with schizophrenia, and 59 with autism) for somatic mutations after whole genome sequencing to a depth of more than 200×. Typically, brains had 20 to 60 detectable single-nucleotide mutations, but ~6% of brains harbored hundreds of somatic mutations. Hypermutability was associated with age and damaging mutations in genes implicated in cancers and, in some brains, reflected in vivo clonal expansions. Somatic duplications, likely arising during development, were found in ~5% of normal and diseased brains, reflecting background mutagenesis. Brains with autism were associated with mutations creating putative transcription factor binding motifs in enhancer-like regions in the developing brain. The top-ranked affected motifs corresponded to MEIS (myeloid ectopic viral integration site) transcription factors, suggesting a potential link between their involvement in gene regulation and autism.

Published
2022

16. Magnetized Ablative Rayleigh-Taylor Instability in 3-D

Author

Walsh, Christopher A.

Subjects
Physics - Plasma Physics, Physics - Computational Physics, Physics - Fluid Dynamics
Abstract

3-D extended-MHD simulations of the magnetized ablative Rayleigh-Taylor instability are presented for the first time. Previous 2-D simulations claiming perturbation suppression by magnetic tension are shown to be misleading, as they do not include the most unstable dimension. For perturbation modes along the applied field direction, the magnetic field simultaneously reduces ablative stabilization and adds magnetic tension stabilization; the stabilizing term is found to dominate for applied fields >5T, with both effects increasing in importance at short wavelengths. For modes perpendicular to the applied field, magnetic tension does not directly stabilize the perturbation, but can result in moderately slower growth due to the perturbation appearing 2-D (albeit in a different orientation to 2-D ICF simulations). In cases where thermal ablative stabilization is dominant the applied field increases the peak bubble-spike height. Resistive diffusion is shown to be important for short wavelengths and long timescales, reducing the effectiveness of tension stabilization.

Published
2021
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17. Biermann Battery Magnetic Fields in ICF Capsules: Total Magnetic Flux Generation

Author

Walsh, Christopher and Clark, Dan

Subjects
Physics - Plasma Physics, Physics - Computational Physics
Abstract

This paper focuses on the process of magnetic flux generation in ICF implosions. Hot-spots are shown to be dominated by fields generated during stagnation, when the temperature and density gradients are largest. A scaling of hot-spot magnetic flux is derived and compared with simulations, revealing that perturbations with both larger amplitudes and higher mode numbers generate more magnetic flux. The model allows for greater understanding of which target designs will be susceptible to MHD effects. For example, the model can be used to ascertain the time when most magnetic flux is generated. If generation is weighted more towards early times, then more high-mode magnetic field loops will be present. A hot-spot with no high-mode perturbations at time of peak neutron production can still contain significant magnetic flux on those scales. By assuming that magnetic flux is deposited at the hot-spot edge by Nernst advection, the model can be used to post-process radiation-hydrodynamics data to estimate magnetic field strengths and magnetizations.

Published
2021
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18. Exploring extreme magnetization phenomena in directly-driven imploding cylindrical targets

Author

Walsh, Christopher, Florido, Ricardo, Bailly-Grandvaux, Mathieu, Suzuki-Vidal, Francisco, Chittenden, Jeremy, Crilly, Aidan, Gigosos, Marco, Mancini, Roberto, Pérez-Callejo, Gabriel, Vlachos, Christos, McGuffey, Christopher, Beg, Farhat, and Santos, Joao

Subjects
Physics - Plasma Physics, Physics - Computational Physics, Physics - Space Physics
Abstract

This paper uses extended-magnetohydrodynamics (MHD) simulations to explore an extreme magnetized plasma regime realisable by cylindrical implosions on the OMEGA laser facility. This regime is characterized by highly compressed magnetic fields (greater than 10~kT across the fuel), which contain a significant proportion of the implosion energy and induce large electrical currents in the plasma. Parameters governing the different magnetization processes such as Ohmic dissipation and suppression of instabilities by magnetic tension are presented, allowing for optimization of experiments to study specific phenomena. For instance, a dopant added to the target gas-fill can enhance magnetic flux compression while enabling spectroscopic diagnosis of the imploding core. In particular, the use of Ar K-shell spectroscopy is investigated by performing detailed non-LTE atomic kinetics and radiative transfer calculations on the MHD data. Direct measurement of the core electron density and temperature would be possible, allowing for both the impact of magnetization on the final temperature and thermal pressure to be obtained. By assuming the magnetic field is frozen into the plasma motion, which is shown to be a good approximation for highly magnetized implosions, spectroscopic diagnosis could be used to estimate which magnetization processes are ruling the implosion dynamics; for example, a relation is given for inferring whether thermally-driven or current-driven transport is dominating.

Published
2021
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19. Updated Magnetized Transport Coefficients: Impact on Laser-Plasmas with Self-Generated or Applied Magnetic Fields

Author

Walsh, Christopher, Sadler, James, and Davies, Jonathan

Subjects
Physics - Plasma Physics, Physics - Computational Physics, Physics - Fluid Dynamics, Physics - Space Physics
Abstract

Errors in the Epperlein & Haines [PoF (1986)] transport coefficients were recently found at low electron magnetizations, with new magnetic transport coefficients proposed simultaneously by two teams [Sadler, Walsh & Li, PRL (2021) and Davies, Wen, Ji & Held, PoP (2021)]; these two separate sets of updated coefficients are shown in this paper to be in agreement. The importance of these new coefficients in laser-plasmas with either self-generated or applied magnetic fields is demonstrated. When an external magnetic field is applied, the cross-gradient-Nernst term twists the field structure; this twisting is reduced by the new coefficients in the low magnetization regime. For plasmas where only self-generated magnetic fields are present, the new coefficients are found to result in the magnetic field moving with the Righi-Leduc heat-flow, enhancing the impact of MHD. Simulations of Biermann Battery magnetic fields around ICF hot-spot perturbations are presented, with cross-gradient-Nernst transport increasing spike penetration.

Published
2021
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20. Exome copy number variant detection, analysis, and classification in a large cohort of families with undiagnosed rare genetic disease

Author

Lemire, Gabrielle, Sanchis-Juan, Alba, Russell, Kathryn, Baxter, Samantha, Chao, Katherine R., Singer-Berk, Moriel, Groopman, Emily, Wong, Isaac, England, Eleina, Goodrich, Julia, Pais, Lynn, Austin-Tse, Christina, DiTroia, Stephanie, O’Heir, Emily, Ganesh, Vijay S., Wojcik, Monica H., Evangelista, Emily, Snow, Hana, Osei-Owusu, Ikeoluwa, Fu, Jack, Singh, Mugdha, Mostovoy, Yulia, Huang, Steve, Garimella, Kiran, Kirkham, Samantha L., Neil, Jennifer E., Shao, Diane D., Walsh, Christopher A., Argilli, Emanuela, Le, Carolyn, Sherr, Elliott H., Gleeson, Joseph G., Shril, Shirlee, Schneider, Ronen, Hildebrandt, Friedhelm, Sankaran, Vijay G., Madden, Jill A., Genetti, Casie A., Beggs, Alan H., Agrawal, Pankaj B., Bujakowska, Kinga M., Place, Emily, Pierce, Eric A., Donkervoort, Sandra, Bönnemann, Carsten G., Gallacher, Lyndon, Stark, Zornitza, Tan, Tiong Yang, White, Susan M., Töpf, Ana, Straub, Volker, Fleming, Mark D., Pollak, Martin R., Õunap, Katrin, Pajusalu, Sander, Donald, Kirsten A., Bruwer, Zandre, Ravenscroft, Gianina, Laing, Nigel G., MacArthur, Daniel G., Rehm, Heidi L., Talkowski, Michael E., Brand, Harrison, and O’Donnell-Luria, Anne

Published
2024
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22. Richard Thompson: Hartford Infinity Music

Author

Walsh, Christopher

Subjects
Music
Abstract

Richard Thompson Hartford Infinity Music Hall, Connecticut, US 4/4/24 Entering with I Misunderstood, Thompson's plaintive take on lost love, his voice at 75 remains strong, as does his inter-song banter. [...]

Published
2024

24. Measurement of magnetic cavitation driven by heat flow in a plasma

Author

Arran, Christopher, Dearling, Adam, Bradford, Philip, Hicks, George. S., Al-Atabi, Saleh, Antonelli, Luca, Ettlinger, Oliver C., Khan, Matthew, Read, Martin P., Glize, Kevin, Notley, Margaret, Walsh, Christopher A., Kingham, Robert J., Najmudin, Zulfikar, Ridgers, Christopher P., and Woolsey, Nigel C.

Subjects
Physics - Plasma Physics
Abstract

We describe the direct measurement of the expulsion of a magnetic field from a plasma driven by heat flow. Using a laser to heat a column of gas within an applied magnetic field, we isolate Nernst advection and show how it changes the field over a nanosecond timescale. Reconstruction of the magnetic field map from proton radiographs demonstrates that the field is advected by heat flow in advance of the plasma expansion. This changes the dynamics of high energy density plasmas, in which heat flows and fields are strongly coupled, and may disrupt magnetised inertial confinement fusion schemes., Comment: 5 pages, 4 figures

Published
2021
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25. An evolutionary perspective on complex neuropsychiatric disease

Author

McClellan, Jon M., Zoghbi, Anthony W., Buxbaum, Joseph D., Cappi, Carolina, Crowley, James J., Flint, Jonathan, Grice, Dorothy E., Gulsuner, Suleyman, Iyegbe, Conrad, Jain, Sanjeev, Kuo, Po-Hsiu, Lattig, Maria Claudia, Passos-Bueno, Maria Rita, Purushottam, Meera, Stein, Dan J., Sunshine, Anna B., Susser, Ezra S., Walsh, Christopher A., Wootton, Olivia, and King, Mary-Claire

Published
2024
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27. Structural models for policy-making: Coping with parametric uncertainty

Author

Eisenhauer, Philipp, Gabler, Janoś, Janys, Lena, and Walsh, Christopher

Subjects
Economics - Econometrics
Abstract

The ex-ante evaluation of policies using structural econometric models is based on estimated parameters as a stand-in for the true parameters. This practice ignores uncertainty in the counterfactual policy predictions of the model. We develop a generic approach that deals with parametric uncertainty using uncertainty sets and frames model-informed policy-making as a decision problem under uncertainty. The seminal human capital investment model by Keane and Wolpin (1997) provides a well-known, influential, and empirically-grounded test case. We document considerable uncertainty in the models's policy predictions and highlight the resulting policy recommendations obtained from using different formal rules of decision-making under uncertainty.

Published
2021

28. Comprehensive identification of somatic nucleotide variants in human brain tissue

Author

Wang, Yifan, Bae, Taejeong, Thorpe, Jeremy, Sherman, Maxwell A, Jones, Attila G, Cho, Sean, Daily, Kenneth, Dou, Yanmei, Ganz, Javier, Galor, Alon, Lobon, Irene, Pattni, Reenal, Rosenbluh, Chaggai, Tomasi, Simone, Tomasini, Livia, Yang, Xiaoxu, Zhou, Bo, Akbarian, Schahram, Ball, Laurel L, Bizzotto, Sara, Emery, Sarah B, Doan, Ryan, Fasching, Liana, Jang, Yeongjun, Juan, David, Lizano, Esther, Luquette, Lovelace J, Moldovan, John B, Narurkar, Rujuta, Oetjens, Matthew T, Rodin, Rachel E, Sekar, Shobana, Shin, Joo Heon, Soriano, Eduardo, Straub, Richard E, Zhou, Weichen, Chess, Andrew, Gleeson, Joseph G, Marquès-Bonet, Tomas, Park, Peter J, Peters, Mette A, Pevsner, Jonathan, Walsh, Christopher A, Weinberger, Daniel R, Vaccarino, Flora M, Moran, John V, Urban, Alexander E, Kidd, Jeffrey M, Mills, Ryan E, and Abyzov, Alexej

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Neurosciences, Human Genome, 1.1 Normal biological development and functioning, Underpinning research, Generic health relevance, Alleles, Brain, Chromosome Mapping, Computational Biology, Genetic Association Studies, Genetic Variation, Genomics, Germ Cells, High-Throughput Nucleotide Sequencing, Humans, Organ Specificity, Polymorphism, Single Nucleotide, Brain Somatic Mosaicism Network, Environmental Sciences, Information and Computing Sciences, Bioinformatics
Abstract

BackgroundPost-zygotic mutations incurred during DNA replication, DNA repair, and other cellular processes lead to somatic mosaicism. Somatic mosaicism is an established cause of various diseases, including cancers. However, detecting mosaic variants in DNA from non-cancerous somatic tissues poses significant challenges, particularly if the variants only are present in a small fraction of cells.ResultsHere, the Brain Somatic Mosaicism Network conducts a coordinated, multi-institutional study to examine the ability of existing methods to detect simulated somatic single-nucleotide variants (SNVs) in DNA mixing experiments, generate multiple replicates of whole-genome sequencing data from the dorsolateral prefrontal cortex, other brain regions, dura mater, and dural fibroblasts of a single neurotypical individual, devise strategies to discover somatic SNVs, and apply various approaches to validate somatic SNVs. These efforts lead to the identification of 43 bona fide somatic SNVs that range in variant allele fractions from ~ 0.005 to ~ 0.28. Guided by these results, we devise best practices for calling mosaic SNVs from 250× whole-genome sequencing data in the accessible portion of the human genome that achieve 90% specificity and sensitivity. Finally, we demonstrate that analysis of multiple bulk DNA samples from a single individual allows the reconstruction of early developmental cell lineage trees.ConclusionsThis study provides a unified set of best practices to detect somatic SNVs in non-cancerous tissues. The data and methods are freely available to the scientific community and should serve as a guide to assess the contributions of somatic SNVs to neuropsychiatric diseases.

Published
2021

29. Symmetric set of transport coefficients for collisional magnetized plasma

Author

Sadler, James D., Walsh, Christopher A., and Li, Hui

Subjects
Physics - Plasma Physics, Physics - Fluid Dynamics
Abstract

In Braginskii extended magneto-hydrodynamics (ExMHD), applicable to collisional astrophysical and high energy density plasmas, the electric field and heat flow are described by the $\alpha$, $\beta$ and $\kappa$ transport coefficients. We show that magnetic transport relies primarily on $\beta_\parallel-\beta_\perp$ and $\alpha_\perp-\alpha_\parallel$, rather than $\alpha_\perp$ and $\beta_\perp$ themselves. However, commonly used coefficient fit functions [Epperlein and Haines, Phys. Fluids 29, 1029 (1986)] cannot accurately calculate these quantities. This means that many ExMHD simulations have significantly over-estimated the cross-gradient Nernst advection, resulting in artificial magnetic dissipation and discontinuities. We repeat the kinetic analysis to provide fits that rectify this problem. Use of these in the Gorgon ExMHD code resolves the known discrepancies with kinetic simulations in the literature. Recognizing the fundamental importance of $\alpha_\perp-\alpha_\parallel$ and $\beta_\parallel-\beta_\perp$, we re-cast the set of coefficients to find that each of them now shares the same underlying properties. This makes explicit the symmetry of the magnetic and thermal transport equations, as well as the symmetry of the coefficients themselves.

Published
2020
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30. Early role for a Na+,K+-ATPase (ATP1A3) in brain development

Author

Smith, Richard S, Florio, Marta, Akula, Shyam K, Neil, Jennifer E, Wang, Yidi, Hill, R Sean, Goldman, Melissa, Mullally, Christopher D, Reed, Nora, Bello-Espinosa, Luis, Flores-Sarnat, Laura, Monteiro, Fabiola Paoli, Erasmo, Casella B, Pinto E Vairo, Filippo, Morava, Eva, Barkovich, A James, Gonzalez-Heydrich, Joseph, Brownstein, Catherine A, McCarroll, Steven A, and Walsh, Christopher A

Subjects
Pediatric, Neurosciences, Genetics, Underpinning research, 1.1 Normal biological development and functioning, Neurological, Adult, Brain, Child, Female, Fetus, Gene Expression Regulation, Developmental, Humans, Infant, Infant, Newborn, Interneurons, Magnetic Resonance Imaging, Male, Mutation, Neocortex, Neurons, Parvalbumins, Phenotype, Polymicrogyria, RNA, Messenger, Single-Cell Analysis, Sodium-Potassium-Exchanging ATPase, cortex development, ATP1A3, developmental channelopathy, polymicrogyria, cortical malformation
Abstract

Osmotic equilibrium and membrane potential in animal cells depend on concentration gradients of sodium (Na+) and potassium (K+) ions across the plasma membrane, a function catalyzed by the Na+,K+-ATPase α-subunit. Here, we describe ATP1A3 variants encoding dysfunctional α3-subunits in children affected by polymicrogyria, a developmental malformation of the cerebral cortex characterized by abnormal folding and laminar organization. To gain cell-biological insights into the spatiotemporal dynamics of prenatal ATP1A3 expression, we built an ATP1A3 transcriptional atlas of fetal cortical development using mRNA in situ hybridization and transcriptomic profiling of ∼125,000 individual cells with single-cell RNA sequencing (Drop-seq) from 11 areas of the midgestational human neocortex. We found that fetal expression of ATP1A3 is most abundant to a subset of excitatory neurons carrying transcriptional signatures of the developing subplate, yet also maintains expression in nonneuronal cell populations. Moving forward a year in human development, we profiled ∼52,000 nuclei from four areas of an infant neocortex and show that ATP1A3 expression persists throughout early postnatal development, most predominantly in inhibitory neurons, including parvalbumin interneurons in the frontal cortex. Finally, we discovered the heteromeric Na+,K+-ATPase pump complex may form nonredundant cell-type-specific α-β isoform combinations, including α3-β1 in excitatory neurons and α3-β2 in inhibitory neurons. Together, the developmental malformation phenotype of affected individuals and single-cell ATP1A3 expression patterns point to a key role for α3 in human cortex development, as well as a cell-type basis for pre- and postnatal ATP1A3-associated diseases.

Published
2021

33. Landmarks of human embryonic development inscribed in somatic mutations

Author

Bizzotto, Sara, Dou, Yanmei, Ganz, Javier, Doan, Ryan N, Kwon, Minseok, Bohrson, Craig L, Kim, Sonia N, Bae, Taejeong, Abyzov, Alexej, Network†, NIMH Brain Somatic Mosaicism, Park, Peter J, and Walsh, Christopher A

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Genetics, Human Genome, Pediatric, Biotechnology, Stem Cell Research - Nonembryonic - Non-Human, Stem Cell Research, 2.1 Biological and endogenous factors, Aetiology, Underpinning research, 1.1 Normal biological development and functioning, Generic health relevance, Adolescent, Adult, Cell Division, Cell Lineage, Clone Cells, Embryonic Development, Female, Gastrula, Gastrulation, Genetic Variation, Germ Layers, Humans, Male, Mutation, Neural Stem Cells, Neurons, Organogenesis, Polymorphism, Single Nucleotide, Prosencephalon, Single-Cell Analysis, Whole Genome Sequencing, NIMH Brain Somatic Mosaicism Network, General Science & Technology
Abstract

Although cell lineage information is fundamental to understanding organismal development, very little direct information is available for humans. We performed high-depth (250×) whole-genome sequencing of multiple tissues from three individuals to identify hundreds of somatic single-nucleotide variants (sSNVs). Using these variants as "endogenous barcodes" in single cells, we reconstructed early embryonic cell divisions. Targeted sequencing of clonal sSNVs in different organs (about 25,000×) and in more than 1000 cortical single cells, as well as single-nucleus RNA sequencing and single-nucleus assay for transposase-accessible chromatin sequencing of ~100,000 cortical single cells, demonstrated asymmetric contributions of early progenitors to extraembryonic tissues, distinct germ layers, and organs. Our data suggest onset of gastrulation at an effective progenitor pool of about 170 cells and about 50 to 100 founders for the forebrain. Thus, mosaic mutations provide a permanent record of human embryonic development at very high resolution.

Published
2021

34. Local Communities Responding To The Homelessness Crisis

Author

Walsh, Christopher J.

Subjects
United States. Supreme Court -- Cases, Homeless persons -- Homes and haunts -- Civil rights -- Cases, Homelessness -- Cases, Judicial opinions -- Cases, Local government -- Social policy -- United States, Public spaces -- Usage, Camp sites, facilities, etc. -- Usage, Company legal issue, Business, international
Abstract

Published: Greater Concord Chamber of Commerce Chamber Review Newsletter (September 2024) September 16, 2024 With Prior New Hampshire Precedent, Recent U.S. Supreme Court Ruling Gives Flexibility The homelessness crisis and [...]

Published
2024

35. Texas Federal Court Sets Aside The FTC's Rule Banning Non-Competes, With The Court's Order Having Nationwide Effect

Author

Walsh, Christopher J.

Subjects
Non-competition agreements -- Cases, Labor contracts -- Cases, Injunctions -- Cases, Company legal issue, Business, international
Abstract

Last week brought a major development in litigation surrounding the FTC's sweeping rule that would ban and render unenforceable most non-compete clauses in employment contracts. Specifically, on August 20, 2024, [...]

Published
2024

36. Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

Author

Marshall, Christian R., Merico, Daniele, Thiruvahindrapuram, Bhooma, Wang, Zhouzhi, Scherer, Stephen W., Howrigan, Daniel P, Ripke, Stephan, Bulik-Sullivan, Brendan, Farh, Kai-How, Fromer, Menachem, Goldstein, Jacqueline I., Huang, Hailiang, Lee, Phil, Daly, Mark J., Neale, Benjamin M., Belliveau, Richard A., Jr., Bergen, Sarah E., Bevilacqua, Elizabeth, Chambert, Kimberley D., O'Dushlaine, Colm, Scolnick, Edward M., Smoller, Jordan W., Moran, Jennifer L., Palotie, Aarno, Petryshen, Tracey L., Wu, Wenting, Greer, Douglas S., Antaki, Danny, Shetty, Aniket, Gujral, Madhusudan, Brandler, William M., Malhotra, Dheeraj, Fuentes Fajarado, Karin V., Maile, Michelle S., Holmans, Peter A., Carrera, Noa, Craddock, Nick, Escott-Price, Valentina, Georgieva, Lyudmila, Hamshere, Marian L., Kavanagh, David, Legge, Sophie E., Pocklington, Andrew J., Richards, Alexander L., Ruderfer, Douglas M., Williams, Nigel M., Kirov, George, Owen, Michael J., Pinto, Dalila, Cai, Guiqing, Davis, Kenneth L., Drapeau, Elodie, Friedman, Joseph I, Haroutunian, Vahram, Parkhomenko, Elena, Reichenberg, Abraham, Silverman, Jeremy M., Buxbaum, Joseph D., Domenici, Enrico, Agartz, Ingrid, Djurovic, Srdjan, Mattingsdal, Morten, Melle, Ingrid, Andreassen, Ole A., Jönsson, Erik G., Söderman, Erik, Albus, Margot, Alexander, Madeline, Laurent, Claudine, Levinson, Douglas F., Amin, Farooq, Atkins, Joshua, Cairns, Murray J., Scott, Rodney J., Tooney, Paul A., Wu, Jing Qin, Bacanu, Silviu A., Bigdeli, Tim B., Reimers, Mark A., Webb, Bradley T., Wolen, Aaron R., Wormley, Brandon K., Kendler, Kenneth S., Riley, Brien P., Kähler, Anna K., Magnusson, Patrik K.E., Hultman, Christina M., Bertalan, Marcelo, Hansen, Thomas, Olsen, Line, Rasmussen, Henrik B., Werge, Thomas, Mattheisen, Manuel, Black, Donald W., Bruggeman, Richard, Buccola, Nancy G., Buckner, Randy L., Roffman, Joshua L., Byerley, William, Cahn, Wiepke, Kahn, René S, Strengman, Eric, Ophoff, Roel A., Carr, Vaughan J., Catts, Stanley V., Henskens, Frans A., Loughland, Carmel M., Michie, Patricia T., Pantelis, Christos, Schall, Ulrich, Jablensky, Assen V., Kelly, Brian J., Campion, Dominique, Cantor, Rita M., Cheng, Wei, Cloninger, C. Robert, Svrakic, Dragan M, Cohen, David, Cormican, Paul, Donohoe, Gary, Morris, Derek W., Corvin, Aiden, Gill, Michael, Crespo-Facorro, Benedicto, Crowley, James J., Farrell, Martilias S., Giusti-Rodríguez, Paola, Kim, Yunjung, Szatkiewicz, Jin P., Williams, Stephanie, Curtis, David, Pimm, Jonathan, Gurling, Hugh, McQuillin, Andrew, Davidson, Michael, Weiser, Mark, Degenhardt, Franziska, Forstner, Andreas J., Herms, Stefan, Hoffmann, Per, Hofman, Andrea, Cichon, Sven, Nöthen, Markus M., Del Favero, Jurgen, DeLisi, Lynn E., McCarley, Robert W., Levy, Deborah L., Mesholam-Gately, Raquelle I., Seidman, Larry J., Dikeos, Dimitris, Papadimitriou, George N., Dinan, Timothy, Duan, Jubao, Sanders, Alan R., Gejman, Pablo V., Gershon, Elliot S., Dudbridge, Frank, Eichhammer, Peter, Eriksson, Johan, Salomaa, Veikko, Essioux, Laurent, Fanous, Ayman H., Knowles, James A., Pato, Michele T., Pato, Carlos N., Frank, Josef, Meier, Sandra, Schulze, Thomas G., Strohmaier, Jana, Witt, Stephanie H., Rietschel, Marcella, Franke, Lude, Karjalainen, Juha, Freedman, Robert, Olincy, Ann, Freimer, Nelson B., Purcell, Shaun M., Roussos, Panos, Stahl, Eli A., Sklar, Pamela, Giegling, Ina, Hartmann, Annette M., Konte, Bettina, Rujescu, Dan, Godard, Stephanie, Hirschhorn, Joel N., Pers, Tune H., Price, Alkes, Esko, Tõnu, Gratten, Jacob, Lee, S. Hong, Visscher, Peter M., Wray, Naomi R., Mowry, Bryan J., de Haan, Lieuwe, Meijer, Carin J., Hansen, Mark, Ikeda, Masashi, Iwata, Nakao, Joa, Inge, Kalaydjieva, Luba, Keller, Matthew C., Kennedy, James L., Zai, Clement C., Knight, Jo, Lerer, Bernard, Liang, Kung-Yee, Lieberman, Jeffrey, Stroup, T. Scott, Lönnqvist, Jouko, Suvisaari, Jaana, Maher, Brion S., Maier, Wolfgang, Mallet, Jacques, McDonald, Colm, McIntosh, Andrew M., Blackwood, Douglas H.R., Metspalu, Andres, Milani, Lili, Milanova, Vihra, Mokrab, Younes, Collier, David A., Müller-Myhsok, Bertram, Murphy, Kieran C., Murray, Robin M., Powell, John, Myin-Germeys, Inez, Van Os, Jim, Nenadic, Igor, Nertney, Deborah A., Nestadt, Gerald, Pulver, Ann E., Nicodemus, Kristin K., Nisenbaum, Laura, Nordin, Annelie, Adolfsson, Rolf, O'Callaghan, Eadbhard, Oh, Sang-Yun, O'Neill, F. Anthony, Paunio, Tiina, Pietiläinen, Olli, Perkins, Diana O., Quested, Digby, Savitz, Adam, Li, Qingqin S., Schwab, Sibylle G., Shi, Jianxin, Spencer, Chris C.A., Thirumalai, Srinivas, Veijola, Juha, Waddington, John, Walsh, Dermot, Wildenauer, Dieter B., Bramon, Elvira, Darvasi, Ariel, Posthuma, Danielle, St. Clair, David, Shanta, Omar, Klein, Marieke, Park, Peter J., Weinberger, Daniel, Moran, John V., Gage, Fred H., Vaccarino, Flora M., Gleeson, Joseph, Mathern, Gary, Courchesne, Eric, Roy, Subhojit, Bizzotto, Sara, Coulter, Michael, Dias, Caroline, D'Gama, Alissa, Ganz, Javier, Hill, Robert, Huang, August Yue, Khoshkhoo, Sattar, Kim, Sonia, Lodato, Michael, Miller, Michael, Borges-Monroy, Rebeca, Rodin, Rachel, Zhou, Zinan, Bohrson, Craig, Chu, Chong, Cortes-Ciriano, Isidro, Dou, Yanmei, Galor, Alon, Gulhan, Doga, Kwon, Minseok, Luquette, Joe, Viswanadham, Vinay, Jones, Attila, Rosenbluh, Chaggai, Cho, Sean, Langmead, Ben, Thorpe, Jeremy, Erwin, Jennifer, Jaffe, Andrew, McConnell, Michael, Narurkar, Rujuta, Paquola, Apua, Shin, Jooheon, Straub, Richard, Abyzov, Alexej, Bae, Taejeong, Jang, Yeongjun, Wang, Yifan, Gage, Fred, Linker, Sara, Reed, Patrick, Wang, Meiyan, Urban, Alexander, Zhou, Bo, Zhu, Xiaowei, Pattni, Reenal, Amero, Aitor Serres, Juan, David, Lobon, Irene, Marques-Bonet, Tomas, Moruno, Manuel Solis, Perez, Raquel Garcia, Povolotskaya, Inna, Soriano, Eduardo, Averbuj, Dan, Ball, Laurel, Breuss, Martin, Yang, Xiaoxu, Chung, Changuk, Emery, Sarah B., Flasch, Diane A., Kidd, Jeffrey M., Kopera, Huira C., Kwan, Kenneth Y., Mills, Ryan E., Moldovan, John B., Sun, Chen, Zhao, Xuefang, Zhou, Weichen, Frisbie, Trenton J., Cherskov, Adriana, Fasching, Liana, Jourdon, Alexandre, Pochareddy, Sirisha, Scuderi, Soraya, Sestan, Nenad, Maury, Eduardo A., Sherman, Maxwell A., Genovese, Giulio, Gilgenast, Thomas G., Kamath, Tushar, Burris, S.J., Rajarajan, Prashanth, Flaherty, Erin, Akbarian, Schahram, Chess, Andrew, McCarroll, Steven A., Loh, Po-Ru, Phillips-Cremins, Jennifer E., Brennand, Kristen J., Macosko, Evan Z., Walters, James T.R., O’Donovan, Michael, Sullivan, Patrick, Sebat, Jonathan, Lee, Eunjung A., and Walsh, Christopher A.

Published
2023
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38. Single-cell genome sequencing of human neurons identifies somatic point mutation and indel enrichment in regulatory elements

Author

Luquette, Lovelace J., Miller, Michael B., Zhou, Zinan, Bohrson, Craig L., Zhao, Yifan, Jin, Hu, Gulhan, Doga, Ganz, Javier, Bizzotto, Sara, Kirkham, Samantha, Hochepied, Tino, Libert, Claude, Galor, Alon, Kim, Junho, Lodato, Michael A., Garaycoechea, Juan I., Gawad, Charles, West, Jay, Walsh, Christopher A., and Park, Peter J.

Published
2022
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39. Bi-allelic variants in INTS11 are associated with a complex neurological disorder

Author

Acosta, Maria T., Adam, Margaret, Adams, David R., Alvey, Justin, Amendola, Laura, Andrews, Ashley, Ashley, Euan A., Azamian, Mahshid S., Bacino, Carlos A., Bademci, Guney, Balasubramanyam, Ashok, Baldridge, Dustin, Bale, Jim, Bamshad, Michael, Barbouth, Deborah, Bayrak-Toydemir, Pinar, Beck, Anita, Beggs, Alan H., Behrens, Edward, Bejerano, Gill, Bellen, Hugo J., Bennet, Jimmy, Berg-Rood, Beverly, Bernstein, Jonathan A., Berry, Gerard T., Bican, Anna, Bivona, Stephanie, Blue, Elizabeth, Bohnsack, John, Bonner, Devon, Botto, Lorenzo, Boyd, Brenna, Briere, Lauren C., Brokamp, Elly, Brown, Gabrielle, Burke, Elizabeth A., Burrage, Lindsay C., Butte, Manish J., Byers, Peter, Byrd, William E., Carey, John, Carrasquillo, Olveen, Cassini, Thomas, Peter Chang, Ta Chen, Chanprasert, Sirisak, Chao, Hsiao-Tuan, Clark, Gary D., Coakley, Terra R., Cobban, Laurel A., Cogan, Joy D., Coggins, Matthew, Cole, F. Sessions, Colley, Heather A., Cooper, Cynthia M., Cope, Heidi, Craigen, William J., Crouse, Andrew B., Cunningham, Michael, D'Souza, Precilla, Dai, Hongzheng, Dasari, Surendra, Davis, Joie, Dayal, Jyoti G., Deardorff, Matthew, Dell'Angelica, Esteban C., Dipple, Katrina, Doherty, Daniel, Dorrani, Naghmeh, Doss, Argenia L., Douine, Emilie D., Duncan, Laura, Earl, Dawn, Eckstein, David J., Emrick, Lisa T., Eng, Christine M., Esteves, Cecilia, Falk, Marni, Fernandez, Liliana, Fieg, Elizabeth L., Fisher, Paul G., Fogel, Brent L., Forghani, Irman, Gahl, William A., Glass, Ian, Gochuico, Bernadette, Godfrey, Rena A., Golden-Grant, Katie, Goldrich, Madison P., Grajewski, Alana, Gutierrez, Irma, Hadley, Don, Hahn, Sihoun, Hamid, Rizwan, Hassey, Kelly, Hayes, Nichole, High, Frances, Hing, Anne, Hisama, Fuki M., Holm, Ingrid A., Hom, Jason, Horike-Pyne, Martha, Huang, Alden, Huang, Yong, Introne, Wendy, Isasi, Rosario, Izumi, Kosuke, Jamal, Fariha, Jarvik, Gail P., Jarvik, Jeffrey, Jayadev, Suman, Jean-Marie, Orpa, Jobanputra, Vaidehi, Karaviti, Lefkothea, Kennedy, Jennifer, Ketkar, Shamika, Kiley, Dana, Kilich, Gonench, Kobren, Shilpa N., Kohane, Isaac S., Kohler, Jennefer N., Krakow, Deborah, Krasnewich, Donna M., Kravets, Elijah, Korrick, Susan, Koziura, Mary, Lalani, Seema R., Lam, Byron, Lam, Christina, LaMoure, Grace L., Lanpher, Brendan C., Lanza, Ian R., LeBlanc, Kimberly, Lee, Brendan H., Levitt, Roy, Lewis, Richard A., Liu, Pengfei, Liu, Xue Zhong, Longo, Nicola, Loo, Sandra K., Loscalzo, Joseph, Maas, Richard L., Macnamara, Ellen F., MacRae, Calum A., Maduro, Valerie V., Mahoney, Rachel, Mak, Bryan C., Malicdan, May Christine V., Mamounas, Laura A., Manolio, Teri A., Mao, Rong, Maravilla, Kenneth, Marom, Ronit, Marth, Gabor, Martin, Beth A., Martin, Martin G., Martínez-Agosto, Julian A., Marwaha, Shruti, McCauley, Jacob, McConkie-Rosell, Allyn, McCray, Alexa T., McGee, Elisabeth, Mefford, Heather, Merritt, J. Lawrence, Might, Matthew, Mirzaa, Ghayda, Morava, Eva, Moretti, Paolo M., Nakano-Okuno, Mariko, Nelson, Stan F., Newman, John H., Nicholas, Sarah K., Nickerson, Deborah, Nieves-Rodriguez, Shirley, Novacic, Donna, Oglesbee, Devin, Orengo, James P., Pace, Laura, Pak, Stephen, Pallais, J. Carl, Palmer, Christina GS., Papp, Jeanette C., Parker, Neil H., Phillips, John A., III, Posey, Jennifer E., Potocki, Lorraine, Pusey, Barbara N., Quinlan, Aaron, Raskind, Wendy, Raja, Archana N., Rao, Deepak A., Raper, Anna, Renteria, Genecee, Reuter, Chloe M., Rives, Lynette, Robertson, Amy K., Rodan, Lance H., Rosenfeld, Jill A., Rosenwasser, Natalie, Rossignol, Francis, Ruzhnikov, Maura, Sacco, Ralph, Sampson, Jacinda B., Saporta, Mario, Schaechter, Judy, Schedl, Timothy, Schoch, Kelly, Scott, C. Ron, Scott, Daryl A., Shashi, Vandana, Shin, Jimann, Silverman, Edwin K., Sinsheimer, Janet S., Sisco, Kathy, Smith, Edward C., Smith, Kevin S., Solem, Emily, Krezel, Lilianna Solnica, Solomon, Ben, Spillmann, Rebecca C., Stoler, Joan M., Sullivan, Jennifer A., Sullivan, Kathleen, Sun, Angela, Sutton, Shirley, Sweetser, David A., Sybert, Virginia, Tabor, Holly K., Tan, Amelia L.M., Tan, Queenie K.- G., Tekin, Mustafa, Telischi, Fred, Thorson, Willa, Tifft, Cynthia J., Toro, Camilo, Tran, Alyssa A., Tucker, Brianna M., Urv, Tiina K., Vanderver, Adeline, Velinder, Matt, Viskochil, Dave, Vogel, Tiphanie P., Wahl, Colleen E., Walker, Melissa, Wallace, Stephanie, Walley, Nicole M., Wambach, Jennifer, Wan, Jijun, Wang, Lee-kai, Wangler, Michael F., Ward, Patricia A., Wegner, Daniel, Weisz-Hubshman, Monika, Wener, Mark, Wenger, Tara, Perry, Katherine Wesseling, Westerfield, Monte, Wheeler, Matthew T., Whitlock, Jordan, Wolfe, Lynne A., Worley, Kim, Xiao, Changrui, Yamamoto, Shinya, Yang, John, Zastrow, Diane B., Zhang, Zhe, Zhao, Chunli, Zuchner, Stephan, Tepe, Burak, Macke, Erica L., Niceta, Marcello, Weisz Hubshman, Monika, Kanca, Oguz, Schultz-Rogers, Laura, Zarate, Yuri A., Schaefer, G. Bradley, Granadillo De Luque, Jorge Luis, Wegner, Daniel J., Cogne, Benjamin, Gilbert-Dussardier, Brigitte, Le Guillou, Xavier, Wagner, Eric J., Pais, Lynn S., Neil, Jennifer E., Mochida, Ganeshwaran H., Walsh, Christopher A., Magal, Nurit, Drasinover, Valerie, Shohat, Mordechai, Schwab, Tanya, Schmitz, Chris, Clark, Karl, Fine, Anthony, Lanpher, Brendan, Gavrilova, Ralitza, Blanc, Pierre, Burglen, Lydie, Afenjar, Alexandra, Steel, Dora, Kurian, Manju A., Prabhakar, Prab, Gößwein, Sophie, Di Donato, Nataliya, Bertini, Enrico S., Tartaglia, Marco, and Klee, Eric W.

Published
2023
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40. Publisher Correction: Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder

Author

Lim, Elaine T, Uddin, Mohammed, De Rubeis, Silvia, Chan, Yingleong, Kamumbu, Anne S, Zhang, Xiaochang, D’Gama, Alissa M, Kim, Sonia N, Hill, Robert Sean, Goldberg, Arthur P, Poultney, Christopher, Minshew, Nancy J, Kushima, Itaru, Aleksic, Branko, Ozaki, Norio, Parellada, Mara, Arango, Celso, Penzol, Maria J, Carracedo, Angel, Kolevzon, Alexander, Hultman, Christina M, Weiss, Lauren A, Fromer, Menachem, Chiocchetti, Andreas G, Freitag, Christine M, Church, George M, Scherer, Stephen W, Buxbaum, Joseph D, and Walsh, Christopher A

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Neurosciences, Psychology, Autism Sequencing Consortium, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2020

41. Regulation of human cerebral cortical development by EXOC7 and EXOC8, components of the exocyst complex, and roles in neural progenitor cell proliferation and survival

Author

Coulter, Michael E, Musaev, Damir, DeGennaro, Ellen M, Zhang, Xiaochang, Henke, Katrin, James, Kiely N, Smith, Richard S, Hill, R Sean, Partlow, Jennifer N, Muna Al-Saffar, Kamumbu, A Stacy, Hatem, Nicole, Barkovich, A James, Aziza, Jacqueline, Chassaing, Nicolas, Zaki, Maha S, Sultan, Tipu, Burglen, Lydie, Rajab, Anna, Al-Gazali, Lihadh, Mochida, Ganeshwaran H, Harris, Matthew P, Gleeson, Joseph G, and Walsh, Christopher A

Subjects
Genetics, Pediatric, Brain Disorders, Congenital Structural Anomalies, Rare Diseases, Mental Health, Neurodegenerative, Neurosciences, Clinical Research, Intellectual and Developmental Disabilities (IDD), 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Aetiology, Underpinning research, Neurological, Animals, Brain Diseases, Cell Proliferation, Homozygote, Humans, Mice, Microcephaly, Zebrafish, exocyst, EXOC7, EXOC8, microcephaly, developmental delay, Clinical Sciences, Genetics & Heredity
Abstract

PurposeThe exocyst complex is a conserved protein complex that mediates fusion of intracellular vesicles to the plasma membrane and is implicated in processes including cell polarity, cell migration, ciliogenesis, cytokinesis, autophagy, and fusion of secretory vesicles. The essential role of these genes in human genetic disorders, however, is unknown.MethodsWe performed homozygosity mapping and exome sequencing of consanguineous families with recessively inherited brain development disorders. We modeled an EXOC7 splice variant in vitro and examined EXOC7 messenger RNA (mRNA) expression in developing mouse and human cortex. We modeled exoc7 loss-of-function in a zebrafish knockout.ResultsWe report variants in exocyst complex members, EXOC7 and EXOC8, in a novel disorder of cerebral cortex development. In EXOC7, we identified four independent partial loss-of-function (LOF) variants in a recessively inherited disorder characterized by brain atrophy, seizures, and developmental delay, and in severe cases, microcephaly and infantile death. In EXOC8, we found a homozygous truncating variant in a family with a similar clinical disorder. We modeled exoc7 deficiency in zebrafish and found the absence of exoc7 causes microcephaly.ConclusionOur results highlight the essential role of the exocyst pathway in normal cortical development and how its perturbation causes complex brain disorders.

Published
2020

44. Spatial Single-cell Analysis Decodes Cortical Layer and Area Specification

Author

Qian, Xuyu, primary, Coleman, Kyle, additional, Jiang, Shunzhou, additional, Kriz, Andrea J, additional, Marciano, Jack H, additional, Luo, Chunyu, additional, Cai, Chunhui, additional, Manam, Monica D, additional, Caglayan, Emre, additional, Otani, Aoi, additional, Ghosh, Urmi, additional, Shao, Diane D, additional, Andersen, Rebecca E, additional, Neil, Jennifer E, additional, Johnson, Robert, additional, LeFevre, Alexandra, additional, Hecht, Jonathan L, additional, Miller, Michael B, additional, Sun, Liang, additional, Stringer, Carsen, additional, Li, Mingyao, additional, and Walsh, Christopher A, additional

Published
2024
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46. Growth Hormone Receptor Antagonist Markedly Improves Gemcitabine Response in a Mouse Xenograft Model of Human Pancreatic Cancer

Author

Basu, Reetobrata, primary, Kulkarni, Prateek, additional, Swegan, Deborah, additional, Duran-Ortiz, Silvana, additional, Ahmad, Arshad, additional, Caggiano, Lydia J, additional, Davis, Emily, additional, Walsh, Christopher, additional, Brenya, Edward, additional, Koshal, Adeel, additional, Brody, Rich, additional, Sandbhor, Uday, additional, Neggers, Sebastian J.C.M.M, additional, and Kopchick, John J, additional

Published
2024
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48. Somatic genomic changes in single Alzheimer’s disease neurons

Author

Miller, Michael B., Huang, August Yue, Kim, Junho, Zhou, Zinan, Kirkham, Samantha L., Maury, Eduardo A., Ziegenfuss, Jennifer S., Reed, Hannah C., Neil, Jennifer E., Rento, Lariza, Ryu, Steven C., Ma, Chanthia C., Luquette, Lovelace J., Ames, Heather M., Oakley, Derek H., Frosch, Matthew P., Hyman, Bradley T., Lodato, Michael A., Lee, Eunjung Alice, and Walsh, Christopher A.

Published
2022
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49. Impaired neurogenesis alters brain biomechanics in a neuroprogenitor-based genetic subtype of congenital hydrocephalus

Author

Duy, Phan Q., Weise, Stefan C., Marini, Claudia, Li, Xiao-Jun, Liang, Dan, Dahl, Peter J., Ma, Shaojie, Spajic, Ana, Dong, Weilai, Juusola, Jane, Kiziltug, Emre, Kundishora, Adam J., Koundal, Sunil, Pedram, Maysam Z., Torres-Fernández, Lucia A., Händler, Kristian, De Domenico, Elena, Becker, Matthias, Ulas, Thomas, Juranek, Stefan A., Cuevas, Elisa, Hao, Le Thi, Jux, Bettina, Sousa, André M. M., Liu, Fuchen, Kim, Suel-Kee, Li, Mingfeng, Yang, Yiying, Takeo, Yutaka, Duque, Alvaro, Nelson-Williams, Carol, Ha, Yonghyun, Selvaganesan, Kartiga, Robert, Stephanie M., Singh, Amrita K., Allington, Garrett, Furey, Charuta G., Timberlake, Andrew T., Reeves, Benjamin C., Smith, Hannah, Dunbar, Ashley, DeSpenza, Jr., Tyrone, Goto, June, Marlier, Arnaud, Moreno-De-Luca, Andres, Yu, Xin, Butler, William E., Carter, Bob S., Lake, Evelyn M. R., Constable, R. Todd, Rakic, Pasko, Lin, Haifan, Deniz, Engin, Benveniste, Helene, Malvankar, Nikhil S., Estrada-Veras, Juvianee I., Walsh, Christopher A., Alper, Seth L., Schultze, Joachim L., Paeschke, Katrin, Doetzlhofer, Angelika, Wulczyn, F. Gregory, Jin, Sheng Chih, Lifton, Richard P., Sestan, Nenad, Kolanus, Waldemar, and Kahle, Kristopher T.

Published
2022
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