Neurosciences Commons^™

Bivip: A Competitive Neural Network For Bilateral Visuo-Haptic Processing, Eleonore Federica Di Rosa, Aaisha Sheth, Jeffrey Min-In Yau, Laura Astolfi, Cristiano Cuppini

Faculty, Staff and Students Publications

Visuo-haptic interactions are gaining interest in perception research because of their relevance to robotics and rehabilitation. While the benefits of integrating concurrent visuo-tactile cues are well-documented, the temporal dynamics of competitive interactions between vision and touch remain less understood. Building on extant empirical evidence of unilateral intersensory switching, we ask whether bilateral detection of visual and tactile stimuli can be explained by cross-sensory competition and explore the underlying sensorineural dynamics via a multi-level neural network model. Tested against results from a speeded reaction time task to unilateral and bilateral visual, tactile, and visuo-tactile targets, the network successfully predicts higher switch …

Variation In Meningioma Recurrence Risk Estimates Across Observational Cohorts: The Influence Of Calendar Time, Who Classifications, Geographical Settings, And Healthcare Systems, Christian Mirian, Lasse Rehné Jensen, Adam Gorm Hoffmann, Tareq A Juratli, Anders Broechner, Sverre H Torp, Helen A Shih, Ramin A Morshed, Jacob S Young, Stephen T Magill, Luca Bertero, Walter Stummer, Dorothee Cäcilia Spille, Benjamin Brokinkel, Soichi Oya, Satoru Miyawaki, Nobuhito Saito, Martin Proescholdt, Yasuhiro Kuroi, Konstantinos Gousias, Matthias Simon, Jennifer Moliterno, Ricardo Prat-Acin, Stéphane Goutagny, Vikram C Prabhu, John T Tsiang, Johannes Wach, Erdem Güresir, Junkoh Yamamoto, Young Zoon Kim, Joo Ho Lee, Daniel W Kim, Matthew Koshy, Karthikeyan Perumal, Mustafa K Baskaya, Donald M Cannon, Dennis C Shrieve, Chang-Ok Suh, Jong Hee Chang, Maria Kamenova, Sven Straumann, Jehuda Soleman, Ilker Y Eyüpoglu, Tony Catalan, Austin Lui, Philip V Theodosopoulos, Michael W Mcdermott, Fang Wang, Pedro Góes, Manoel Antonio De Paiva Neto, Ricardo Komotar, Michael E Ivan, Aria Jamshidi, Evan Luther, Luis Souhami, Marie-Christine Guiot, Tamás Csonka, Toshiki Endo, Olivia Claire Barrett, Randy Jensen, Tejpal Gupta, Akash J Patel, Tiemo J Klisch, Jun Won Kim, Francesco Maiuri, Valeria Barresi, María Dolores Tabernero, Simon Skyrman, Ian Law, Bjarne Winther Kristensen, Tina Nørgaard Munch, Torstein Meling, Kåre Fugleholm, Paul Blanche, Tiit Mathiesen, Andrea Daniela Maier

Duncan NRI Faculty and Staff Publications

Purpose: Recurrence risk estimates underpin meningioma research, including molecular classification and clinical trial benchmarking, yet are often based on retrospective or historical data. The aim of this study was to assess the variation of recurrence risk estimates across calendar periods, WHO classification editions, geographical settings, and healthcare systems.thetermine METHODS: We analyzed 4,111 patients with primary WHO-1/-2 meningiomas from 31 centers in 15 countries (1990-2019). Recurrence was defined according to local radiological assessment. The 5- and 10-year recurrence risks were estimated using regression standardization with inverse probability of censoring weights, adjusting for key clinical, surgical, and histopathological variables.

Results: Recurrence risk …

Digital Markers For Passive Remote Monitoring Of Bipolar Disorder: Systematic Review, Thomas P Kutcher, Isha Chakraborty, Kristin Kostick-Quenet, Akane Sano, Nidal Moukaddam, Jeffrey A Herron, Wayne K Goodman, Sameer A Sheth, Ashutosh Sabharwal, Nicole R Provenza

Duncan NRI Faculty and Staff Publications

Background: Bipolar disorder (BD) features episodic shifts among mania, hypomania, depression, mixed states, and euthymia. Timely detection of mood transitions is difficult due to infrequent clinical touchpoints. Digital health technologies, including wearables and smartphones, offer a unique opportunity to passively and continuously monitor behavior and physiology that could reflect underlying mood dynamics in real-world settings.

Objective: This study aimed to systematically review passively collected digital markers for BD mood states, characterize devices/modalities and analytic approaches, appraise risk of bias, and identify design gaps and priorities for clinical translation.

Methods: Following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) …

Translational Reading Frame Predicts The Pathogenicity Of C-Terminal Frameshift Deletions In Mecp2, Jacky Guy, Elena Hein, Beatrice Alexander-Howden, Timur Von Bock Und Polach, Tricia Mathieson, Benjamin P Kleinstiver, Huda Y Zoghbi, Adrian Bird

Duncan NRI Faculty and Staff Publications

Mutations in the MECP2 gene cause the severe neurological disorder Rett syndrome. A cluster of frameshift-causing C-terminal deletions (CTDs) removes ~100 amino acids and accounts for approximately 10% of RTT-causing mutations. Their pathogenicity is unexpected because this C-terminal domain is dispensable in mice. Analysis of pathogenic and benign human MECP2 variants reveals that some individuals with apparently typical CTDs do not develop Rett syndrome, confirming that C-terminal truncations are not intrinsically pathogenic. Using human sequence data and mouse models we show that pathogenicity results from a marked reduction in MeCP2 levels and depends on the presence of a proline proline …

Shared Neural Geometries For Bilingual Semantic Representations In Human Hippocampal Neurons, Xinyuan Yan, Ana G Chavez, Melissa Franch, Kalman A Katlowitz, Ivy Gautam, Brian Kim, Aaditya Krishna, Aadit Shrivastava, Katie Van Arsdel, James Belanger, Assia Chericoni, Taha Ismail, Elizabeth A Mickiewicz, Danika Paulo, Hanlin Zhu, Alica M Goldman, Vaishnav Krishnan, Atul Maheshwari, Eleonora Bartoli, Nicole R Provenza, Seng Bum Michael Yoo, Benjamin Y Hayden, Sameer A Sheth

Duncan NRI Faculty and Staff Publications

The human brain has the remarkable ability to comprehend and express similar concepts in multiple languages. To understand how it does so, we examined responses of hippocampal neurons during passive listening, directed speaking, and spontaneous conversation in both English and Spanish in a small group of balanced bilinguals. We found a small number of putative "cross-language neurons," whose responses to equivalent words (e.g., "tierra" and "earth") are correlated. However, neurons' semantic tunings differed substantially by language, suggesting language-specific neural implementations. Instead, the crucial driver of translation was a preserved geometric organization of neural responses between the two languages, one that …

A Blended Genome And Exome Sequencing Method Captures Genetic Variation In An Unbiased And Cost-Effective Manner, Toni A Boltz, Benjamin B Chu, Matthew Defelice, Calwing Liao, Julia M Sealock, Robert Ye, Jacqueline I Goldstein, Lerato Majara, Jack M Fu, Susan K Service, Lingyu Zhan, Sarah E Medland, Sinéad B Chapman, Simone Rubinacci, Jonna L Grimsby, Tamrat Abebe, Melkam Alemayehu, Fred K Ashaba, Elizabeth G Atkinson, Tim B Bigdeli, Amanda B Bradway, Harrison Brand, Lori B Chibnik, Samuel Deluca, Ana M Diaz-Zuluaga, Abebaw Fekadu, Michael Gatzen, Bizu Gelaye, Stella Gichuru, Marissa L Gildea, Toni C Hill, Hailiang Huang, Kalyn M Hubbard, Wilfred E Injera, Roxanne James, Moses Joloba, Christopher Kachulis, Phillip R Kalmbach, Rogers Kamulegeya, Gabriel Kigen, Soyeon Kim, Nastassja Koen, Edith K Kwobah, Joseph Kyebuzibwa, Seungmo Lee, Niall J Lennon, Penelope A Lind, Esteban A Lopera-Maya, Johnstone Makale, Serghei Mangul, Justin Mcmahon, Pierre Mowlem, Henry Musinguzi, Rehema M Mwema, Noeline Nakasujja, Carter P Newman, Lethukuthula L Nkambule, Conor R O'Neil, Ana Maria Olivares, Catherine M Olsen, Linnet Ongeri, Sophie J Parsa, Adele Pretorius, Shengying Qin, Raj Ramesar, Faye L Reagan, Chiara Sabatti, Jacquelyn A Schneider, Welelta Shiferaw, Christine Stevens, Anne Stevenson, Erik Stricker, Rocky E Stroud, Jessie Tang, Megan Townsend, David Whiteman, Mary T Yohannes, Mingrui Yu, Kai Yuan, Dickens Akena, Lukoye Atwoli, Symon M Kariuki, Karestan C Koenen, Charles R J C Newton, Dan J Stein, Solomon Teferra, Zukiswa Zingela, Carlos N Pato, Michele T Pato, Carlos Lopez-Jaramillo, Nelson B Freimer, Roel A Ophoff, Loes M Olde Loohuis, Michael E Talkowski, Benjamin M Neale, Daniel P Howrigan, Alicia R Martin

Duncan NRI Faculty and Staff Publications

Here we developed and deployed the blended genome exome (BGE) method, a DNA library approach that generates low-pass whole-genome (1–4× mean depth) and deep whole-exome (30–40× mean depth) data in a single sequencing run. BGE is cost-effective, empowers most genomic discoveries possible with deep whole-genome sequencing and captures global common single-nucleotide polymorphism diversity. We applied BGE to sequence >53,000 samples from the PUMAS Project (Populations Underrepresented in Mental Illness Associations Studies), including African, African American and Latin American populations. Imputed genotypes showed high concordance with Illumina Global Screening Array calls (R2 ≥ 95% for minor allele frequency ≥1%; …

Hippo Signaling Regulates Cuticle Pigmentation And Dopamine Metabolism In Drosophila, Shelley B Gibson, Samantha L Deal, Ye-Jin Park, Bo Sun, Yanyan Qi, Jung-Wan Mok, Hyung-Lok Chung, Hongjie Li, Shinya Yamamoto

Duncan NRI Faculty and Staff Publications

Pigmentation plays multiple important roles in development, physiology and evolution. Melanization of the insect cuticle requires dopamine as a precursor of melanin and involves key enzymes in dopamine biosynthesis including Tyrosine hydroxylase (TH) and Dopa decarboxylase (Ddc). Some studies have hinted that disruption of the evolutionarily conserved Hippo signaling pathway, which has been primarily studied in the context of tissue growth, may lead to changes in cuticle pigmentation in the fruit fly Drosophila melanogaster. However, to our knowledge, there have not been any systematic investigations into their potential mechanistic links. In this study, we identified that all genes that comprise …

Extending Genome-Wide Association Studies To Admixed Cohorts With High Degrees Of Relatedness, Taotao Tan, Alejandra Vergara-Lope, José Jaime Martínez-Magaña, Nirav N Shah, Yi-Sian Lin, Kai Yuan, Jaime Berumen, Jesus Alegre-Díaz, Pablo Kuri-Morales, Roberto Tapia-Conyer, Joel Gelenter, Janitza L Montalvo-Ortiz, Wei Zhou, Jason M Torres, Elizabeth G Atkinson

Duncan NRI Faculty and Staff Publications

Admixed populations comprise a large portion of the human population worldwide, but are often excluded from genome-wide association studies (GWASs) due to analytic challenges. Our group developed Tractor, a local-ancestry-informed GWAS tool designed for admixed samples that produces accurate ancestry-specific effect sizes and boosts the discovery power to identify ancestry-enriched loci. However, Tractor operates under an assumption of unrelated samples. Here, to address this gap, we propose Tractor-Mix, which allows for well-calibrated association studies in datasets containing admixed samples with relatedness. Extensive simulations show that this method is competitive with other state-of-the-art approaches that do not produce ancestry-specific results. Empirical …

Hp1bp3 Loss Links Chromatin Reorganization To Metabolic Vulnerability In Glioma, Brittney Lozzi, Taylor A Gatesman, Pushan Dasgupta, Debosmita Sardar, Yeunjung Ko, Chenyu Mao, Hsiao-Chi Chen, Rachel N Curry, Dongjoo Choi, Carrie A Mohila, Melissa L Bondy, Ganesh Rao, Marco Gallo, Sameer Agnihotri, Benjamin Deneen

Duncan NRI Faculty and Staff Publications

High-grade gliomas (HGGs) are aggressive brain tumors with poor prognosis, driven in part by metabolic and epigenetic adaptations. Methionine metabolism supports HGG growth by supplying S-adenosylmethionine for methylation reactions, yet how nutrient availability influences chromatin organization in HGG remains incompletely understood. Using an immunocompetent mouse model of HGG, we found that dietary methionine restriction reduced tumor proliferation, extended survival, and induced partial nuclear inversion. We identified Hp1bp3 as a key regulator of tumor growth that functions by interacting with nuclear tethering proteins to mediate chromatin reorganization. Loss of Hp1bp3 results in the upregulation of histone demethylases leading to selective depletion …

Efficacy And Safety Of A Bodyweight-Adjusted Higher Dose Of Ocrelizumab In Relapsing (Musette) And Primary Progressive (Gavotte) Multiple Sclerosis: Two Multicentre, Randomised, Double-Blind, Parallel-Group Phase 3b Trials., Stephen L Hauser, Gavin Giovannoni, Xavier Montalban, Jiwon Oh, Amit Bar-Or, Maria Pia Sormani, Martin S Weber, Sharon Stoll, Jacqueline A Nicholas, Tetyana Nehrych, Robert Bonek, Krzysztof Selmaj, Maciej Maciejowski, Dusanka Zecevic, Catarina Raposo, Rebecca Owen, Ulrike Bonati, Katrin Madjar, Eva Harfst, Qing Wang, Anastasiia Raievska, Marianna Manfrini, Hans-Martin Schneble, Ludwig Kappos, Musette And Gavotte Study Groups

Neuroscience Articles

BACKGROUND: Ocrelizumab is a humanised anti-CD20 monoclonal antibody approved for people with relapsing (RMS) or primary progressive multiple sclerosis (PPMS). In a post-hoc analysis of phase 3 trials in RMS and PPMS using a 600 mg dose, higher exposure to ocrelizumab was associated with greater B-cell depletion and lower risk of confirmed disability progression. Here, we prospectively assessed the efficacy and safety of a high dose of ocrelizumab in patients with RMS or PPMS.

METHODS: Two multicentre, double-blind, phase 3 controlled trials were conducted to compare high-dose ocrelizumab with the approved 600 mg dose of the drug in patients with …

Deep-Learning Endomicroscope With Large Field-Of-View And Depth-Of-Field For Real-Time In Vivo Imaging Of Epithelial Cancer Hallmarks, Huayu Hou, Jimin Wu, Jinyun Liu, Vivek Boominathan, Argaja Shende, Karthik Goli, Jennifer Carns, Richard A Schwarz, Ann M Gillenwater, Preetha Ramalingam, Mila P Salcedo, Kathleen M Schmeler, Tomasz S Tkaczyk, Jacob T Robinson, Ashok Veeraraghavan, Rebecca R Richards-Kortum

Faculty, Staff and Students Publications

In vivo microscopy (IVM) has shown great promise to improve early detection of epithelial precancer, but it suffers from fundamental trade-offs that limit the resolution, field-of-view (FOV) and depth-of-field (DOF). Here, we present PrecisionView, a compact, deep learning-enabled endomicroscope that breaks these constraints and achieves 20 mm2 FOV and 500 µm DOF with 4 µm resolution, representing approximately 5× increase in FOV and 8× larger DOF compared to conventional IVM with similar resolution. PrecisionView integrates a deep learning-optimized phase mask and real-time reconstruction, enabling rapid in vivo assessment of two key hallmarks of cancer: epithelial cell nuclear morphology and subsurface …

Genetic Analysis Of The X-Linked Adrenoleukodystrophy Gene Abcd1 In Drosophila Uncovers A Conserved Phenotype, Joshua Manor, Sharayu V Jangam, Hyung-Lok Chung, Pranjali Bhagwat, Jonathan C Andrews, Hillary Chester, Shu Kondo, Saurabh Srivastav, Juan Botas, Ann B Moser, Suzette M Huguenin, Michael F Wangler

Duncan NRI Faculty and Staff Publications

X-linked adrenoleukodystrophy (X-ALD) is a progressive neurodegenerative disorder caused by a loss-of-function (LOF) mutation in the ATP-binding cassette subfamily D member 1 (ABCD1) gene, leading to the accumulation of very long-chain fatty acids (VLCFAs). This disorder exhibits striking heterogeneity; some male patients develop an early childhood neuroinflammatory demyelination disorder, while other patients, including adult males and most affected female carriers, experience a chronic progressive myelopathy. Adrenocortical failure is observed in almost all male patients, with the age of onset varying, sometimes being the first diagnostic finding. The gene underlying this spectrum of disease encodes an ATP-binding cassette (ABC) transporter that …

Adhesion G Protein-Coupled Receptors, Tobias Langenhan, Garret R Anderson, Demet Araç, Gabriela Aust, Monserrat Avila-Zozaya, Sofie Morsing Bagger, Patrick Barth, Sandra Berndt, Stephen C Blacklow, Beatriz Blanco-Redondo, Antony A Boucard, James P Bridges, Lara-Sophie Brodmerkel, Kathleen M Caron, Yin Kwan Chung, Andrew N Dates, Virginea De Araujo Farias, Daniel Del Toro, Joseph G Duman, Felix B Engel, David M Favara, Caroline J Formstone, Chaoyu Fu, Alain Garcia De Las Bayonas, Anastasia Georgiadi, David E Gloriam, Randy A Hall, Jörg Hamann, Peter W Hildebrand, Cheng-Chih Hsiao, Bill X Huang, Jonathan A Javitch, Hee-Yong Kim, Robert J Kittel, Gunnar Kleinau, Richard Leduc, Ines Liebscher, Hsi-Hsien Lin, Joshua Linnert, Marie-Gabrielle Ludwig, David C Martinelli, Signe Mathiasen, Daniel Matúš, Mariam Melkumyan, Ana L Moreno-Salinas, Jan Mulder, Michael A Nash, Kasturi Pal, Daniel T Pederick, Nicole A Perry-Hauser, Xianhua Piao, Yu-Qi Ping, Dimitris G Placantonakis, Fabian Pohl, Simone Prömel, Mette M Rosenkilde, Laurent Sabbagh, Richard C Sando, Patrick Scheerer, Torsten Schöneberg, Elena Seiradake, Mareike Selcho, Florian Seufert, Abhishek K Singh, Georgios Skiniotis, Katja Spiess, Norbert Sträter, David Strutt, Thomas C Südhof, Jinpeng Sun, Gregory G Tall, Doreen Thor, Douglas G Tilley, Kimberley F Tolias, Mario Vallon, Erwin G Van Meir, Benoit Vanhollebeke, Giselle R Wiggin, Uwe Wolfrum, Jie Yan, Nathan A Zaidman, Yimin Zou, Nicole Scholz

Faculty, Staff and Students Publications

Adhesion G protein-coupled receptors (aGPCRs) constitute a structurally and functionally distinct group within the superfamily of GPCRs. In 2015, the International Union of Pharmacology invited the Adhesion GPCR Consortium to publish a comprehensive review about aGPCRs and establish a unified nomenclature. Since then, substantial progress has been made in delineating the biological roles, molecular architecture, biochemical properties, expression profiles, ligand repertoire, and activation and signaling strategies of aGPCRs. Commensurate with these advances, their relevance to human pathophysiology has become increasingly apparent. In a coordinated effort, the Adhesion GPCR Consortium has reviewed recent progress in this field and provides a comprehensive …

Adhesion G Protein-Coupled Receptors, Tobias Langenhan, Garret R Anderson, Demet Araç, Gabriela Aust, Monserrat Avila-Zozaya, Sofie Morsing Bagger, Patrick Barth, Sandra Berndt, Stephen C Blacklow, Beatriz Blanco-Redondo, Antony A Boucard, James P Bridges, Lara-Sophie Brodmerkel, Kathleen M Caron, Yin Kwan Chung, Andrew N Dates, Virginea De Araujo Farias, Daniel Del Toro, Joseph G Duman, Felix B Engel, David M Favara, Caroline J Formstone, Chaoyu Fu, Alain Garcia De Las Bayonas, Anastasia Georgiadi, David E Gloriam, Randy A Hall, Jörg Hamann, Peter W Hildebrand, Cheng-Chih Hsiao, Bill X Huang, Jonathan A Javitch, Hee-Yong Kim, Robert J Kittel, Gunnar Kleinau, Richard Leduc, Ines Liebscher, Hsi-Hsien Lin, Joshua Linnert, Marie-Gabrielle Ludwig, David C Martinelli, Signe Mathiasen, Daniel Matúš, Mariam Melkumyan, Ana L Moreno-Salinas, Jan Mulder, Michael A Nash, Kasturi Pal, Daniel T Pederick, Nicole A Perry-Hauser, Xianhua Piao, Yu-Qi Ping, Dimitris G Placantonakis, Fabian Pohl, Simone Prömel, Mette M Rosenkilde, Laurent Sabbagh, Richard C Sando, Patrick Scheerer, Torsten Schöneberg, Elena Seiradake, Mareike Selcho, Florian Seufert, Abhishek K Singh, Georgios Skiniotis, Katja Spiess, Norbert Sträter, David Strutt, Thomas C Südhof, Jinpeng Sun, Gregory G Tall, Doreen Thor, Douglas G Tilley, Kimberley F Tolias, Mario Vallon, Erwin G Van Meir, Benoit Vanhollebeke, Giselle R Wiggin, Uwe Wolfrum, Jie Yan, Nathan A Zaidman, Yimin Zou, Nicole Scholz

Faculty, Staff and Students Publications

Adhesion G protein-coupled receptors (aGPCRs) constitute a structurally and functionally distinct group within the superfamily of GPCRs. In 2015, the International Union of Pharmacology invited the Adhesion GPCR Consortium to publish a comprehensive review about aGPCRs and establish a unified nomenclature. Since then, substantial progress has been made in delineating the biological roles, molecular architecture, biochemical properties, expression profiles, ligand repertoire, and activation and signaling strategies of aGPCRs. Commensurate with these advances, their relevance to human pathophysiology has become increasingly apparent. In a coordinated effort, the Adhesion GPCR Consortium has reviewed recent progress in this field and provides a comprehensive …

Platelets Cause Microvascular Occlusion And Delayed Neurological Deficits After Subarachnoid Hemorrhage In Mice., Ari Dienel, Sung-Ha Hong, Kiara Torres, Kanako Matsumura, Jose Guzman, Peeyush Thankamani Pandit, Bibek Samal, Harveen Kaur, Samitha Nemirajaiah, Angelica Bernal, H Alex Choi, Louise D Mccullough, Spiros L Blackburn, Jaroslaw Aronowski, Devin W Mcbride

Faculty, Staff and Student Publications

After subarachnoid hemorrhage (SAH), some patients develop delayed neurological deficits (DND). Microthrombi are considered a contributing factor to DND, but clinical trials of antiplatelets had mixed results. Existing research suggests that platelets play a role in the etiology of DND, but no comprehensive study has tested causality between platelets and DND after SAH. Here we hypothesize that after SAH, platelet activation promotes microthrombi formation, occlusion of the brain microvasculature and contributes to DND, and that inhibiting platelet aggregation is a therapeutic strategy. Mice experiencing SAH were administered various interventions. The animals were subjected to stimulation of platelets, platelet depletion, or …

Efficient In Vivo Pharmacological Inhibition Of Δfosb, An Ap-1 Transcription Factor, In The Brain, Sean Mcneme, Anil Kumar, Yun Young Yim, Brandon W Hughes, Corey St Romain, Yi Li, Ashwani Kumar, Qichao Bao, Molly Estill, Shanghua Fan, Nadeen Takatka, Earnest P Chen, Matthew Rivera, Haiying Chen, Alfred J Robison, Mischa Machius, Stephen J Haggarty, Jeannie Chin, Eric J Nestler, Jia Zhou, Gabby Rudenko

Faculty, Staff and Students Publications

ΔFOSB, an unusually stable member of the AP-1 family of transcription factors, mediates long-term maladaptations that play a key role in the pathogenesis of drug addiction, cognitive decline, dyskinesia, and several other chronic neurological and psychiatric conditions. We have recently identified that 2-phenoxybenzenesulfonic acid-containing compounds disrupt the binding of ΔFOSB to DNA in vitro in cell-based assays, and one such compound, JPC0661, disrupts ΔFOSB binding to genomic DNA in vivo in the mouse brain with partial efficiency. JPC0661 binds to a groove outside of the DNA-binding cleft of the ΔFOSB/JUND bZIP heterodimer in a cocrystal structure. Here, we generated a …

Phenome-Wide Analysis Of Copy Number Variants In 470,727 Uk Biobank Genomes, Xueqing Zoe Zou, Fengyuan Hu, Haiyi Lou, Oliver S Burren, Xiaoyin Li, Karyn Megy, Eleanor Wheeler, Qiang Wu, Santosh S Atanur, Marcin Karpinski, Douglas Loesch, Zammy Fairhurst-Hunter, Sri V V Deevi, Erin Oerton, Sean Wen, Xiao Jiang, Cecilia Salvoro, Jonathan Mitchell, Abhishek Nag, Ben Hollis, Amanda O'Neill, Jen Harrow, Stewart Macarthur, Sebastian Wasilewski, Sean O'Dell, Lifeng Tian, Katherine R Smith, Guillermo Del Angel, Margarete Fabre, Ryan S Dhindsa, Quanli Wang, Slavé Petrovski, Keren Carss

Duncan NRI Faculty and Staff Publications

Copy number variants (CNVs) are key drivers of human diversity and disease risk1. Here we evaluate the role of CNVs across a broad range of human phenotypes and diseases by analysing CNVs from 470,727 UK Biobank whole-genome sequences and conducting a variant- and gene-level phenome-wide association study (PheWAS) with 2,941 plasma protein abundance measurements, 13,336 binary clinical phenotypes and 1,911 quantitative traits. Proteomic analyses validated functional associations of CNVs with nearby genes (cis-protein quantitative trait loci; cis-pQTLs)—with deletions and duplications typically associated with reduced and increased protein levels, respectively—and uncovered previously unknown protein–protein interactions …

Pd-L1 Positivity Predicts A Unique Hyperaggressive Tumor Group Within Meng C Meningiomas, Vijay Nitturi, Shervin Hosseingholi Nouri, Collin English, Hsiang-Chih Lu, Elizabeth Ledbetter, Diego Rojas, Sean Lau, Malcolm Mcdonald, Jacob J Mandel, Abdul Basit Khan, Arif O Harmanci, Akdes S Harmanci, Tiemo Klisch, Akash J Patel

Duncan NRI Faculty and Staff Publications

Molecular profiling has identified 3 groups of meningiomas, with MenG C tumors exhibiting the vast majority of recurrences. Efforts to find effective treatments for recurrent meningiomas have remained elusive. Higher WHO-grade meningiomas have exhibited greater Programmed Death Ligand 1 (PD-L1) expression through various methods, but the prognostic value of PD-L1 expression has not been described in the context of molecular profiling. Additionally, trials investigating PD-1/PD-L1-targeted immunotherapies have produced disappointing results. Here, we find that PD-L1 positivity, while prevalent in MenG C tumors, does not predict recurrence in the benign MenG A and B tumors. PD-L1 positivity also occurs independently of …

The Role Of Top-Down Appetite Self-Regulation In The Development Of Healthy Eating Behaviors Among Children: A Narrative Review And Socialization Framework, David J Bridgett, Sheryl O Hughes, Matthew Broussard, Daniela Mccourt, Christina M Croce, Jennifer O Fisher

Faculty, Staff and Students Publications

Appetite self-regulation (ASR) among children is thought to have a fundamental role in shaping the development of healthy eating behaviors, dietary intake, and growth during childhood. Parallel to developmental frameworks for understanding "general" self-regulation among children, ASR has been described as involving children's use of "top-down" cognitive processes to moderate "bottom-up" biological drives around food approach and avoidance in the interest of achieving desired eating behaviors or outcomes. Whereas bottom-up ASR processes during early childhood are well characterized, particularly in the context of dysregulation and obesity risk, the role of top-down ASR processes in the development of healthy eating behaviors …

Responsive Neurostimulation In Children, Adolescents, And Young Adults-Longitudinal Effectiveness And Safety, Steven T Lee, Shital Patel, Cemal Karakas, Kimberly Houck, Cristina Trandafir, Matthew J Mcginley, Deepankar Mohanty, James J Riviello, Howard L Weiner, Daniel Curry, Irfan Ali

Faculty, Staff and Students Publications

Drug-resistant epilepsy (DRE) remains challenging to treat, and seizure control often fluctuates over time. Responsive neurostimulation (RNS) is increasingly used in pediatric and young adult populations, yet long-term effectiveness and safety data are limited. We evaluated longitudinal seizure control trajectories and safety of RNS in children, adolescents, and young adults treated at our center. Seizure frequency was assessed at approximately 6-month intervals from serial follow-up visits through the most recent follow-up, with each sampled visit categorized by ≥ 50 % (all-responder, AR) or ≥90 % (super-responder, SR) seizure reduction. We examined the persistence and durability of seizure control and used …

Leveraging Clinical Sleep Data Across Multiple Pediatric Cohorts For Insights Into Neurodevelopment: The Retrospective Analysis Of Sleep In Pediatric (Rasp) Cohorts Study, Naihua N Gong, Aditya Mahat, Samya Ahmad, Daniel Glaze, Mirjana Maletic-Savatic, Matthew Mcginley, Anne Marie Morse, Alcibiades J Rodriguez, Audrey Thurm, Susan Redline, Kiran Maski, Peter Davis, Shaun Purcell, Ashura Buckley

Faculty, Staff and Students Publications

Sleep disturbances are prominent across neurodevelopmental disorders (NDDs) and may reflect specific abnormalities in brain development and function. Overnight polysomnography (PSG) allows for detailed investigation of sleep architecture, offering a unique window into neurocircuit function. Analysis of existing pediatric PSGs from clinical studies could enhance the availability of sleep studies in pediatric patients with NDDs towards a better understanding of mechanisms underlying abnormal development in NDDs. Here, we introduce and characterize a retrospective collection of 1527 clinical pediatric overnight PSGs across five different sites. We first developed an automated stager trained on independent pediatric sleep data, which yielded better performance …

Consensus Paper: Models Of Cerebellar Functions, Shinji Kakei, Andreea C Bostan, Timothy J Ebner, Mohammad Amin Fakharian, Hiroaki Gomi, Xavier Guell, Marie Hemelt, Huu Hoang, Court Hull, Masato Inoue, Takahiro Ishikawa, Masashi Kameda, Mitsuo Kawato, Shigeru Kitazawa, Mario Manto, Javier F Medina, Hiroshi Mitoma, Keiko Ohmae, Shogo Ohmae, Ken-Ichi Okada, Laurentiu S Popa, Jeremy D Schmahmann, Reza Shadmehr, Peter L Strick, Hirokazu Tanaka, Masaki Tanaka, Tadashi Yamazaki

Faculty, Staff and Students Publications

For a long time, from the nineteenth century to most of the twentieth century, the cerebellum was thought to be an organ that regulates movement. Towards the end of the twentieth century, the brain functions associated with the cerebellum began to extend beyond motor control. Now, there is a consensus that the cerebellum is involved not only in motor functions but also in the most basic autonomic functions and the most complex cognitive and emotional functions, with a focus on predictions and internal models. A new functional model of the cerebellum is needed to explain all layers of brain functions …

Population-Scale Sequencing Resolves Determinants Of Persistent Ebv Dna, Sherry S Nyeo, Erin M Cumming, Oliver S Burren, Meghana S Pagadala, Jacob C Gutierrez, Thahmina A Ali, Laura C Kida, Yifan Chen, Hoyin Chu, Fengyuan Hu, Xueqing Zoe Zou, Benjamin Hollis, Margarete A Fabre, Stewart Macarthur, Quanli Wang, Leif S Ludwig, Kushal K Dey, Slavé Petrovski, Ryan S Dhindsa, Caleb A Lareau

Duncan NRI Faculty and Staff Publications

Epstein–Barr virus (EBV) is an endemic herpesvirus implicated in autoimmunity, cancer and neurological disorders. Although primary infection is often subclinical, persistent EBV infection can drive immune dysregulation and long-term complications. Despite the ubiquity of infection, the determinants of EBV persistence following primary exposure remain poorly understood, although human genetic variation partially contributes to this phenotypic spectrum1–3. Here we demonstrate that existing whole genome sequencing (WGS) data of human populations can be used to quantify persistent EBV DNA. Using WGS and health record data from the UK Biobank (n = 490,560) and All of Us ( …

Rare Heterozygous Missense Variants In Vsx2 Are Associated With Retinal Detachment, Daniel C Brock, Justin S Dhindsa, Yifan Chen, Vida Ravanmehr, Jonathan Mitchell, Fengyuan Hu, Xiaoyin Li, Likhita Nandigam, Quanli Wang, Kevin Wu, Jessica C Butts, Hardeep S Dhindsa, Benjamin J Frankfort, Nicholas M Tran, Slavé Petrovski, Ryan S Dhindsa

Duncan NRI Faculty and Staff Publications

Retinal detachment (RD) is a sight-threatening emergency requiring urgent intervention to prevent permanent vision loss. While both environmental and genetic risk factors contribute to RD, its complete genetic architecture remains unknown. Here, we performed the largest whole genome sequencing-based case-control study in RD to date, including data from 7,276 RD cases and 236,741 controls in the UK Biobank. Through variant- and gene-level association analyses, we identified VSX2 as a genetic determinant of RD risk while confirming established associations including FAT3, RDH5, and COL2A1. Gene-level collapsing analysis revealed that rare heterozygous missense variants in VSX2 confer a 2.8-fold …

Hiv Vpr Induces Demethylation Of The Snca Antisense Promoter, Leading To Neurocognitive Impairment, Maryline Santerre, Ying Wang, Daniel Kalamarides, Jin Park, Lynn G Kirby, Jeannie Chin, Jaroslav Jelinek, Natalia Shcherbik, Bassel E Sawaya

Faculty, Staff and Students Publications

Human immunodeficiency virus type 1 (HIV-1) alpha-synuclein (α-Syn) aggregation is a hallmark of neurodegenerative diseases. Accumulation and aggregation of α-Syn are often observed in individuals with HIV-1 cognitive impairments. The direct mechanistic link between α-Syn dysregulation and HIV-associated neurocognitive disorders (HAND) remains unclear. Emerging evidence suggests that epigenetic changes, particularly deoxyribonucleic acid (DNA) demethylation, influence α-Syn regulation. We show that the HIV-1 protein viral protein R (Vpr) demethylates the antisense promoter within intron 1 of the alpha-synuclein gene (SNCA), potentially contributing to increased α-Syn expression. Elevated α-Syn promotes aggregation, causing synaptic dysfunction and impaired mitochondrial transport. These processes contribute to …

Tead-Independent Mechanisms Of Yap Function In Cardiomyocyte Cell Cycle Reentry, Bing Xie, Jeffrey Steimle, Vaibhav Deshmukh, Lin Liu, Chang-Ru Tsai, Todd R Heallen, Wyatt Paltzer, Yuka Morikawa, Fansen Meng, Jun Wang, James F Martin

Faculty, Staff and Students Publications

Adult mammalian hearts exhibit limited regenerative capacity because of the restricted renewal of cardiomyocytes. Recent studies reveal that mammalian hearts exhibit transient regenerative potential within a short time frame after birth, suggesting a regulatory mechanism that prevents adult hearts from initiating a regenerative response to cardiac injury. Here, we discovered that an active form of YAP, named YAP6SA, which is not inhibited by the Hippo signaling pathway and does not interact with TEADs, induces cardiomyocyte cell cycle reentry. In addition, YAP6SA interacts with scaffold protein MPDZ to regulate Rho GTPases and promote cell cycle progression in cardiomyocytes (CMs). Importantly, YAP6SA …

Using The Linear References From The Pangenome To Discover Missing Autism Variants, Yang Sui, Jiadong Lin, Michelle D Noyes, Youngjun Kwon, Isaac Wong, Nidhi Koundinya, William T Harvey, Mei Wu, Kendra Hoekzema, Katherine M Munson, Gage H Garcia, Jordan Knuth, Julie Wertz, Tianyun Wang, Kelsey Hennick, Druha Karunakaran, Rafael A Polo Prieto, Rebecca Meyer-Schuman, Fisher Cherry, Davut Pehlivan, Bernhard Suter, Jonas A Gustafson, Danny E Miller, Human Pangenome Reference Consortium (Hprc), Hanna Berk-Rauch, Tomasz J Nowakowski, Aravinda Chakravarti, Huda Y Zoghbi, Evan E Eichler

Duncan NRI Faculty and Staff Publications

To better understand large-effect pathogenic variation associated with autism, we generated long-read sequencing (LRS) data to construct phased and near-complete genome assemblies (average contig N50 = 43 Mbp, QV = 56) for 189 individuals from 51 families with unsolved cases. We applied read- and assembly-based strategies to facilitate comprehensive characterization of de novo mutations, structural variants (SVs), and DNA methylation. Using LRS pangenome controls, we efficiently filtered >97% of common SVs exclusive to 87 offspring. We find no evidence of increased autosomal SV burden for probands when compared to unaffected siblings yet observe a suggestive trend toward an increased SV …

Pathogenesis Of Polyglutamine Diseases: Piecing Together A Complex Molecular Puzzle, Esmeralda Villavicencio Gonzalez, Huda Y Zoghbi

Duncan NRI Faculty and Staff Publications

Polyglutamine (polyQ) diseases, caused by a CAG repeat expansion encoding a glutamine tract in nine distinct proteins, present a complex molecular puzzle in which each piece contributes to neurodegeneration. While each of the causative proteins has a distinct function, the downstream consequences of polyQ toxicity are often similar, including protein accumulation, transcriptional dysregulation, somatic CAG repeat instability, disrupted energy homeostasis, compromised synaptic function, and selective neuronal death. This review summarizes emerging insights into how proteins with an expanded polyQ tract disrupt distinct cellular functions, and we examine a multitude of discoveries that are inspiring and reshaping novel therapeutic strategies.

35 Individuals With Huwe1-Related Neurodevelopmental Disorder And Suggested Clinical Evaluations, Mindy H. Li, Deziree L. Coleman, Kelsey Hogan, Danielle Luz, Lindsay Bhandari, Newell Belnap, Tiffany Busa, Charles Coutton, Klaus Dieterich, Svetlana Gorokhova, Clara Hildebrandt, Rachel Logan, Milena Mariani, Manuela Morleo, Vincenzo Nigro, John Pappas, Rachel Rabin, Kelly Schoch, Angelo Selicorni, Vandana Shashi, Rebecca Spillman, Jennifer Sullivan, Charlotte Tardy, Samantha A. Schrier Vergano, Brock Grill, Kristin Baranano

Department of Pediatrics Faculty Publications

HUWE1 (HECT, UBA, and WWE Domain Containing E3 Ubiquitin Protein Ligase1, OMIM 300697), located at Xp11.22, encodes a ubiquitin ligase that is highly conserved across species. Genetic variants in HUWE1 described in multiple independent studies cause X-linked intellectual disability, including in the patients identified by Juberg, Marsidi, and Brooks. This report describes 35 additional cases of individuals with variants in HUWE1 and suggested guidelines for clinical management. Our study includes several female cases, which have not been widely reported previously. Our findings confirm earlier reported clinical features including developmental delay, autism, hypotonia, short stature, and dysmorphic facial features as well …

Noradrenergic Innervation Across Brain Regions Is Altered By Aging And By Disease Progression In A Mouse Model Of Alzheimer’S Disease Neuropathology, Nicole M Hernandez, Manuel Silva-Pérez, Jeannie Chin

Faculty, Staff and Students Publications

Norepinephrine plays critical roles in modulating arousal and attention, is highly dynamic in awake, behaving individuals, and has anti-inflammatory and neuroprotective actions. Notably, the locus coeruleus (LC), the primary source of norepinephrine in the central nervous system, is among the first brain regions to show pathological alterations in early stages of Alzheimer's disease (AD). LC neuronal loss and associated reductions in norepinephrine in the brain have therefore been postulated to play a key role in AD pathophysiology. LC neurons and their axons have been studied in several mouse models of AD-related neuropathology to investigate their contribution to brain dysfunction in …