Digital Commons Network^™

Adaptive Neuromodulation Dialogues: Navigating Current Challenges And Emerging Innovations In Neuromodulation System Development, Frederik Lampert, Matthew R Baker, Michael A Jensen, Amir H Ayyoubi, Christian Bentler, Jessica L Bowersock, Rosana Esteller, Jeffrey A Herron, Graham W Johnson, Daryl R Kipke, Christopher K Kovach, Vaclav Kremen, Filip Mivalt, Joseph S Neimat, Theoden I Netoff, Enrico Opri, Alexander Rockhill, Joshua M Rosenow, Kristin K Sellers, Nathan P Staff, Chandra Prakash Swamy, Ashwin Viswanathan, Gerwin Schalk, Timothy Denison, Dora Hermes, Nuri F Ince, Peter Brunner, Gregory A Worrell, Kai J Miller

Faculty, Staff and Students Publications

Adaptive neuromodulation systems and implantable brain-computer interfaces have made notable strides in recent years, translating experimental prototypes into clinical applications and garnering substantial attention from the public. This surge in interest is accompanied by increased scrutiny related to the safety, efficacy, and ethical implications of these systems, all of which must be directly addressed as we introduce new neurotechnologies. In response, we have synthesized the insights resulting from discussions between groups of experts in the field and summarized them into five key domains essential to therapeutic device development: (1) analyzing current landscape of neuromodulation devices and translational platforms (2) identifying …

Mechanistic And Functional Characterization Of Abtb2 As A Novel Target For Pancreatic Cancer Therapy, Nan Lyu, Olamide T Olaoba, Qiongling Wang, Harinarayanan Janakiraman, Xinjian Liu, Ernest Ramsay Camp, Kun Cheng, Eric T Kimchi, Yi Miao, Kevin F Staveley-O'Carroll, Guangfu Li

Faculty, Staff and Students Publications

BTB/POZ domain-containing proteins are increasingly recognized for their context-dependent roles in cancer, acting as either tumor suppressors or oncogenic drivers depending on the cancer type. Among them, the function of ankyrin repeat and BTB domain-containing protein 2 (ABTB2) in pancreatic ductal adenocarcinoma (PDAC), a highly lethal malignancy, has remained unexplored. In this study, we employed comprehensive functional genomics approaches—siRNA/shRNA knockdown, CRISPR-Cas9 knockout, plasmid-based overexpression, and a Cre-LoxP transgenic mouse model—to systemically modulate ABTB2 expression in human and murine PDAC cell lines, as well as in the KPC mouse model of PDAC. Our gain- and loss-of-function studies revealed that ABTB2 plays …

Life-Threatening Bradycardia In Anti-Nmda-Receptor Encephalitis And A Novel Use For Permanent Pacing, Sarah Tucker, Abhijit Das, Andres Jimenez, Areeba Basit, Yike Jiang, Emily A Smitherman, Heather Van Mater, Taylor Howard, Alexander J Sandweiss, Kristen S Fisher

Faculty, Staff and Students Publications

Background: Pediatric anti-NMDA receptor encephalitis (pNMDARE) is an autoantibody-mediated disorder that can cause severe autonomic dysfunction, including symptomatic bradycardia and asystole. Dysautonomia can last for years, making it very challenging to manage.

Objective: To describe outcomes of 5 pNMDARE patients with life-threatening bradycardic and/or asystolic events who were managed with permanent or semi-permanent pacemaker implantation.

Methods: We performed a retrospective chart review of 5 patients from multiple institutions. We included patients with a diagnosis of pNMDARE (confirmed by positive cerebrospinal fluid and/or serum anti-NMDAR antibodies) who had a permanent or semi-permanent pacemaker placed due to symptomatic bradycardia, sinus pauses, and/or …

Mineralocorticoid Receptor Antagonists For Acute Myocardial Infarction: A Systematic Review And Meta-Analysis Of Randomised Controlled Trials, Song Peng Ang, Jia Ee Chia, Bruno Bezerra Lima, Jose Iglesias, Eunseuk Lee, Chayakrit Krittanawong, Mahboob Alam, Debabrata Mukherjee

Faculty, Staff and Students Publications

Background: The role of mineralocorticoid receptor antagonists (MRAs) in acute myocardial infarction (MI) remains controversial, with conflicting evidence from landmark trials. We aimed to assess the impact of MRAs on mortality and cardiovascular outcomes post-acute MI.

Methods: We systematically searched PubMed, Embase and Cochrane CENTRAL databases up to February 2025 for randomised controlled trials comparing MRAs with placebo or standard care in adults experiencing acute MI. Primary outcome was all-cause mortality; secondary outcomes included cardiovascular mortality, heart failure, recurrent MI and ventricular arrhythmia. Data were pooled using random-effects models, with heterogeneity explored via subgroup analyses and meta-regression.

Results: 15 trials …

Clinical Practice Variation Among Pediatric Rheumatologists Treating Kawasaki Disease: Results Of A North American Survey, Daniel Ibanez, Bianca Lang, Julia Shalen, Ali Yalcindag, Linda Wagner-Weiner, Kenneth N Schikler, Shoghik Akoghlanian, Hulya Bukulmez, Kristen Hayward, Laura Berbert, Sivia Lapidus, Andrea A Ramirez, Cagri Yildirim-Toruner

Faculty, Staff and Students Publications

Background: The best treatment for children with KD who fail to respond to the first dose of IVIG (refractory KD) is currently unknown. The purpose of this study was to determine treatment practices of pediatric rheumatologists in North America who manage IVIG-refractory KD.

Methods: A 34-item web-based survey was sent to 102 randomly selected members of the Childhood Arthritis and Rheumatology Research Alliance (CARRA). The anonymous survey addressed the use of primary intensification as well as the treatment of IVIG-refractory KD.

Results: The response rate was 82%; 56% (all pediatric rheumatologists) completed the survey. Primary intensification was …

Mbnl Loss Of Function In Smooth Muscle As A Model For Myotonic Dystrophy Associated Gastrointestinal Dysmotility, Janel A M Peterson, Jesus A Frias, Andrew N Miller, Krishnakant G Soni, Yi Zhang, Zheng Xia, John W Day, Geoffrey A Preidis, Thomas A Cooper

Faculty, Staff and Students Publications

Myotonic dystrophy type 1 (DM1) is the most common adult-onset muscular dystrophy and severely affects multiple organ systems, including the brain, heart, skeletal muscle, and gastrointestinal (GI) tract. Despite 80% of individuals with DM1 experiencing GI dysfunction that affects their daily life, the mechanisms of GI dysmotility in DM1 remain an understudied aspect of the disease. DM1 is caused by a CTG repeat expansion in the DMPK gene that, when expressed as an expanded CUG repeat RNA, sequesters and reduces the activity of the muscleblind-like (MBNL) RNA-binding protein family. We developed a mouse line with conditional, smooth muscle-specific knockout of …

A Long Non-Coding Rna Leat1 Mediates The Hormone Responsiveness Of Efnb2 During Male Urogenital Development, Deidre Mattiske, Pascal Bernard, Paul E Gradie, Richard R Behringer, Paul A Overbeek, Rachel J O'Neill, Tiffany Phillips, Melanie Stewart, Neil Youngson, Gerard Tarulli, Andrew J Pask

Faculty, Staff and Students Publications

The novel long non-coding RNA (lncRNA) Leat1 is extraordinarily conserved in both its location (syntenic with EfnB2, an essential gene in anogenital patterning) and sequence. Here we show that Leat1 is upregulated following the production of testosterone from the developing testis in mice and interacts with EfnB2, positively regulating its expression. Leat1 expression is suppressed by estrogen, which in turn suppresses the expression of EfnB2. Moreover, the loss of Leat1 leads to reduced EfnB2, resulting in a severe hypospadias phenotype. The human LEAT1 gene is also co-expressed with EFNB2 in the developing human penis, suggesting a conserved function for this …

Facts And Hopes Of Chimeric Antigen Receptor-Redirected Nk T Cells, Amy N Courtney, Xin Zhou, Gengwen Tian, Ying Wang, Leonid S Metelitsa, Gianpietro Dotti

Faculty, Staff and Students Publications

Chimeric antigen receptor (CAR)-engineered invariant NK T cells (CAR-NKT) are a novel cell platform for cancer immunotherapy. Unlike conventional T cells, NKTs are characterized by innate antitumor properties, minimal alloreactivity, and a unique ability to modulate the tumor microenvironment. This article provides a comprehensive overview of preclinical and early clinical studies evaluating CAR-NKTs in both autologous and allogeneic clinical settings. We discuss the contributions of CAR signaling domains, cytokine coexpression, and other functional measures that correlate with CAR-NKT persistence, function, and metabolic fitness. We also discuss the critical role of immunocompetent animal models in elucidating the interactions of CAR-NKTs with …

Transdiagnostic Links Of Reward Processing In Obsessive-Compulsive Disorder And Depression, Kevin M Wagner, Matti Cervin, Jessica S C Cheng, Jasmine Arriaga, Vanessa Zavala Cruz, Dayan Berrones, Josselyn S Muñoz, Renee M Frederick, Jacey L Anderberg, Belinda E Núñez Bracho, Victor R Adorno, Leonardo F Fontenelle, Andrew D Wiese, Latin American Trans-Ancestry Initiative For Ocd Genomics (Latino), Brazilian Obsessive-Compulsive Spectrum Disorder Working Group (Gttoc), James J Crowley, Eric A Storch

Faculty, Staff and Students Publications

Objectives: Transdiagnostic models aim to uncover shared mechanisms across mental disorders. Reward responsiveness (the ability to experience pleasure from rewarding stimuli) is a plausible, yet underexplored, transdiagnostic mechanism linking obsessive-compulsive disorder (OCD) and depression. This study used network analysis to (1) examine how key reward responsiveness domains are interlinked in individuals with OCD and (2) explore how each domain is uniquely associated with OCD and depression.

Methods: A total of 1345 individuals with a history of OCD symptoms (ages 18-88, 71 % women) from Latino communities in the United States (including Puerto Rico) and nine Latin American countries completed validated …

Mrna Vaccines Encoding Variant Forms Of Sm-Tsp-2 Confer Protective Immunity Against Schistosoma Mansoni, Athos Silva De Oliveira, Sevan Alwan, Philip T Loverde, Ramiz Shaheed, Pranav Mandyam, Rakesh Adhikari, Peter Hotez, Maria Elena Bottazzi, Jeroen Pollet

Faculty, Staff and Students Publications

This study explored the development and evaluation of mRNA vaccine candidates targeting Schistosoma mansoni tetraspanin-2 (Sm-TSP-2). We designed constructs encoding either full-length Sm-TSP-2, or its large extracellular loop (EC2) domain in secretory, membrane-anchored, or cytosolic forms. In a murine model, the secreted and membrane-anchored versions of Sm-TSP-2-EC2 induced the highest antigen-specific antibody titers. These two construct designs, along with full-length Sm-TSP-2 mRNA, also significantly reduced adult worm and egg burden compared to controls. The membrane-anchored Sm-TSP-2-EC2 mRNA was the most effective, lowering worm and egg burdens by 66.7% and 66.9%, respectively. Protective responses induced by the mRNA vaccines were comparable …

Mitochondrial Complex Ii Orchestrates Divergent Effects In Cd4+ And Cd8+ T Cells, Keisuke Seike, Shih-Chun A Chu, Yuichi Sumii, Takashi Ikeda, Meng-Chih Wu, Laure Maneix, Dongchang Zhao, Yaping Sun, Marcin Cieslik, Pavan Reddy

Faculty, Staff and Students Publications

Mitochondrial metabolism orchestrates T cell functions, yet the role of specific mitochondrial components in distinct T cell subsets remains poorly understood. Here, we explored the role of mitochondrial complex II (MC II), the only complex from the electron transport chain (ETC) that plays a role in both ETC and metabolism, in regulating T cell functions. Surprisingly, MC II exerts divergent effects on CD4+ and CD8+ T cell activation and function. Using T cell-specific MC II subunit, succinate dehydrogenase A-deficient (SDHA-deficient) mice, we integrated single-cell RNA-seq and metabolic profiling, with in vitro and in vivo T cell functional assays to illuminate …

Protein-Nucleic Acid Language Model-Assisted Design Of Precise And Compact Adenine Base Editor, Jingxuan Ren, Jiawei Yao, Qiuyu Cao, Yinuo Li, Yang Li, Ziyi Zhang, Xiyu Ge, Shengfang Wang, Yang Zhang, Xiaogang Wang, Xiaohui Zhang

Faculty, Staff and Students Publications

Adenine base editors (ABEs) are powerful tools for gene therapy. However, efficient version of ABEs (e.g. ABE8e) always induce excessive bystander and off-target editing events and are large in size, hindering their potential in clinical disease treatment. Here, we develop a pre-trained Protein-Nucleic Acid Constrained Language Model to design ABE8e with high activity, reduced editing window and decreased size. By further engineering, the smallest ABE8e- PNLM-pcABE- with a 27% size reduction, exhibits high activity, precise 3-nt editing window, and reduced off-target events near background level in HEK293T cells. Compared to ABE8e, PNLM-pcABE has up to 133.5-fold precision improvement in pathogenic …

Stakeholder Criteria For Trust In Artificial Intelligence-Based Computer Perception Tools In Health Care: Qualitative Interview Study, Ansh Rai, Meghan E Hurley, John Herrington, Eric A Storch, Casey J Zampella, Julia Parrish-Morris, Anika Sonig, Gabriel Lázaro-Muñoz, Kristin Kostick-Quenet

Faculty, Staff and Students Publications

Background: Computer perception (CP) technologies hold significant promise for advancing precision mental health care systems, given their ability to leverage algorithmic analysis of continuous, passive sensing data from wearables and smartphones (eg, behavioral activity, geolocation, vocal features, and ambient environmental data) to infer clinically meaningful behavioral and physiological states. However, successful implementation critically depends on cultivating well-founded stakeholder trust.

Objective: This study aims to investigate, across adolescents, caregivers, clinicians, and developers, the contingencies under which CP technologies are deemed trustworthy in health care.

Methods: We conducted 80 semistructured interviews with a purposive sample of adolescents (n=20) diagnosed with autism, Tourette …

Structural Birth Defects And Leukemia Risk In Children With Down Syndrome, Ching-Ju Hsu, Jeremy M Schraw, Sonja A Rasmussen, Tiffany M Chambers, Tania A Desrosiers, Chad D Huff, Amanda E Janitz, Russell S Kirby, Eirini Nestoridi, Wendy N Nembhard, Jason L Salemi, Charles Shumate, Jean Paul Tanner, Mahsa M Yazdy, Michael E Scheurer, Karen R Rabin, Philip J Lupo

Faculty, Staff and Students Publications

Birth defects are associated with increased cancer risk in the general pediatric population, yet their impact on leukemia risk in children with Down syndrome (DS) remains uncertain. We assessed this using data from 26,660 children with DS in the Genetic Overlap Between Anomalies and Cancer in Kids Registry Linkage Study. Among them, 71.9% had at least one major birth defect, predominantly involving the cardiac (64.2%), musculoskeletal (21%), and gastrointestinal systems (6.8%). The cumulative incidence of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) was comparable in children with and without co-occurring defects. Adjusted hazard ratios (aHR) for ALL and …

International Consensus Guidelines For The Conduct And Reporting Of Car T-Cell Clinical Trials In Aml, Swati Naik, Richard Aplenc, Susanne H C Baumeister, Marco Becilli, Anand S Bhagwat, Challice L Bonifant, Lihua E Budde, Christopher D Chien, Kevin J Curran, Anthony F Daniyan, Alexandra Dreyzin, Rebecca A Gardner, Sara Ghorashian, Stephen Gottschalk, Laquisa C Hill, M Eric Kohler, Adam Lamble, Franco Locatelli, Maksim Mamonkin, Bilal Omer, Jae H Park, Concetta Quintarelli, Benedetta Rambaldi, Rebecca M Richards, David A Sallman, Tim Sauer, Nirali N Shah, Marion Subklewe, Corinne Summers, Sarah K Tasian, Naomi Taylor, Sarah Tettamanti, Michael R Verneris, M Paulina Velasquez, Saar I Gill

Faculty, Staff and Students Publications

Early clinical experience with the use of chimeric antigen receptor (CAR) T-cell therapies for patients with acute myeloid leukemia (AML) has been beset by high rates of toxicities and low rates of response. We convened an international workshop with the goal of bringing investigators in the field of AML-directed CAR T-cell therapy together to facilitate discussion of challenges and to brainstorm potential solutions. Based on discussions at the workshop, it was evident that (1) treating and targeting AML with CAR T cells is associated with unique clinical challenges, and (2) variability in clinical trial design, definitions of toxicities, correlative data …

Tgfbr2 Coordinates The Endometrial Response To Estrogen, Regulating Endometrial Hyperplasia And Fertility, Sydney E Parks, Suni Tang, Anna Catherine Unser, Ananya L Bhonsley, Eunbi M Chung, Peixin Jiang, Audrey Savolainen, Vanessa J Joseph, Dominique I Cope, Ramya P Masand, Renata Prunskaite-Hyyryläinen, Diana Monsivais

Faculty, Staff and Students Publications

Proper endometrial function is critical for establishing and maintaining healthy pregnancies, as well as preventing the pathogenesis of conditions such as endometrial hyperplasia and endometrial cancer. The TGFβ signaling pathway regulates key aspects of endometrial biology, although the direct effects of many individual receptors remain unstudied. In this study, we characterize the role of TGFβR2 within the endometrium using a progesterone receptor-cre conditional knock-out mouse model (Tgfbr2flox/flox;Pgrcre/+; “Tgfbr2 cKO”). We found that conditional deletion of TGFβR2 resulted in female infertility, endometrial hyperplasia, altered estrogen and progesterone response, and, only in bred females, reproductive tract …

Rare Epigenetic Alterations Are Conserved Across Hematopoietic Differentiation Stages After Mycobacterial Infection, Brandon T Tran, Pamela N Luna, Ruoqiong Cao, Duy T Le, Apoorva Thatavarty, Laure Maneix, Bailee N Kain, Scott Koh, Andre Catic, Katherine Y King

Faculty, Staff and Students Publications

Infection leads to durable cell-autonomous changes in hematopoietic stem and progenitor cells (HSPCs), resulting in production of innate immune cells with heightened immunity. The mechanisms underlying this phenomenon, termed central trained immunity, remain poorly understood. We hypothesized that infection induces histone modifications leading to changes in chromatin accessibility that are conserved during differentiation from HSPCs to myeloid progenitors and monocytes. We conducted genome-wide surveillance of histone marks H3K27ac and H3K4me3 and chromatin accessibility in hematopoietic stem cells, multipotent progenitor 3, granulocyte-monocyte progenitors, monocytes and macrophages of naïve and Mycobacterium avium infected mice. Interferon signaling pathways and related transcription factor binding …

Implementing The Nyu Electronic Patient Visit Assessment (Epva), Janet H Van Cleave, Abraham A Brody, Dena Schulman-Green, Kenneth S Hu, Zujun Li, Stephen B Johnson, Vincent J Major, Christopher E Lominska, Jessica R Bauman, Alexander N Hanania, Ghia V Tatlonghari, Marcely Tsikis, Brian L Egleston

Faculty, Staff and Students Publications

Background: Aggressive treatment with multimodal therapies such as surgery, chemotherapy, and radiation therapy has improved survival in head and neck cancer (HNC) but at a human cost of a substantial symptom burden and impact on quality of life. We developed the NYU Electronic Patient Visit Assessment (ePVA)© for HNC as a digital patient-reported symptom monitoring system that enables early symptom detection and real-time interventions at the point of care. With this study protocol, we aim to test the effectiveness of the ePVA in improving HNC outcomes in real-world settings and to identify implementation strategies optimizing its effectiveness.

Methods: We will …

To Jump Or Not To Jump: Comparing Effects Of Phenotypic Plasticity On The Visual Responses And Escape Behavior Of Locusts And Grasshoppers, Soumi Mitra, Saina Namazifard, David Mario Bellini, Alexis Leigh Sarne, Bidisha Halder, Margaret Ruth Eisenbrandt, Aliya Macknojia, Jiayi Luo, Samme Xie, Hojun Song, Chenghang Zong, Fabrizio Gabbiani, Richard Burkett Dewell

Faculty, Staff and Students Publications

Locusts exhibit remarkable phenotypic plasticity changing their appearance and behavior from solitary to gregarious when population density increases. These changes include morphological differences in the size and shape of brain regions, but little is known about plasticity within individual neurons and alterations in behavior not directly related to aggregation or swarming. We investigated looming escape behavior and the properties of a well-studied collision-detection neuron in gregarious and solitarious animals of three closely related species, the desert locust (Schistocerca gregaria), the Central American locust (S. piceifrons) and the American bird grasshopper (S. americana). For this neuron, the lobula giant movement detector …

Comprehensive Cmr Evaluation Including 4d Flow-Derived E/A Vorticity Ratio In Overweight Adults With And Without Type 2 Diabetes Mellitus, Sungho Park, Erin K Englund, Takashi Fujiwara, Daniel Enge, Michal Schäfer, Jochen Gerstner Saucedo, Ethan W Clark, Layla A Abushamat, Rebecca L Scalzo, Brian Fonseca, Kendall S Hunter, Mary D Sammel, Judith G Regensteiner, Jane E B Reusch, Alex J Barker

Faculty, Staff and Students Publications

Aims: This study aimed to assess the impacts of overweight and type 2 diabetes (T2D) on early hemodynamic and left ventricular (LV) changes using comprehensive cardiovascular magnetic resonance imaging (CMR) in three age- and sex-similar groups: lean individuals (LI group), BMI-similar overweight controls without T2D (CWO group) and overweight individuals with uncomplicated T2D (T2D group).

Methods: Middle-aged participants included 13 in the LI group, 37 in the CWO group, and 28 in the T2D group. Baseline assessments included cardiac and vascular function measured by CMR, thoracic echocardiography, insulin sensitivity, clinical measures, and cardiorespiratory fitness. 4D flow CMR was used to …

Sex Hormones Influence Ormdl3 Expression: Implications For Sex-Associated Asthma Phenotype, Elisabetta Granato, Ida Cerqua, Antonietta Rossi, Maria Antonietta Riemma, Maria Chiara Monti, Giusy Ferraro, Barbara Romano, Maria Francesca Nanì, Danilo D'Avino, Martina Simonelli, Joshua Malo, Francesca Polverino, Bruno D'Agostino, Giuseppe Cirino, Fiorentina Roviezzo

Faculty, Staff and Students Publications

Background: Genetic polymorphisms in sphingolipid metabolism, particularly involving the orosomucoid-like 3 (ORMDL3) gene, have been associated with asthma risk. Notably, asthma prevalence and severity exhibit pronounced sex differences, emerging in childhood and persisting into adulthood. However, the molecular mechanisms underlying this sexual dimorphism remain incompletely elucidated.

Objective: We investigated whether ORMDL3 contributes to sex differences in airway function and asthma-like features.

Methods: ORMDL3 expression was measured in lung tissues from healthy male and female human donors and in human bronchial epithelial cells (BEAS-2B) after exposure to 17β-estradiol (E2), Dermatophagoides pteronyssinus 1 (Der p 1), or both. A murine preparation of …

Yap-Induced Glycolysis Drives Fibroinflammation And Disrupts Fibroblast Fidelity, Chang-Ru Tsai, Lin Liu, Yi Zhao, Jong H Kim, Paulo Czarnewski, Rich Gang Li, Fansen Meng, Mingjie Zheng, Jeffrey Steimle, Xiaolei Zhao, Francisco Grisanti, Zheng Sun, Jun Wang, Md Abul Hassan Samee, Xiao Li, James F Martin

Faculty, Staff and Students Publications

Background: Separation of the pulmonic and systemic circulation is essential for terrestrial life, and mammals have evolved distinct cardiac chambers with specialized structures and functions. Transcriptomics profiling revealed cellular heterogeneity between heart chambers. However, the mechanisms underlying chamber-specific transcriptomic and metabolic differences-and their functional significance-remain poorly understood. The Hippo/YAP (yes-associated protein) pathway is a conserved signaling network that regulates diverse cellular processes. The Hippo kinases inhibit YAP in cardiac fibroblasts (CF) to restrict fibrosis and inflammation. Nonetheless, how YAP regulates the metabolic microenvironment during homeostasis and fibroinflammation remains unclear.

Methods: We investigated YAP and glycolysis activity in the 4 cardiac …

Functional Vs Anatomical Cortico-Striatal Connectivity In The Macaque Brain, Wei Tang, Megan E Monko, Zoe Liu, Ana M G Manea, Fernando A Ortega, Damyan Hart, Jason Zhou, Jan Zimmermann, Sarah R Heilbronner

Faculty, Staff and Students Publications

The cerebral cortex provides the main input to the striatum, constituting the first step in cortico-basal ganglia loops. Decades of careful anatomical tract-tracing research have established the exquisite topography of each cortical region's projection to the striatum in nonhuman primates. In parallel, neuroimaging research has demonstrated the relationship between cortico-striatal resting-state functional connectivity and specific cognitive, behavioral, psychiatric, and neurological states in humans. However, still unclear is the extent to which functional connectivity recapitulates the specific topographies of cortico-striatal anatomical connectivity. Here, we combined datasets of cortico-striatal anatomical and functional connectivity in macaques to determine the degree of overlap between …

Pitx2 Dosage-Dependent Changes In Pacemaker Cell State Underlie Sinus Node Dysfunction And Atrial Arrhythmias, Lieve E Van Der Maarel, M Ridwane Mungroo, Otto J Mulleners, Mathilde R Rivaud, Arie O Verkerk, Karel Van Duijvenboden, Freek H T Tiel Groenestege, Jeffrey D Steimle, Lianne Fokkert, Corrie De Gier-De Vries, Mischa Klerk, Arie R Boender, James F Martin, Bjarke Jensen, Gerard J J Boink, Harsha D Devalla, Vincent M Christoffels

Faculty, Staff and Students Publications

Physiologically relevant increases in transcription factor dosage and their role in development and disease remain largely unexplored. Genomic deletions upstream of the Paired-like homeodomain transcription factor gene (PITX2), identified in patients with sinus node dysfunction and atrial fibrillation and modeled in mice (delB), rewire the local epigenetic landscape, increasing PITX2 expression. Here, we demonstrate that pacemaker cardiomyocytes in the embryonic delB sinus node ectopically express PITX2 at physiological dosages in a heterogeneous pattern. The prenatal delB sinus node forms discrete subdomains showing PITX2 dosage-dependent mild or severe loss of pacemaker cardiomyocyte identity. Respective subdomain sizes and severity of sinus node …

Dinaciclib Improves Treatment Response In Chemoresistant Hepatoblastoma, Brian T Hickner, Andres F Espinoza, Rohit K Srivastava, Roma H Patel, Priyanka Rao, Nicholas A O'Brien, Kalyani R Patel, Andrew A Badachhape, Abhishek Kona, Dolores H López-Terrada, Sarah E Woodfield, Sanjeev A Vasudevan

Faculty, Staff and Students Publications

Chemoresistant hepatoblastoma (HB) is associated with poor outcomes. Cyclin-dependent kinases (CDKs) are potential therapeutic targets because of their critical role in cell growth and chemoresistance. To evaluate the efficacy of CDK inhibition, HB cell lines were treated with dinaciclib and evaluated with cytotoxic, cell-death reversal, and immunoblotting assays. A HB patient-derived xenograft (PDX) model was treated with placebo, vincristine + irinotecan (VI), dinaciclib, or VI + dinaciclib to evaluate tumor growth and response to therapy. We found that dinaciclib had a marked effect on HB cell viability, induced PARP cleavage, and decreased CDK9 protein expression in vitro. Overexpression of CDK9 …

A Mouse Model Of Lipoatrophy Reveals Relationships Between Beige Fat Appearance And Female Fertility, Elizabeth S Anaya, William Dion, Pradip K Saha, Aaron R Cox, Evelyn De Groot, Avery A Ahmed, Jessica B Felix, Bokai Zhu, Stephanie A Pangas, Sean M Hartig

Faculty, Staff and Students Publications

White adipose tissue (WAT) performs vital metabolic and endocrine functions, but roles in female reproduction remain understudied and poorly understood. Here, we report that female mice experiencing progressive lipoatrophy after knockout of Ubc9 in adipocytes (Ubc9fKO) displayed disrupted estrous cycles, reduced ovarian reserve, and subfertility. During aging, female Ubc9fKO mice lose subcutaneous WAT more quickly than their male counterparts and weigh less than littermate controls. Subcutaneous WAT excised from female Ubc9fKO mice strongly enriched for thermogenesis genes generally associated with metabolic benefits. Female Ubc9fKO mice exhibited hypermetabolism and accumulated thermogenic, Uncoupling Protein 1-expressing beige fat cells in residual subcutaneous WAT …

A Comprehensive Study Of C-Kit-Expressing Amacrine Cells In The Mammalian Retina, Zheng Jiang, Wen Shen

Faculty, Staff and Students Publications

Amacrine cells assemble complex circuits in the inner retina, where they integrate, modulate, and relay spatial and temporal information to retinal ganglion cells. Nevertheless, their organization and functional diversity are still not fully understood. In this study, we identify a distinct group of amacrine cells that express the stem cell factor receptor-c-Kit. Using combined techniques of anti-CD117 (c-Kit) immunolabeling, confocal imaging, and computational algorithms, we characterize the morphological features and spatial distribution of the c-Kit-expressing amacrine cells. Our results show that c-Kit-expressing amacrine cells are GABA-positive neurons with medium to wide dendritic fields that stratify within the specific strata in …

Super-Fast, Super-Early: High-Frequency Oscillations May Be A Prelude To Alzheimer's Dementia In Down Syndrome, Manuel Silva-Pérez, Jeannie Chin

Faculty, Staff and Students Publications

Alzheimer's disease (AD) dementia has near full penetrance in adults with Down syndrome (DS) and is strongly linked to late-onset myoclonic epilepsy in Down syndrome (LOMEDS). However, promising biomarkers of epileptogenicity, such as high-frequency oscillations (HFOs >250 Hz), have not been studied. This study is the first to use wideband polysomnography in DS to investigate if HFOs occurred and preceded AD dementia and LOMEDS. Methods: Wideband (0.1 to 500 Hz, 2048 Hz) polysomnography was performed using the international 10–20 system. HFOs were automatically detected during slow-wave sleep, followed by manual review. Results: Fourteen individuals with DS and five age-matched euploid …

Revealing The Nervous System Requirements Of Alzheimer Disease Risk Genes In Drosophila, Jennifer M Deger, Shabab B Hannan, Mingxue Gu, Colleen E Strohlein, Lindsey D Goodman, Sasidhar Pasupuleti, Zahid Shaik, Liwen Ma, Yarong Li, Jiayang Li, Morgan C Stephens, Michal Tyrlík, Zhandong Liu, Ismael Al-Ramahi, Juan Botas, Chad A Shaw, Oguz Kanca, Hugo J Bellen, Joshua M Shulman

Faculty, Staff and Students Publications

Most Alzheimer disease (AD) susceptibility genes have poorly understood roles in the central nervous system (CNS). To address this gap, we systematically characterized 100 conserved candidate AD risk genes using a cross-species strategy in the fruit fly, Drosophila melanogaster. Genes were prioritized based primarily on human functional genomic evidence. We generated custom loss-of-function alleles for each of the conserved fly orthologs. Most of the genes are expressed in the adult brain, including 24 neuron- and 13 glia-specific expression patterns. Overall, we identify 50 candidate AD risk gene homologs with requirements for CNS structure or function, including 18 whose loss of …

Unconventional Binding Of Calmodulin To Chk2 Kinase Inhibits Catalytic Activity, Christopher R Horne, Tingting Wang, Samuel N Young, Toby A Dite, Hunter G Nyvall, Sushant Suresh, Katherine A Davies, Abner Gonzalez Castro, Vineet Vaibhav, Lucy J Mather, Laura F Dagley, Matthew J Belousoff, Gerard Manning, Anthony R Means, John E Burke, Janni Petersen, John W Scott, James M Murphy

Faculty, Staff and Students Publications

Calmodulin (CaM) serves an essential role in eukaryotic cells as a Ca2+ sensor. Ca2+ binding leads to conformation changes in CaM that enable engagement of a repertoire of enzymes and the regulation of their catalytic activities. Classically, Ca2+-CaM binds to an inhibitory pseudosubstrate sequence C-terminal to the kinase domain in members of the Ca2+-CaM-dependent protein kinase (CAMK) family and relieves inhibition to promote catalytic activity. Here, we report an unexpected mechanism by which CaM can bind CHK2 kinase to inhibit its kinase activity. Using biochemical, biophysical and structural mass spectrometry, we identify a direct interaction of Ca2+-CaM with the CHK2 …