Neurosciences Commons^™

Irregular Assessment Times In Pragmatic Randomized Clinical Trials, Andrea Apter, Frances K Barg, Sanjib Basu, Alex Federman, Winifred J Hamilton, Jerry A Krishnan, Tianjing Li, Russell Localio, Christine Pindle, Daniel O Scharfstein, Justin D Smith, Kaharu Sumino

Faculty, Staff and Students Publications

Deviation from protocolized assessment times is commonplace in pragmatic randomized clinical trials. Working with a stakeholder advisory board for a Patient-Centered Outcomes Research Institute®-funded project on statistical methods for handling potential biases introduced by irregular assessment times, we identified reasons for off-schedule or missed assessments. We used the Consolidated Framework for Implementation Research 2.0 to organize our findings. We conjectured that timely completion of outcome assessments is a function of multiple determinants, only some related to participants' health status. We identified potential determinants that can be modified during the protocol design stage and can be reassessed and mitigated during trial …

Age-Related Tfeb Downregulation In Proximal Tubules Causes Systemic Metabolic Disorders And Occasional Apolipoprotein A4-Related Amyloidosis, Jun Nakamura, Takeshi Yamamoto, Yoshitsugu Takabatake, Tomoko Namba-Hamano, Atsushi Takahashi, Jun Matsuda, Satoshi Minami, Shinsuke Sakai, Hiroaki Yonishi, Shihomi Maeda, Sho Matsui, Hideaki Kawai, Isao Matsui, Tadashi Yamamuro, Ryuya Edahiro, Seiji Takashima, Akira Takasawa, Yukinori Okada, Tamotsu Yoshimori, Andrea Ballabio, Yoshitaka Isaka

Duncan NRI Faculty and Staff Publications

With the aging of society, the incidence of chronic kidney disease (CKD), a common cause of death, has been increasing. Transcription factor EB (TFEB), the master transcriptional regulator of the autophagy/lysosomal pathway, is regarded as a promising candidate for preventing various age-related diseases. However, whether TFEB in the proximal tubules plays a significant role in elderly patients with CKD remains unknown. First, we found that nuclear TFEB localization in proximal tubular epithelial cells (PTECs) declined with age in both mice and humans. Next, we generated PTEC-specific Tfeb-deficient mice and bred them for up to 24 months. We found that TFEB …

Macrowire For Intracranial Thrombectomy: An Early Experience Of A New Device And Technique For Anterior Circulation Large Vessel Occlusion Stroke, Kaustubh Limaye, Sami Al Kasab, Jaidevsinh Dolia, Mohamad Ezzeldin, Daniel Vela Duarte, Vinodh Doss, Sourabh Lahoti, David Hasan, Alejandro Spiotta, Khaled Asi, Vasu Saini, Tapan Mehta, Ameer Hassan, Diogo Haussen, Dileep Yavagal, Jesse Jones, Omar Tanweer, Waleed Brinjikji

Faculty, Staff and Students Publications

BACKGROUND AND PURPOSE: Mechanical thrombectomy (MT) has become the standard of care for treatment of acute ischemic stroke secondary to large vessel occlusion up to 24 h from the last known normal time. With ADAPT and SOLUMBRA techniques, classically, a large bore aspiration catheter is delivered over a microcatheter and microwire crossing the clot to perform thrombectomy. Recently, a novel macrowire (Colossus 035 in.) has been introduced as a potential alternative to the use of microwire-microcatheter to allow the delivery of the aspiration catheter (ID = 0.070 in. up to 0.088 in.) over a macrowire alone.

OBJECTIVE: To test the …

Identification Of An Early Subset Of Cerebellar Nuclei Neurons In Mice, Maryam Rahimi-Balaei, Shayan Amiri, Thomas Lamonerie, Sih-Rong Wu, Huda Y Zoghbi, G Giacomo Consalez, Daniel Goldowitz, Hassan Marzban

Duncan NRI Faculty and Staff Publications

Cerebellar nuclei (CN) neurons serve as the primary output of the cerebellum and originate from the cerebellar primordium at early stages of cerebellar development. These neurons are diverse, integrating information from the cerebellar cortex and relaying it to various brain regions. Employing various methodologies, we have characterized a specific subset of CN neurons that do not originate from the rhombic lip or ventricular zone of the cerebellar primordium. Embryos were collected at early stages of development and processed for immunohistochemistry (IHC), western blotting, in situ hybridization (ISH), embryonic culture, DiI labeling, and flow cytometry analysis (FCM). Our findings indicate that …

Global Impact Of Aging On The Hemodynamic Response Function In The Gray Matter Of Human Cerebral Cortex, Nooshin J Fesharaki, Amanda Taylor, Keisjon Mosby, Ruosha Li, Jung Hwan Kim, David Ress

Faculty, Staff and Students Publications

In functional magnetic resonance imaging, the hemodynamic response function (HRF) is a stereotypical response to local changes in cerebral hemodynamics and oxygen metabolism due to briefly (< 4 s) evoked neural activity. Accordingly, the HRF is often used as an impulse response with the assumption of linearity in data analysis. In cognitive aging studies, it has been very common to interpret differences in brain activation as age-related changes in neural activity. Contrary to this assumption, however, evidence has accrued that normal aging may also significantly affect the vasculature, thereby affecting cerebral hemodynamics and metabolism, confounding interpretation of fMRI cognitive aging studies. In this study, use was made of a multisensory task to evoke the HRF in ~87% of cerebral cortex in cognitively intact adults with ages ranging from 22 to 75 years. This widespread activation enabled us to investigate age trends in the spatial distributions of HRF characteristics within the majority of cortical gray matter, which we termed as global age trends. The task evoked both positive and negative HRFs, which were characterized using model-free parameters in native-space coordinates. We found significant global age trends in the distributions of HRF parameters in terms of both amplitudes (e.g., peak amplitude and contrast-to-noise ratio) and temporal dynamics (e.g., full-width-at-half-maximum). Our findings offer insight into how age-dependent changes affect neurovascular coupling and show promise for use of HRF parameters as non-invasive indicators for age-related pathology.

Simple Improvements In Vector Design Afford Substantial Gains In Aav Delivery Of Aggregation-Slowing Aβ Variants, Ella Borgenheimer, Cameron Trueblood, Bryan L Nguyen, William R Lagor, Joanna L Jankowsky

Faculty, Staff and Students Publications

Adeno-associated virus (AAV) gene therapy for neurological disease has gained traction due to stunning advances in capsid evolution for CNS targeting. With AAV brain delivery now in focus, conventional improvements in viral expression vectors offer a complementary route for optimizing gene delivery. We previously introduced a novel AAV gene therapy to slow amyloid aggregation in the brain based on neuronal release of an Aβ sequence variant that inhibited fibrilization of wild-type Aβ. Here we explore three coding elements of the virally delivered DNA plasmid in an effort to maximize the production of therapeutic peptide in the brain. We demonstrate that …

Clinical And Radiologic Findings In Children With Anomalous Pontine Cranial Nerves, Karen K Moeller, Brandon H Tran, Thierry A G M Huisman, Nilesh K Desai, Marcia K Kukreja, Rajan P Patel, Uma S Ramaswamy, Carol Liu, Stephen F Kralik

Faculty, Staff and Students Publications

We retrospectively reviewed the clinical and radiologic findings in 17 children with an aberrant cisternal cranial nerve 7 (CN7), and found that these patients had additional anomalies involving other pontine cranial nerves (CNs). The hallmark imaging feature identified in all patients was an aberrant cisternal segment of an enlarged-appearing CN7. The abnormal nerve coursed anteriorly toward the Gasserian ganglion, where it fanned out toward the internal auditory canal, Meckel cave, or both. This finding was accompanied by a small cisternal CN5, which often had a lateral bowed appearance. CN5 and CN7 were abnormally close to each other. Meckel's cave appeared …

Spino-Plastic Surgery: Addressing Spinal Tumors With New Techniques, Casey Martinez, Isra Abdulwadood, Sebastian Winocour, Alexander E Ropper, Marco Innocenti, Michael Bohl, Maziyar Kalani, Edward M Reece

Faculty, Staff and Students Publications

Background/Objectives: Spino-plastic surgery describes a specialized, multidisciplinary approach to addressing various spinal pathologies. The field is the innovative product of a multidisciplinary collaboration between plastic and reconstructive, orthopedic, and neurosurgery. Over the last few decades, this collaboration has borne promising surgical techniques and treatment plans geared toward restoring form, function, and aesthetics in patients with a variety of spinal conditions, including failed fusions, pseudoarthrosis, and the need for oncologic reconstruction. This paper explores the application of spino-plastic surgery in the context of post-sarcoma resection reconstructions, focusing on the efficacy in addressing the unique challenges posed by extensive tissue loss and …

Rna Splicing As A Biomarker And Phenotypic Driver Of Meningioma Dna-Methylation Groups, Nathan K Leclair, Abrar Choudury, William C Chen, Stephen T Magill, Kathleen Mccortney, Craig M Horbinski, Zhenhong Chen, Ezequiel Goldschmidt, Charlotte D Eaton, Ketan R Bulsara, Wenya Linda Bi, Akash J Patel, Felix Sahm, David Raleigh, Olga Anczukow

Faculty, Staff and Students Publications

BACKGROUND: Advances in our understanding of the molecular biology of meningiomas have led to significant gains in the ability to predict patient prognosis and tumor recurrence and to identify novel targets for therapeutic design. Specifically, classification of meningiomas based on DNA methylation has greatly improved our ability to risk stratify patients, however new questions have arisen in terms of the underlying impact these DNA-methylation signatures have on meningioma biology.

METHODS: This study utilizes RNA-sequencing data from 486 meningioma samples corresponding to 3 meningioma DNA-methylation groups (merlin-intact, immune-enriched, and hypermitotic), followed by in vitro experiments utilizing human meningioma cell lines.

RESULTS: …

3d Genome Topology Distinguishes Molecular Subgroups Of Medulloblastoma, John J Y Lee, Michael J Johnston, Hamza Farooq, Huey-Miin Chen, Subhi Talal Younes, Raul Suarez, Melissa Zwaig, Nikoleta Juretic, William A Weiss, Jiannis Ragoussis, Nada Jabado, Michael D Taylor, Marco Gallo

Faculty, Staff and Students Publications

Four main medulloblastoma (MB) molecular subtypes have been identified based on transcriptional, DNA methylation, and genetic profiles. However, it is currently not known whether 3D genome architecture differs between MB subtypes. To address this question, we performed in situ Hi-C to reconstruct the 3D genome architecture of MB subtypes. In total, we generated Hi-C and matching transcriptome data for 28 surgical specimens and Hi-C data for one patient-derived xenograft. The average resolution of the Hi-C maps was 6,833 bp. Using these data, we found that insulation scores of topologically associating domains (TADs) were effective at distinguishing MB molecular subgroups. TAD …

Prenatal Assessment Of Brain Malformations On Neuroimaging: An Expert Panel Review, Ivana Pogledic, Kshitij Mankad, Mariasavina Severino, Tally Lerman-Sagie, Andras Jakab, Efrat Hadi, Anna C Jansen, Nadia Bahi-Buisson, Natalya Di Donato, Renske Oegema, Christian Mitter, Ivan Capo, Matthew T Whitehead, Parthiv Haldipur, Grazia Mancini, Thierry A G M Huisman, Andrea Righini, Bill Dobyns, James A Barkovich, Natasa Jovanov Milosevic, Gregor Kasprian, Maarten Lequin

Faculty, Staff and Students Publications

Brain malformations represent a heterogeneous group of abnormalities of neural morphogenesis, often associated with aberrations of neuronal connectivity and brain volume. Prenatal detection of brain malformations requires a clear understanding of embryology and developmental morphology through the various stages of gestation. This expert panel review is written with the central aim of providing an easy-to-understand road map to improve prenatal detection and characterization of structural malformations based on the current understanding of normal and aberrant brain development. For every developmental stage, the utility of each available neuroimaging modality, including prenatal multiplanar neuro sonography, anatomical MRI and advanced MRI techniques, as …

A Comparison Of Vestibular Function In Young Adult Musicians And Non-Musician Peers, Alexandria W. Greene, Ashley G. Flagge, Nicholas S. Stanley

Ashley Flagge Publications

Purpose: The majority of college-level musicians exceed the daily recommended noise dose level during instrumental practices and performances, although less than one-third report wearing hearing protection while playing their instruments. Although the hazardous effects of music on the auditory system have been established, even in young adult musicians still early in their musical careers, the effects of music on the vestibular system are still unclear. The purpose of the present study was to examine vestibular/balance differences between young adult musicians and non-musicians to determine the effects of music exposure on the vestibular system.

Method: Young adult participants aged 18-27 years …

Urinary Metal Levels, Cognitive Test Performance, And Dementia In The Multi-Ethnic Study Of Atherosclerosis, Arce Domingo-Relloso, Katlyn E Mcgraw, Susan R Heckbert, Jose A Luchsinger, Kathrin Schilling, Ronald A Glabonjat, Irene Martinez-Morata, Melanie Mayer, Yongmei Liu, Alexis C Wood, Jeff Goldsmith, Kathleen M Hayden, Mohamad Habes, Ilya M Nasrallah, R Nick Bryan, Tanweer Rashid, Wendy S Post, Jerome I Rotter, Priya Palta, Linda Valeri, Timothy M Hughes, Ana Navas-Acien

Faculty, Staff and Students Publications

IMPORTANCE: Metals are established neurotoxicants, but evidence of their association with cognitive performance at low chronic exposure levels is limited.

OBJECTIVE: To investigate the association of urinary metal levels, individually and as a mixture, with cognitive tests and dementia diagnosis, including effect modification by apolipoprotein ε4 allele (APOE4).

DESIGN, SETTING, AND PARTICIPANTS: The multicenter prospective cohort Multi-Ethnic Study of Atherosclerosis (MESA) was started from July 2000 to August 2002, with follow-up through 2018. A total of 6303 MESA participants were included. Data analysis was performed from October 12, 2023, to June 13, 2024.

EXPOSURE: Urine samples were collected at baseline …

Individualized Functional Magnetic Resonance Imaging Neuromodulation Enhances Visuospatial Perception: A Proof-Of-Concept Study, Anthony Allam, Vincent Allam, Sandy Reddy, Eric M Rohren, Sameer A Sheth, Emmanouil Froudarakis, T Dorina Papageorgiou

Duncan NRI Faculty and Staff Publications

This proof-of-concept study uses individualized functional magnetic resonance imaging neuromodulation (iNM) to explore the mechanisms that enhance BOLD signals in visuospatial perception (VP) networks that are crucial for navigation. Healthy participants (n = 8) performed a VP up- and down-direction discrimination task at full and subthreshold coherence through peripheral vision, and superimposed direction through visual imagery (VI) at central space under iNM and control conditions. iNM targets individualized anatomical and functional middle- and medial-superior temporal (MST) networks that control VP. We found that iNM engaged selective exteroceptive and interoceptive attention (SEIA) and motor planning (MP) networks. Specifically, iNM increased …

Retinal Ganglion Cell Circuits And Glial Interactions In Humans And Mice, Kang-Chieh Huang, Mohamed Tawfik, Melanie A Samuel

Faculty, Staff and Students Publications

Retinal ganglion cells (RGCs) are the brain's gateway for vision, and their degeneration underlies several blinding diseases. RGCs interact with other neuronal cell types, microglia, and astrocytes in the retina and in the brain. Much knowledge has been gained about RGCs and glia from mice and other model organisms, often with the assumption that certain aspects of their biology may be conserved in humans. However, RGCs vary considerably between species, which could affect how they interact with their neuronal and glial partners. This review details which RGC and glial features are conserved between mice, humans, and primates, and which differ. …

Analysis Of Dna Methylation In Gliomas: Assessment Of Preanalytical Variables, Karol Bomsztyk, Daniel Mar, Oleg Denisenko, Suzanne Powell, Monika Vishnoi, Zheng Yin, Jennifer Delegard, Caroline Hadley, Nitin Tandon, Akash J Patel, Anoop P Patel, Richard G Ellenbogen, Rohan Ramakrishna, Robert C Rostomily

Faculty, Staff and Students Publications

Precision oncology is driven by biomarkers. For glioblastoma multiforme (GBM), the most common malignant adult primary brain tumor, O6-methylguanine-DNA methyltransferase (MGMT) gene promoter methylation is an important prognostic and treatment clinical biomarker. Time consuming pre-analytical steps such as biospecimen storage, fixation, sampling, and processing are sources of data irreproducibility, and all these pre-analytical variables are confounded by intratumor heterogeneity of MGMT promoter methylation. To assess the effect of pre-analytical variables on GBM DNA methylation, tissue storage/sampling (CryoGrid), sample preparation multi-sonicator (PIXUL), and 5-methylcytosine (5mC) DNA immunoprecipitation (Matrix MeDIP-qPCR/seq) platforms were used. MGMT promoter methylation status assayed by MeDIP-qPCR was …

A Reproducible Pipeline For Parcellation Of The Anterior Limb Of The Internal Capsule, Karianne Sretavan, Henry Braun, Zoe Liu, Daniel Bullock, Tara Palnitkar, Remi Patriat, Jayashree Chandrasekaran, Samuel Brenny, Matthew D Johnson, Alik S Widge, Noam Harel, Sarah R Heilbronner

Faculty, Staff and Students Publications

Background: The anterior limb of the internal capsule (ALIC) is a white matter structure that connects the prefrontal cortex (PFC) to the brainstem, thalamus, and subthalamic nucleus. It is a target for deep brain stimulation for obsessive-compulsive disorder. There is strong interest in improving deep brain stimulation targeting by using diffusion tractography to reconstruct and target specific ALIC fiber pathways, but this methodology is susceptible to errors and lacks validation. To address these limitations, we developed a novel diffusion tractography pipeline that generates reliable and biologically validated ALIC white matter reconstructions.

Methods: Following algorithm development and refinement, we analyzed 43 …

Chronic Β3-Ar Stimulation Activates Distinct Thermogenic Mechanisms In Brown And White Adipose Tissue And Improves Systemic Metabolism In Aged Mice, Duraipandy Natarajan, Bhuvana Plakkot, Kritika Tiwari, Shoba Ekambaram, Weidong Wang, Michael Rudolph, Mahmoud A Mohammad, Shaji K Chacko, Madhan Subramanian, Stefano Tarantini, Andriy Yabluchanskiy, Zoltan Ungvari, Anna Csiszar, Priya Balasubramanian

Faculty, Staff and Students Publications

Adipose thermogenesis has been actively investigated as a therapeutic target for improving metabolic dysfunction in obesity. However, its applicability to middle-aged and older populations, which bear the highest obesity prevalence in the United States (approximately 40%), remains uncertain due to age-related decline in thermogenic responses. In this study, we investigated the effects of chronic thermogenic stimulation using the β3-adrenergic (AR) agonist CL316,243 (CL) on systemic metabolism and adipose function in aged (18-month-old) C57BL/6JN mice. Sustained β3-AR treatment resulted in reduced fat mass, increased energy expenditure, increased fatty acid oxidation and mitochondrial activity in adipose depots, improved glucose homeostasis, and a …

Association Of Common And Rare Variants With Alzheimer’S Disease In More Than 13,000 Diverse Individuals With Whole-Genome Sequencing From The Alzheimer’S Disease Sequencing Project, Wan-Ping Lee, Seung Hoan Choi, Margaret G Shea, Po-Liang Cheng, Beth A Dombroski, Achilleas N Pitsillides, Nancy L Heard-Costa, Hui Wang, Katia Bulekova, Amanda B Kuzma, Yuk Yee Leung, John J Farrell, Honghuang Lin, Brian W Kunkle, Adam Naj, Elizabeth E Blue, Frederick Nusetor, Dongyu Wang, Eric Boerwinkle, William S Bush, Xiaoling Zhang, Philip L De Jager, Josée Dupuis, Lindsay A Farrer, Myriam Fornage, Eden Martin, Margaret Pericak-Vance, Sudha Seshadri, Ellen M Wijsman, Li-San Wang, Alzheimer's Disease Sequencing Project;, Gerard D Schellenberg, Anita L Destefano, Jonathan L Haines, Gina M Peloso

Faculty, Staff and Student Publications

INTRODUCTION: Alzheimer's disease (AD) is a common disorder of the elderly that is both highly heritable and genetically heterogeneous.

METHODS: We investigated the association of AD with both common variants and aggregates of rare coding and non-coding variants in 13,371 individuals of diverse ancestry with whole genome sequencing (WGS) data.

RESULTS: Pooled-population analyses of all individuals identified genetic variants at apolipoprotein E (APOE) and BIN1 associated with AD (p < 5 × 10

DISCUSSION: We observed that complementary pooled-population and subgroup-specific analyses offered unique insights into the genetic architecture of AD.

HIGHLIGHTS: We determine the association of genetic variants with Alzheimer's disease (AD) using …

Neurocognitive Functioning Of Patients With Sinonasal And Nasopharyngeal Cancers Treated With Multimodality Therapy, Dan Yaniv, Lindsay M Niccolai, Jeffrey S Wefel, Catherine M Sullaway, Jack Phan, Clifton David Fuller, Kareem B Haroun, Ehab Y Hanna, Shirley Y Su

Faculty, Staff and Student Publications

Importance Few recent studies have examined neurocognitive functioning (NCF) in patients with sinonasal and nasopharyngeal cancers (NPCs) prior to and following multimodality therapy or the potential differences in NCF by disease variables such as disease site.

Objective The objective of this study is to determine rates of NCF impairments prior to and following multimodality therapy, declines in NCF following radiotherapy (RT), and possible differences in NCF by the disease site.

Design, Setting, and Participants We conducted a retrospective chart review of 39 patients with sinonasal and NPCs who underwent comprehensive neuropsychological evaluations. Twenty patients were evaluated prior to RT, of …

Normative Neuroimaging Library: Designing A Comprehensive And Demographically Diverse Dataset Of Healthy Controls To Support Traumatic Brain Injury Diagnostic And Therapeutic Development, Allyson T Gage, James R Stone, Elisabeth A Wilde, Stephen R Mccauley, Robert C Welsh, John P Mugler, Nick Tustison, Brian Avants, Christopher T Whitlow, Lee Lancashire, Seema D Bhatt, Magali Haas

Faculty, Staff and Students Publications

The past decade has seen impressive advances in neuroimaging, moving from qualitative to quantitative outputs. Available techniques now allow for the inference of microscopic changes occurring in white and gray matter, along with alterations in physiology and function. These existing and emerging techniques hold the potential of providing unprecedented capabilities in achieving a diagnosis and predicting outcomes for traumatic brain injury (TBI) and a variety of other neurological diseases. To see this promise move from the research lab into clinical care, an understanding is needed of what normal data look like for all age ranges, sex, and other demographic and …

Impact Of Prenatal Genomics On Clinical Genetics Practice, Roni Zemet, Ignatia B Van Den Veyver

Duncan NRI Faculty and Staff Publications

Genetic testing for prenatal diagnosis in the pre-genomic era primarily focused on detecting common fetal aneuploidies, using methods that combine maternal factors and imaging findings. The genomic era, ushered in by the emergence of new technologies like chromosomal microarray analysis and next-generation sequencing, has transformed prenatal diagnosis. These new tools enable screening and testing for a broad spectrum of genetic conditions, from chromosomal to monogenic disorders, and significantly enhance diagnostic precision and efficacy. This chapter reviews the transition from traditional karyotyping to comprehensive sequencing-based genomic analyses. We discuss both the clinical utility and the challenges of integrating prenatal exome and …

Genetics Of Cerebral Palsy: Diagnosis, Differential Diagnosis, And Beyond, Dae-Hyun Jang, Jaewon Kim, Aloysia Leisanne Schwabe, Timothy Edward Lotze

Faculty, Staff and Students Publications

Cerebral palsy (CP) is the most common motor disability in children, characterized by diverse clinical manifestations and often uncertain etiology, which has spurred increasing interest in genetic diagnostics. This review synthesizes findings from various studies to enhance understanding of CP's genetic underpinnings. The discussion is structured around five key areas: monogenic causes and copy number variants directly linked to CP, differential genetic disorders including atypical CP and mimics, ambiguous genetic influences, co-occurrence with other neurodevelopmental disorders, and polygenic risk factors. Case studies illustrate the clinical application of these genetic insights, underscoring the complexity of diagnosing CP due to the phenotypic …

Tyk2 Regulates Tau Levels, Phosphorylation And Aggregation In A Tauopathy Mouse Model, Jiyoen Kim, Bakhos Tadros, Yan Hong Liang, Youngdoo Kim, Cristian Lasagna-Reeves, Jun Young Sonn, Dah-Eun Chloe Chung, Bradley Hyman, David M Holtzman, Huda Yahya Zoghbi

Faculty, Staff and Students Publications

Alzheimer's disease is one of at least 26 diseases characterized by tau-positive accumulation in neurons, glia or both. However, it is still unclear what modifications cause soluble tau to transform into insoluble aggregates. We previously performed genetic screens that identified tyrosine kinase 2 (TYK2) as a candidate regulator of tau levels. Here we verified this finding and found that TYK2 phosphorylates tau at tyrosine 29 (Tyr29) leading to its stabilization and promoting its aggregation in human cells. We discovered that TYK2-mediated Tyr29 phosphorylation interferes with autophagic clearance of tau. We also show that TYK2-mediated phosphorylation of Tyr29 facilitates pathological tau …

The Brain Initiative Data-Sharing Ecosystem: Characteristics, Challenges, Benefits, And Opportunities, Sudhanvan Iyer, Kathryn Maxson Jones, Jill O Robinson, Nicole R Provenza, Dominique Duncan, Gabriel Lázaro-Muñoz, Amy L Mcguire, Sameer A Sheth, Mary A Majumder

Faculty, Staff and Students Publications

In this paper, we provide an overview and analysis of the BRAIN Initiative data-sharing ecosystem. First, we compare and contrast the characteristics of the seven BRAIN Initiative data archives germane to data sharing and reuse, namely data submission and access procedures and aspects of interoperability. Second, we discuss challenges, benefits, and future opportunities, focusing on issues largely specific to sharing human data and drawing on N = 34 interviews with diverse stakeholders. The BRAIN Initiative-funded archive ecosystem faces interoperability and data stewardship challenges, such as achieving and maintaining interoperability of data and archives and harmonizing research participants’ informed consents for …

Mechanisms Of Memory-Supporting Neuronal Dynamics In Hippocampal Area Ca3, Yiding Li, John J Briguglio, Sandro Romani, Jeffrey C Magee

Faculty, Staff and Students Publications

Hippocampal CA3 is central to memory formation and retrieval. Although various network mechanisms have been proposed, direct evidence is lacking. Using intracellular Vm recordings and optogenetic manipulations in behaving mice, we found that CA3 place-field activity is produced by a symmetric form of behavioral timescale synaptic plasticity (BTSP) at recurrent synapses among CA3 pyramidal neurons but not at synapses from the dentate gyrus (DG). Additional manipulations revealed that excitatory input from the entorhinal cortex (EC) but not the DG was required to update place cell activity based on the animal’s movement. These data were captured by a computational model that …

Neuroprotective Effect Of L-Dopa-Induced Interleukin-13 On Striatonigral Degeneration In Cerebral Ischemia, Eunhae Jeon, Myeong-Seong Seo, Enkhmaa Lkhagva-Yondon, Yu-Ree Lim, Seung-Woo Kim, Yu Jeong Kang, Jun Seok Lee, Byoung Dae Lee, Rayul Wi, So-Yoon Won, Young Cheul Chung, Eun S Park, Eunhee Kim, Byung Kwan Jin, Myung-Shin Jeon

Faculty, Staff and Student Publications

Levodopa (L-DOPA) treatment is a clinically effective strategy for improving motor function in patients with ischemic stroke. However, the mechanisms by which modulating the dopamine system relieves the pathology of the ischemic brain remain unclear. Emerging evidence from an experimental mouse model of ischemic stroke, established by middle cerebral artery occlusion (MCAO), suggested that L-DOPA has the potential to modulate the inflammatory and immune response that occurs during a stroke. Here, we aimed to demonstrate the therapeutic effect of L-DOPA in regulating the systemic immune response and improving functional deficits in mice with ischemia. Transient MCAO led to progressive degeneration …

Firearm Access, Carriage And Use In An Ethnically Diverse Sample Of Young Adults In Texas, Usa, Yu Lu, Elizabeth Baumler, Annalyn Saludares Demello, Leila Wood, Hillary Mcguire, Jeff R Temple

Faculty, Staff and Student Publications

Background Despite the high rates of firearm ownership and firearm-related injuries and mortalities in Southern US states, understandings on the factors contributing to these are lacking.

Methods Using wave 10 (2021) data from a longitudinal study, we examined firearm-related experiences among 636 ethnically diverse young adults (mean age=26 years; 62% female) in Texas, USA.

Results Just over half of participants had ready access to firearms, with 22.3% having carried a firearm outside of their home, 4.9% having been threatened with a firearm by a romantic partner and 4.4% by a non-romantic partner. More firearm access and carriage were reported in …

Plasmodium Berghei Liver Stage Parasites Exploit Host Gabarap Proteins For Tfeb Activation, Jacqueline Schmuckli-Maurer, Annina F Bindschedler, Rahel Wacker, Oliver M Würgler, Ruth Rehmann, Timothy Lehmberg, Leon O Murphy, Thanh N Nguyen, Michael Lazarou, Jlenia Monfregola, Andrea Ballabio, Volker T Heussler

Duncan NRI Faculty and Staff Publications

Plasmodium, the causative agent of malaria, infects hepatocytes prior to establishing a symptomatic blood stage infection. During this liver stage development, parasites reside in a parasitophorous vacuole (PV), whose membrane acts as the critical interface between the parasite and the host cell. It is well-established that host cell autophagy-related processes significantly impact the development of Plasmodium liver stages. Expression of genes related to autophagy and lysosomal biogenesis is orchestrated by transcription factor EB (TFEB). In this study, we explored the activation of host cell TFEB in Plasmodium berghei-infected cells during the liver stage of the parasite. Our results …

The Pipeline Embolization Device For The Treatment Of Intracranial Aneurysms In Pediatric Patients With Tuberous Sclerosis Complex: Illustrative Cases, Eveline Teresa Hidalgo, Eric A Grin, Omar Tanweer, Cordelia Orillac, Jason K Chu, Peter Kan, Howard L Weiner

Faculty, Staff and Students Publications

BACKGROUND: Tuberous sclerosis complex (TSC) is a neurocutaneous disorder characterized by the multisystem development of benign tumors. Patients with TSC are also at an increased risk of developing intracranial aneurysms early in life. While aneurysms have historically been treated with open surgical clipping, endovascular approaches are increasingly being used in both pediatric and adult populations.

OBSERVATIONS: In this case series, the authors report the endovascular treatment of three young patients with TSC and fusiform intracranial aneurysms using the Pipeline embolization device (PED) for flow diversion of the affected artery. In all cases, complete aneurysm occlusion was observed, with good parent …