Neurosciences Commons^™

Life On The Dry Side: A Roadmap To Understanding Desiccation Tolerance And Accelerating Translational Applications, R A Marks, J T B Ekwealor, M A S Artur, L Bondi, T C Boothby, O M S Carmo, D C Centeno, K K Coe, H J W Dace, S Field, A Hutt, S Porembski, A Thalhammer, L Van Der Pas, A J Wood, P Alpert, D Bartels, S Boeynaems, M N Datar, T Giese, W I Seidou, S M Kirchner, J Köhler, U G V S S Kumara, J Kyung, R Lyall, B D Mishler, J B V T Ndongmo, M S Otegui, V Reddy, J Rexroth, S M Tebele, R Vanburen, J Verdier, U C Vothknecht, M F Wittenberg, E Zokov, M J Oliver, S Y Rhee

Duncan NRI Faculty and Staff Publications

To thrive in extreme conditions, organisms have evolved a diverse arsenal of adaptations that confer resilience. These species, their traits, and the mechanisms underlying them comprise a valuable resource that can be mined for numerous conceptual insights and applied objectives. One of the most dramatic adaptations to water limitation is desiccation tolerance. Understanding the mechanisms underlying desiccation tolerance has important potential implications for medicine, biotechnology, agriculture, and conservation. However, progress has been hindered by a lack of standardization across sub-disciplines, complicating the integration of data and slowing the translation of basic discoveries into practical applications. Here, we synthesize current knowledge …

Breaking The Synaptic Vesicle Cycle: Mechanistic Insights Into Presynaptic Dysfunctions In Epilepsy, Kevin Jiang, Lu-Tang Yang, Mingshan Xue

Duncan NRI Faculty and Staff Publications

Synaptic dysfunction is a hallmark of many neurological disorders including epilepsy. An increasing number of epilepsy-causing pathogenic variants are being identified in genes encoding presynaptic proteins that affect every step of the synaptic vesicle cycle, from vesicle loading, tethering, docking, priming, calcium sensing, fusing, to recycling. These different molecular dysfunctions result in converging impairment of presynaptic neurotransmitter release, yet lead to diverse epileptic disorders. This review focuses on representative monogenic epileptic disorders caused by pathogenic variants of key presynaptic proteins involved in different stages of the synaptic vesicle cycle: SYN1 (vesicle pool regulation), STXBP1 (vesicle docking, priming, and fusion), and …

De Novo Variants In Cdkl1 And Cdkl2 Are Associated With Neurodevelopmental Symptoms, Ali H Bereshneh, Jonathan C Andrews, Daniel F Eberl, Guney Bademci, Nicholas A Borja, Stephanie Bivona, Wendy K Chung, Shinya Yamamoto, Michael F Wangler, Shane Mckee, Mustafa Tekin, Hugo J Bellen, Oguz Kanca

Duncan NRI Faculty and Staff Publications

The CDKL (cyclin-dependent kinase-like) family consists of five members in humans, CDKL1-5, that encode serine-threonine kinases. The only member that has been associated with a Mendelian disorder is CDKL5, and variants in CDKL5 cause developmental and epileptic encephalopathy type 2 (DEE2). Here, we study four de novo variants in CDKL2 identified in five individuals, including three unrelated probands and monozygotic twins. These individuals present with overlapping symptoms, including global developmental delay, intellectual disability, childhood-onset epilepsy, dyspraxia, and speech deficits. We also identified two individuals with de novo missense variants in CDKL1 in the published Deciphering Developmental Disorders (DDD) and GeneDx …

Low-Grade Glial/Glioneuronal Tumor With Yap1::Fam118b Fusion: A Novel Molecular Finding, Fouad El-Dana, Kenneth Aldape, Zied Abdullaev, Sameer Anil Sheth, Jacob Mandel, Hsiang-Chih Lu

Faculty, Staff and Students Publications

No abstract provided.

Corrigendum To "Door-To-Needle Time Trends After Transition To Tenecteplase: A Multicenter Texas Stroke Registry" [Journal Of Stroke And Cerebrovascular Diseases 33 (2024) 107774], Nathaniel Rodriguez, Sidarrth Prasad, Daiwai M Olson, Sujani Bandela, Gretchel Gealogo Brown, Yoon Kwon, Mehari Gebreyohanns, Erica M Jones, Nneka L Ifejika, Suzanne Stone, Jane A Anderson, Sean I Savitz, Salvador Cruz-Flores, Steven J Warach, Mark P Goldberg, Lee A Birnbaum

Faculty, Staff and Students Publications

No abstract provided.

Foraging Animals Use Dynamic Bayesian Updating To Model Meta-Uncertainty In Environment Representations, James Webb, Paul Steffan, Benjamin Y Hayden, Daeyeol Lee, Caleb Kemere, Matthew Mcginley

Faculty, Staff and Students Publications

Foraging theory predicts animal behavior in many contexts. In patch-based foraging behaviors, the marginal value theorem (MVT) gives the optimal strategy for deterministic environments whose parameters are fully known to the forager. In natural settings, environmental parameters exhibit variability and are only partially known to the animal based on its experience, creating uncertainty. Models of uncertainty in foraging are well established. However, natural environments also exhibit unpredicted changes in their statistics. As a result, animals must ascertain whether the currently observed quality of the environment is consistent with their internal models, or whether something has changed, creating meta-uncertainty. Behavioral strategies …

Neurd Offers Automated Proofreading And Feature Extraction For Connectomics, Brendan Celii, Stelios Papadopoulos, Zhuokun Ding, Paul G Fahey, Eric Wang, Christos Papadopoulos, Alexander B Kunin, Saumil Patel, J Alexander Bae, Agnes L Bodor, Derrick Brittain, Joann Buchanan, Daniel J Bumbarger, Manuel A Castro, Erick Cobos, Sven Dorkenwald, Leila Elabbady, Akhilesh Halageri, Zhen Jia, Chris Jordan, Dan Kapner, Nico Kemnitz, Sam Kinn, Kisuk Lee, Kai Li, Ran Lu, Thomas Macrina, Gayathri Mahalingam, Eric Mitchell, Shanka Subhra Mondal, Shang Mu, Barak Nehoran, Sergiy Popovych, Casey M Schneider-Mizell, William Silversmith, Marc Takeno, Russel Torres, Nicholas L Turner, William Wong, Jingpeng Wu, Szi-Chieh Yu, Wenjing Yin, Daniel Xenes, Lindsey M Kitchell, Patricia K Rivlin, Victoria A Rose, Caitlyn A Bishop, Brock Wester, Emmanouil Froudarakis, Edgar Y Walker, Fabian Sinz, H Sebastian Seung, Forrest Collman, Nuno Maçarico Da Costa, R Clay Reid, Xaq Pitkow, Andreas S Tolias, Jacob Reimer

Faculty, Staff and Students Publications

We are in the era of millimetre-scale electron microscopy volumes collected at nanometre resolution1,2. Dense reconstruction of cellular compartments in these electron microscopy volumes has been enabled by recent advances in machine learning3–6. Automated segmentation methods produce exceptionally accurate reconstructions of cells, but post hoc proofreading is still required to generate large connectomes that are free of merge and split errors. The elaborate 3D meshes of neurons in these volumes contain detailed morphological information at multiple scales, from the diameter, shape and branching patterns of axons and dendrites, down to the fine-scale …

Functional Connectomics Reveals General Wiring Rule In Mouse Visual Cortex, Zhuokun Ding, Paul G Fahey, Stelios Papadopoulos, Eric Y Wang, Brendan Celii, Christos Papadopoulos, Andersen Chang, Alexander B Kunin, Dat Tran, Jiakun Fu, Zhiwei Ding, Saumil Patel, Lydia Ntanavara, Rachel Froebe, Kayla Ponder, Taliah Muhammad, J Alexander Bae, Agnes L Bodor, Derrick Brittain, Joann Buchanan, Daniel J Bumbarger, Manuel A Castro, Erick Cobos, Sven Dorkenwald, Leila Elabbady, Akhilesh Halageri, Zhen Jia, Chris Jordan, Dan Kapner, Nico Kemnitz, Sam Kinn, Kisuk Lee, Kai Li, Ran Lu, Thomas Macrina, Gayathri Mahalingam, Eric Mitchell, Shanka Subhra Mondal, Shang Mu, Barak Nehoran, Sergiy Popovych, Casey M Schneider-Mizell, William Silversmith, Marc Takeno, Russel Torres, Nicholas L Turner, William Wong, Jingpeng Wu, Wenjing Yin, Szi-Chieh Yu, Dimitri Yatsenko, Emmanouil Froudarakis, Fabian Sinz, Krešimir Josić, Robert Rosenbaum, H Sebastian Seung, Forrest Collman, Nuno Maçarico Da Costa, R Clay Reid, Edgar Y Walker, Xaq Pitkow, Jacob Reimer, Andreas S Tolias

Faculty, Staff and Students Publications

Understanding the relationship between circuit connectivity and function is crucial for uncovering how the brain computes. In mouse primary visual cortex, excitatory neurons with similar response properties are more likely to be synaptically connected1–8; however, broader connectivity rules remain unknown. Here we leverage the millimetre-scale MICrONS dataset to analyse synaptic connectivity and functional properties of neurons across cortical layers and areas. Our results reveal that neurons with similar response properties are preferentially connected within and across layers and areas—including feedback connections—supporting the universality of ‘like-to-like’ connectivity across the visual hierarchy. Using a validated digital twin model, …

Predictors And Outcomes Of First Pass Efficacy In Posterior Circulation Strokes: Insights From Star Collaboration, Muhammad U Hafeez, Muhammed A Essibayi, Daniel Raper, Omar Tanweer, Mithun Sattur, Sami Al-Kasab, Joshua Burks, Robert Townsend, Diana Alsbrook, Travis Dumont, Min S Park, Nitin Goyal, Adam S Arthur, Ilko Maier, Justin Mascitelli, Robert Starke, Stacey Wolfe, Kyle Fargen, Alejandro Spiotta, Peter T Kan

Faculty, Staff and Students Publications

Background: First-pass efficacy (FPE) has been established as an important predictor of favorable functional outcomes after endovascular thrombectomy (ET) in anterior circulation strokes. In this retrospective cohort study, we investigate predictors and clinical outcomes of FPE in posterior circulation strokes (pcAIS).

Methods: The Stroke Thrombectomy and Aneurysm Registry database was used to identify pcAIS patients who achieved FPE. Their baseline characteristics and outcomes were compared with the non-FPE group. The primary outcome was a 90-day modified Rankin Scale (mRS) of 0-3. Univariate (UVA) and multivariate (MVA) analyses were done to evaluate predictors of FPE. Safety outcomes included distal emboli, vessel …

Tardive Dyskinesia Versus Tardive Syndrome What Is In A Name?, Karen Frei, Alicia Scott, Stanley N Caroff, Joseph Jankovic, William Ondo, Leslie Citrome, Robert Hauser, Joseph H Friedman, Roongroj Bhidayasiri, Martha Sajatovic, Dennis Alters, Jonathan Meyer, Stuart Factor, E K Tan, G Remington, Ira Glick, Hubert Fernandez, Cynthia Comella, John Kane, Joseph Mcevoy, Delwyn Miller, Clement C Zai, J P Lindenmayer, Richard Trosch, Daniel D Truong

Faculty, Staff and Students Publications

No abstract provided.

Inhibitory Specificity From A Connectomic Census Of Mouse Visual Cortex, Casey M Schneider-Mizell, Agnes L Bodor, Derrick Brittain, Joann Buchanan, Daniel J Bumbarger, Leila Elabbady, Clare Gamlin, Daniel Kapner, Sam Kinn, Gayathri Mahalingam, Sharmishtaa Seshamani, Shelby Suckow, Marc Takeno, Russel Torres, Wenjing Yin, Sven Dorkenwald, J Alexander Bae, Manuel A Castro, Akhilesh Halageri, Zhen Jia, Chris Jordan, Nico Kemnitz, Kisuk Lee, Kai Li, Ran Lu, Thomas Macrina, Eric Mitchell, Shanka Subhra Mondal, Shang Mu, Barak Nehoran, Sergiy Popovych, William Silversmith, Nicholas L Turner, William Wong, Jingpeng Wu, Jacob Reimer, Andreas S Tolias, H Sebastian Seung, R Clay Reid, Forrest Collman, Nuno Maçarico Da Costa

Faculty, Staff and Students Publications

Mammalian cortex features a vast diversity of neuronal cell types, each with characteristic anatomical, molecular and functional properties1. Synaptic connectivity shapes how each cell type participates in the cortical circuit, but mapping connectivity rules at the resolution of distinct cell types remains difficult. Here we used millimetre-scale volumetric electron microscopy2 to investigate the connectivity of all inhibitory neurons across a densely segmented neuronal population of 1,352 cells spanning all layers of mouse visual cortex, producing a wiring diagram of inhibition with more than 70,000 synapses. Inspired by classical neuroanatomy, we classified inhibitory neurons based on targeting of …

Comparison Between Dynamic Models For Predicting Response To Corticosteroids In Alcohol-Associated Hepatitis: A Global Cohort Study, Francisco Idalsoaga, Luis Antonio Díaz, Leonardo Guizzetti, Winston Dunn, Heer Mehta, Jorge Arnold, Gustavo Ayares, Rokhsana Mortuza, Gurpreet Mahli, Alvi H Islam, Shiv K Sarin, Rakhi Maiwall, Wei Zhang, Steve Qian, Douglas Simonetto, Ashwani K Singal, Mohamed A Elfeki, Carolina Ramirez-Cadiz, Joaquín Cabezas, Victor Echavarría, Meritxell Ventura Cots, María Fátima Higuera-De La Tijera, Juan G Abraldes, Mustafa Al-Karaghouli, Prasun K Jalal, Mohamad Ali Ibrahim, Guadalupe García-Tsao, Daniela Goyes, Lubomir Skladaný, Daniel J Havaj, Karolina Sulejova, Svetlana Adamcova Selcanova, Diego Rincón, Vijay H Shah, Patrick S Kamath, Marco Arrese, Ramon Bataller, Juan Pablo Arab

Faculty, Staff and Students Publications

Several dynamic models predict mortality and corticosteroid response in alcohol-associated hepatitis (AH), yet no consensus exists on the most effective model. This study aimed to assess predictive models for corticosteroid response and short-term mortality in severe AH within a global cohort. We conducted a multi-national study of patients with severe AH treated with corticosteroids for at least 7 days, enrolled between 2009 and 2019. Dynamic models-Lille-4, Lille-7, trajectory of serum bilirubin (TSB), and neutrophil-to-lymphocyte ratio (NLR)-were used to estimate 30- and 90-day mortality. Lille-7 demonstrated the highest accuracy for both 30- and 90-day mortality.

Moderate Alcohol-Associated Hepatitis: A Real-World Multicenter Study, Francisco Idalsoaga, Luis Antonio Díaz, Winston Dunn, Heer Mehta, Karen Muñoz, Vicente Caldentey, Jorge Arnold, Gustavo Ayares, Rokhsana Mortuza, Shiv K Sarin, Rakhi Maiwall, Wei Zhang, Steve Qian, Douglas Simonetto, Ashwani K Singal, Mohamed A Elfeki, Carolina Ramirez-Cadiz, Gurpreet Malhi, Adan Ahmed, Hoomam Homsi, Zinia Abid, Joaquín Cabezas, Victor Echavarría, Maria Poca, German Soriano, Berta Cuyas, Meritxell Ventura Cots, María Fátima Higuera-De La Tijera, Maria Ayala-Valverde, Diego Perez, Jaime Gomez, Juan G Abraldes, Mustafa Al-Karaghouli, Prasun K Jalal, Mohamad Ali Ibrahim, Guadalupe García-Tsao, Daniela Goyes, Lubomir Skladaný, Daniel J Havaj, Karolina Sulejova, Svetlana Adamcova Selcanova, Diego Rincón, Kristina R Chacko, Juan C Restrepo, Pamela Yaquich, Luis G Toro, Vijay Shah, Marco Arrese, Patrick S Kamath, Ramon Bataller, Juan Pablo Arab

Faculty, Staff and Students Publications

Background: Severe alcohol-associated hepatitis (sAH) is a well-characterized disease with high short-term mortality. However, there is limited research on those with a "less severe condition" (moderate AH). This study aims to characterize in-depth patients with moderate AH (mAH), including the performance of mortality scoring systems, key prognostic factors, and survival over time.

Methods: A multicenter retrospective cohort study (2009-2019) included patients with mAH (MELD score ≤20 at admission). Cox regression and receiver operating characteristic curves with AUC were used for analysis.

Results: We included 1845 patients with AH (20 centers, 8 countries) between 2009 and 2019. mAH was defined as …

A Multipronged Effort To Incorporate Professionalism Into Campuswide Programming Through A Center For Professionalism, Kyler M Godwin, Asma Ali, Larry Laufman, Ellen M Friedman

Faculty, Staff and Students Publications

Background Professionalism, a core competency for graduate medical education accreditation, has a clear educational mandate. However, the pathway to successful incorporation of professionalism within organizational culture has not been established. Integration of professionalism within the learning environment requires intentional design and formal education. Objective To describe the integration of professionalism in the learning environment through formal education and programming and report feasibility and acceptability data.

Methods The Center for Professionalism (Center) was developed in 2013 to align with the learning and clinical environments of our academic medical center. Primary drivers of a culture of professionalism were identified through input from …

Glucose Uptake In Pigment Glia Suppresses Tau-Induced Inflammation And Photoreceptor Degeneration, Mikiko Oka, Sho Nakajima, Emiko Suzuki, Shinya Yamamoto, Kanae Ando

Duncan NRI Faculty and Staff Publications

Brain inflammation contributes to the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD). Glucose hypometabolism and glial activation are pathological features seen in AD brains; however, the connection between the two is not fully understood. Using a Drosophila model of AD, we identified that glucose metabolism in glia plays a critical role in neuroinflammation under disease conditions. Expression of human MATP (hereafter referred to as Tau) in the retinal cells, including photoreceptor neurons and pigment glia, causes photoreceptor degeneration accompanied by the formation of dark-stained round inclusion-like structures and swelling of the lamina cortex. We found that inclusion-like structures …

De Novo Variants In Rybp Are Associated With A Severe Neurodevelopmental Disorder And Congenital Anomalies, Monika Weisz-Hubshman, Lindsay C Burrage, Sharayu V Jangam, Jill A Rosenfeld, Sandra Von Hardenberg, Anke Bergmann, Manuela Friederike Richter, Malgorzata Rydzanicz, Rafal Ploski, Agnieszka Stembalska, Wendy K Chung, Rebecca R Hernan, Foong Y Lim, Theresa Brunet, Steffen Syrbe, Boris Keren, Solveig Heide, David R Murdock, Hongzheng Dai, Fan Xia, Shamika Ketkar, Brian Dawson, Vinodh Narayanan, Hillary K Graves, Undiagnosed Diseases Network, Michael F Wangler, Carlos Bacino, Brendan Lee

Duncan NRI Faculty and Staff Publications

Purpose: Polycomb group proteins are key epigenetic transcriptional regulators. Multiple neurodevelopmental disorders are associated with pathogenic variants of the genes encoding Polycomb group proteins. RYBP is a core component of the noncanonical Polycomb Repressor Complex 1; however, its role in disease is unclear.

Methods: Functional consequences of RYBP variants were assessed using in vitro cellular and in vivo Drosophila melanogaster studies.

Results: We described 7 individuals with heterozygous de novo variants of RYBP and their clinical findings, including severe developmental delay, dysmorphisms, and multiple congenital anomalies. We showed that all single-nucleotide variants in RYBP localize to the N-terminal domain of …

Anesthetic Considerations For The Transsphenoidal Resection Of A Pituitary Tumor In An Acromegalic Patient: A Case Report, Kennedy P Kirkpatrick, Anvinh Nguyen

Faculty, Staff and Students Publications

Acromegaly can result in many physiological changes that create multiple challenges for the anesthesiologist. Excess growth hormone secretion can result in altered facies, airway obstruction, ventilation challenges, and intubation difficulties. Moreover, hormonal changes can cause electrolyte imbalances, poor glycemic regulation, and hypertension. In addition, radial arterial invasive blood pressure monitoring can be relatively contraindicated given poor ulnar collateral circulation. In this case report, we discuss an acromegalic patient with severe facial, cardiovascular, and respiratory changes who successfully underwent transsphenoidal pituitary gland resection under general anesthesia. We describe our anesthetic approach toward caring for a patient with acromegaly.

Foundation Model Of Neural Activity Predicts Response To New Stimulus Types, Eric Y Wang, Paul G Fahey, Zhuokun Ding, Stelios Papadopoulos, Kayla Ponder, Marissa A Weis, Andersen Chang, Taliah Muhammad, Saumil Patel, Zhiwei Ding, Dat Tran, Jiakun Fu, Casey M Schneider-Mizell, Microns Consortium, R Clay Reid, Forrest Collman, Nuno Maçarico Da Costa, Katrin Franke, Alexander S Ecker, Jacob Reimer, Xaq Pitkow, Fabian H Sinz, Andreas S Tolias

Faculty, Staff and Students Publications

The complexity of neural circuits makes it challenging to decipher the brain’s algorithms of intelligence. Recent breakthroughs in deep learning have produced models that accurately simulate brain activity, enhancing our understanding of the brain’s computational objectives and neural coding. However, it is difficult for such models to generalize beyond their training distribution, limiting their utility. The emergence of foundation models1 trained on vast datasets has introduced a new artificial intelligence paradigm with remarkable generalization capabilities. Here we collected large amounts of neural activity from visual cortices of multiple mice and trained a foundation model to accurately predict neuronal responses …

Alpha-Synuclein Phosphomimetic Y39e And S129d Knock-In Mice Show Cytosolic Alpha-Synuclein Localization Without Developing Neurodegeneration Or Motor Deficits, Youngdoo Kim, Bhupesh Vaidya, Joseph Mcinnes, Huda Y Zoghbi

Duncan NRI Faculty and Staff Publications

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor and nonmotor symptoms. Its pathological hallmarks include the accumulation of misfolded alpha-synuclein (α-Syn) in Lewy bodies and Lewy neurites. Phosphorylation of α-Syn is a prominent feature of these inclusions, but its role in disease pathogenesis remains unclear. To identify the role of α-Syn phosphorylation in synucleinopathy, we generated two Snca knock-in (KI) mouse models carrying phosphomimetic mutations at SncaY39 or SncaS129 (Snca^Y39E or Snca^S129D) which manipulated epitopes phosphorylated in the PD brain. Both Snca^Y39E and Snca^S129D KI mice displayed increased α-Syn phosphorylation, enhanced …

Spetzler-Martin Grade Iv Cerebral Arteriovenous Malformations In Adult Patients: A Propensity-Score Matched Analysis Of Resection And Stereotactic Radiosurgery, Salem M Tos, Mahmoud Osama, Georgios Mantziaris, Bardia Hajikarimloo, Nimer Adeeb, Sandeep Kandregula, Hamza Adel Salim, Basel Musmar, Christopher S Ogilvy, Douglas Kondziolka, Adam A Dmytriw, Kareem El Naamani, Ahmed Abdelsalam, Deepak Kumbhare, Sanjeev Gummadi, Cagdas Ataoglu, Muhammed Amir Essibayi, Ufuk Erginoglu, Abdullah Keles, Sandeep Muram, Daniel Sconzo, Howard Riina, Arwin Rezai, Johannes Pöppe, Rajeev D Sen, Louis J Kim, Omar Alwakaa, Christoph J Griessenauer, Pascal Jabbour, Stavropoula I Tjoumakaris, Jan-Karl Burkhardt, Robert M Starke, Mustafa K Baskaya, Laligam N Sekhar, Michael R Levitt, David J Altschul, Neil Haranhalli, Malia Mcavoy, Abdallah Abushehab, Assala Aslan, Christian Swaid, Adib Abla, Christopher Stapleton, Matthew Koch, Visish M Srinivasan, Peng R Chen, Spiros Blackburn, Omar Choudhri, Bryan Pukenas, Darren Orbach, Edward Smith, Markus Möhlenbruch, Ali Alaraj, Ali Aziz-Sultan, Aman B Patel, Amey Savardekar, Hugo H Cuellar, Kathleen Dlouhy, Tarek El Ahmadieh, Michael Lawton, Adnan Siddiqui, Jacques Morcos, Bharat Guthikonda, Jason Sheehan

Faculty, Staff and Student Publications

Spetzler-Martin Grade IV arteriovenous malformations (AVMs) are challenging due to high risks associated with both treatment and natural progression. This study compares the outcomes of microsurgical resection and stereotactic radiosurgery (SRS) in high-grade AVMs, analyzing obliteration rates, complications, and functional outcomes. A retrospective cohort of 96 patients treated with either microsurgical resection (33 patients) or SRS (63 patients) was analyzed. Propensity-score matching was employed to account for baseline variables such as AVM size (cm), preoperative embolization and rupture status. Primary endpoints included AVM obliteration, complication rates, and modified Rankin Scale (mRS) scores. After matching, 31 patients per group were analyzed. …

Distinct Patterns Of Pv And Sst Gabaergic Neuronal Activity In The Basal Forebrain During Olfactory-Guided Behavior In Mice, Elizabeth H Moss, Evelyne K Tantry, Elaine Le, Pey-Shyuan Chin, Priscilla Ambrosi, Katie L Brandel-Ankrapp, Benjamin R Arenkiel

Duncan NRI Faculty and Staff Publications

Sensory perception relies on the flexible detection and interpretation of stimuli across variable contexts, conditions, and behavioral states. The basal forebrain (BF) is a hub for behavioral state regulation, supplying dense cholinergic and GABAergic projections to various brain regions involved in sensory processing. Of GABAergic neurons in the BF, parvalbumin (PV) and somatostatin (SST) subtypes serve opposing roles toward regulating behavioral states. To elucidate the role of BF circuits in sensory-guided behavior, we investigated GABAergic signaling dynamics during odor-guided decision-making in male and female mice. We used fiber photometry to record cell type-specific BF activity during an odor discrimination task …

Identification And Catalog Of Viral Transcriptional Regulators In Human Diseases, Citu Citu, Le Chang, Astrid M Manuel, Nitesh Enduru, Zhongming Zhao

Faculty, Staff and Student Publications

Viral genomes encode viral transcriptional regulators (vTRs) that manipulate host gene expression to facilitate replication and evade immune detection. Nevertheless, their role in non-cancerous diseases remains largely underexplored. Here, we unveiled 268 new candidate vTRs from 14 of the 20 viral families we investigated. We mapped vTRs' genome-wide binding profiles and identified their potential human targets, which were enriched in immune-mediated pathways, neurodegenerative disorders, and cancers. Through vTR DNA-binding preference analysis, 283 virus-specific and human-like motifs were identified. Prioritized Epstein-Barr virus (EBV) vTR target genes were associated with multiple sclerosis (MS), rheumatoid arthritis, and systemic lupus erythematosus. The partitioned heritability …

Protocol For Unlocking Alternative Polyadenylation Insights From Bulk Rna-Seq Data With Polyaminer-Bulk, Venkata Jonnakuti, Sriya Jonnakuti, Hari Krishna Yalamanchili

Duncan NRI Faculty and Staff Publications

PolyAMiner-Bulk, a deep-learning-based algorithm to decode alternative polyadenylation (APA) dynamics from bulk RNA sequencing (RNA-seq) data, enables scientists to identify and quantify APA events from processed bulk RNA-seq data. The protocol allows researchers to explore differential APA usage between two conditions and gain a better understanding of post-transcriptional regulatory mechanisms. The major steps involve input data preparation, executing PolyAMiner-Bulk, and interpreting the results. A basic familiarity with pre-processing bulk RNA-seq data and command-line tools is suggested.

For complete details on the use and execution of this protocol, please refer to Jonnakuti et al.¹

Diverse Ancestral Representation Improves Genetic Intolerance Metrics, Alexander L Han, Chloe F Sands, Dorota Matelska, Jessica C Butts, Vida Ravanmehr, Fengyuan Hu, Esmeralda Villavicencio Gonzalez, Nicholas Katsanis, Carlos D Bustamante, Quanli Wang, Slavé Petrovski, Dimitrios Vitsios, Ryan S Dhindsa

Duncan NRI Faculty and Staff Publications

The unprecedented scale of genomic databases has revolutionized our ability to identify regions in the human genome intolerant to variation—regions often implicated in disease. However, these datasets remain constrained by limited ancestral diversity. Here, we analyze whole-exome sequencing data from 460,551 UK Biobank and 125,748 Genome Aggregation Database (gnomAD) participants across multiple ancestries to test several key intolerance metrics, including the Residual Variance Intolerance Score (RVIS), Missense Tolerance Ratio (MTR), and Loss-of-Function Observed/Expected ratio (LOF O/E). We demonstrate that increasing ancestral representation, rather than sample size alone, critically drives their performance. Scores trained on variation observed in African and Admixed …

Investigation Of Dynamic Regulation Of Tfeb Nuclear Shuttling By Microfluidics And Quantitative Modelling, Iacopo Ruolo, Sara Napolitano, Lorena Postiglione, Gennaro Napolitano, Andrea Ballabio, Diego Di Bernardo

Duncan NRI Faculty and Staff Publications

Transcription Factor EB (TFEB) controls lysosomal biogenesis and autophagy in response to nutritional status and other stress factors. Although its regulation by nuclear translocation is known to involve a complex network of well-studied regulatory processes, the precise contribution of each of these mechanisms is unclear. Using microfluidics technology and real-time imaging coupled with mathematical modelling, we explored the dynamic regulation of TFEB under different conditions. We found that TFEB nuclear translocation upon nutrient deprivation happens in two phases: a fast one characterised by a transient boost in TFEB dephosphorylation dependent on transient calcium release mediated by mucolipin 1 (MCOLN1) followed …

Preoperative Brain Volume Loss Is Associated With Postoperative Delirium In Advanced Heart Failure Patients Supported By Left Ventricular Assist Device, Iván Murrieta-Álvarez, Jacob P Scioscia, José M Benítez-Salazar, Jason Uwaeze, Zicheng Xu, Guangyao Zheng, Shiyi Li, Vladimir Braverman, Carl P Walther, Alexis E Shafii, Camila Hochman-Mendez, Todd K Rosengart, Kenneth K Liao, Nandan K Mondal

Faculty, Staff and Students Publications

Delirium is a common neurological complication in patients with advanced heart failure (ADHF) following left ventricular assist device (LVAD) implantation, significantly impacting recovery. This study aimed to analyze non-contrast computed tomography (CT) scans of the brain in ADHF patients undergoing LVAD implantation to determine the association between pre-existing brain atrophy and postoperative delirium. A study involving 166 ADHF patients was conducted from March 2020 to July 2023. Non-contrast CT scans were analyzed using advanced quantitative neuroimaging techniques before implantation. The primary marker assessed was the lateral ventricle fraction (LVF), with secondary markers including cortical gray matter fraction (cGMF), white matter …

Exploration Of Working Memory Retrieval Stage For Mild Cognitive Impairment: Time-Varying Causality Analysis Of Electroencephalogram Based On Dynamic Brain Networks, Yi Jiang, Zhiwei Guo, Xiaobo Zhou, Ning Jiang, Jiayuan He

Faculty, Staff and Student Publications

Background: Mild Cognitive Impairment (MCI) is an intermediate stage between the expected cognitive decline of normal aging and Alzheimer's disease (AD). Its management is crucial for it helps intervene and slow the progression of cognitive decline to AD. However, the understanding of the MCI mechanism is not completely clear. As working memory (WM) damage is a common symptom of MCI, this study focused on the core stage of WM, i.e., the memory retrieval stage, to investigate information processing and the causality relationships among brain regions based on electroencephalogram (EEG) signals.

Method: 21 MCI and 20 normal cognitive control (NC) participants …

Longitudinal Multi-Omics In Alpha-Synuclein Drosophila Model Discriminates Disease- From Age-Associated Pathologies In Parkinson’S Disease, Justin Moore, Timothy Wu, Justin Dhindsa, Omar El Fadel, Anh Le, Alma Perez, Bismark Amoh, Akash Tarkunde, Katy F Zhu, Matthew Avalos, Eric B Dammer, Duc M Duong, Nicholas T Seyfried, Joshua M Shulman, Ismael Al-Ramahi, Juan Botas

Duncan NRI Faculty and Staff Publications

Parkinson's disease (PD) starts decades before symptoms appear, usually in the later decades of life, when age-related changes are occurring. To identify molecular changes early in the disease course and distinguish PD pathologies from aging, we generated Drosophila expressing alpha-synuclein (αSyn) in neurons and performed longitudinal bulk transcriptomics and proteomics on brains at six time points across the lifespan and compared the data to healthy control flies as well as human post-mortem brain datasets. We found that translational and energy metabolism pathways were downregulated in αSyn flies at the earliest timepoints; comparison with the aged control flies suggests that elevated …

Genome-Wide Prediction Of Dominant And Recessive Neurodevelopmental Disorder-Associated Genes, Ryan S Dhindsa, Blake A Weido, Justin S Dhindsa, Arya J Shetty, Chloe F Sands, Slavé Petrovski, Dimitrios Vitsios, Anthony W Zoghbi

Duncan NRI Faculty and Staff Publications

Despite great progress, thousands of neurodevelopmental disorder (NDD) risk genes remain to be discovered. We present a computational approach that accelerates NDD risk gene identification using machine learning. First, we demonstrate that models trained solely on single-cell RNA sequencing data can robustly predict genes implicated in autism spectrum disorder (ASD), developmental and epileptic encephalopathy (DEE), and developmental delay (DD). Notably, we find differences in gene expression patterns of genes with monoallelic and bi-allelic inheritance patterns in the developing human cortex. We then integrate expression data with 300 orthogonal features, including intolerance metrics, protein-protein interaction data, and others, in a semi-supervised …

Oxidized Carbon Nanoparticles Enhance Cellular Energetics With Application To Injured Brain, Karthik Mouli, Anton V Liopo, Emily A Mchugh, Erica Underwood, Jing Zhao, Pramod K Dash, Anh T T Vo, Vikas H Malojirao, Muralidhar L Hegde, James M Tour, Paul J Derry, Thomas A Kent

Faculty, Staff and Student Publications

Pro-energetic effects of functionalized, oxidized carbon nanozymes (OCNs) are reported. OCNs, derived from harsh acid oxidation of single-wall carbon nanotubes or activated charcoal are previously shown to possess multiple nanozymatic activities including mimicking superoxide dismutase and catalyzing the oxidation of reduced nicotinamide adenine dinucleotide (NADH) to NAD+. These actions are predicted to generate a glycolytic shift and enhance mitochondrial energetics under impaired conditions. Impaired mitochondrial energy metabolism is increasingly recognized as an important facet of traumatic brain injury (TBI) pathophysiology and decreases the efficiency of electron transport chain (ETC)-coupled adenosine triphosphate (ATP) and NAD+ regeneration. In vitro, OCNs promote a …