Medical Sciences Commons^™

Apathy Self-Awareness And Its Neural Correlates In Parkinson’S Disease, Hannah Conn, Hideo Suzuki, Zekai Jin, Ana Marin, Xi Zhu, Seonjoo Lee, Edward Huey, Ratko Radakovic, Sarah R Heilbronner, Nora Vanegas-Arroyave

Faculty, Staff and Students Publications

Apathy is a prevalent non-motor symptom in Parkinson's disease (PD) that negatively impacts quality of life. Impaired self-awareness of apathy (ISA-a) further impacts patient care by limiting engagement. While apathy has been associated with reduced fronto-striatal functional connectivity (FC), the neural basis of ISA-a remains unclear. We examined ISA-a in 52 individuals and the neural basis of ISA-a in 35 individuals with PD using a dimensional approach (i.e., initiation, executive, and emotional apathy) and resting-state fMRI (3T scanner). Apathetic PD patients (42%) showed poorer self-awareness than non-apathetic peers. Apathetic PD patients showed a trend towards reduced FC between the left …

Disinhibited Behavior Associated With Rapid Clinical Response To Deep Brain Stimulation For Obsessive-Compulsive Disorder: Illustrative Cases, Sarah S Soubra, Tommy B Liu, Zain U Naqvi, Thomas Hamre, Danika L Paulo, Kalman A Katlowitz, Nisha Giridharan, Katie Van Arsdel, Jonathan H Bentley, Kasra A Mansourian, Davin Devara, Eric A Storch, Sarah R Heilbronner, Sameer A Sheth, Wayne Goodman, Nicole R Provenza

Faculty, Staff and Students Publications

Background: Deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) can alleviate symptoms of obsessive-compulsive disorder (OCD) refractory to conventional therapies. Overstimulation, however, can elicit pathological behaviors marked by disinhibition and recklessness.

Observations: Two patients with OCD underwent DBS of the VC/VS region and met responder status within 1 month of stimulation onset, as evidenced by a ≥ 35% reduction in their Yale-Brown Obsessive Compulsive Scale score. Notably, both patients exhibited signs of disinhibited behavior soon after DBS activation, including gambling, sleep disruption, and interpersonal relationship volatility. Through careful management, responder status persisted stably beyond the transient period of …

Multisite Assembly Of Gateway Induced Clones (Magic): A Flexible Cloning Toolbox For Use In Vertebrate Model Systems, William B Gillespie, Yuwen Zhang, Oscar E Ruiz, Juan Cerda, Joshua Ortiz-Guzman, Michelle Sherman, Williamson D Turner, Gabrielle Largoza, Lili E Mosser, Esther Fujimoto, Chi-Bin Chien, Kristen M Kwan, Benjamin R Arenkiel, W Patrick Devine, Joshua D Wythe

Duncan NRI Faculty and Staff Publications

Here, we present MultiSite Assembly of Gateway Induced Clones (MAGIC), which leverages Gateway-based recombinatorial cloning technology for rapid, modular assembly of plasmids to facilitate transgenesis in cells and vertebrate animal models. The MAGIC collection of plasmids spans a range of in vitro and in vivo uses, from tools for optically and chemically tunable gene expression, to simultaneous expression of microRNAs and fluorescent reporters, to a suite of distinct subcellular compartmental fluorescent reporters, to Cre and Dre recombinase-dependent gene expression. MAGIC system components are compatible with existing MultiSite Gateway Tol2 systems currently used in zebrafish and mammalian lentiviral and adenoviral Destination …

Weight Loss And A Shunt On “Off”: An Odd Case Of Overshunting In An Idiopathic Intracranial Hypertension Patient Illustrative Case, Thomas Hamre, Ashley Ricciardelli, Alex Flores, Ashwin Viswanathan

Faculty, Staff and Students Publications

Background: CSF diversion with ventriculoperitoneal (VP) shunts is a common treatment for idiopathic intracranial hypertension (IIH). Rarely, overshunting can occur. Diagnosing and managing overshunting in an IIH patient with a shunt can be challenging. The authors present a unique etiology of overshunting successfully treated with shunt ligation.

Observations: A 48-year-old female with IIH who had undergone VP shunt placement with a programmable Certas valve presented with symptoms concerning for low-pressure headaches following a 25-kg weight loss. Intracranial pressure (ICP) monitoring along with an inpatient headache diary facilitated the diagnosis of intracranial hypotension secondary to CSF overdrainage through the shunt. Following …

Ezhip Boosts Neuronal-Like Synaptic Gene Programs And Depresses Polyamine Metabolism, Elham Hasheminasabgorji, Huey-Miin Chen, Taylor A Gatesman, Subhi Talal Younes, Gabrielle A Nobles, Farhang Jaryani, Heather Mao, Kwanha Yu, Benjamin Deneen, Wee Yong, Michael D Taylor, Sameer Agnihotri, Marco Gallo

Faculty, Staff and Students Publications

It is currently understood that the characteristic loss of the repressive histone mark H3K27me3 in PFA ependymoma and diffuse midline glioma (DMG) are caused by complementary mechanisms mediated by EZHIP and the oncohistone H3K27M, respectively. To support the complementarity of these mechanisms, rare H3K27M-negative DMGs express EZHIP. Interestingly, EZHIP is one of the few genes recurrently mutated in PFA. The significance of EZHIP mutations in PFA, and whether EZHIP has wider functions in addition to repression of H3K27me3 deposition, are not known. Here, we investigated the mutational landscape of EZHIP in pediatric brain tumors. We found that EZHIP mutations occur …

Neural Signatures And Personalized Neuromodulation In A Subject Experiencing Context-Dependent Inhibitory Control Deficits, Layth S Mattar, Shraddha Shah, Lily S Chamakura, Denise Oswalt, Yue Zhang, Davin Devara, Jung Uk Kang, Zahra Jourahmad, Ryan Jafri, Geoffrey Liu, Joshua Adkinson, Isabel A Danstrom, Xiaoxu Fan, Yvonne Y Reed, Kelly R Bijanki, Alica Goldman, Lu Lin, Vaishnav Krishnan, Nicole R Provenza, Andrew J Watrous, Sameer A Sheth, Sarah R Heilbronner, Garrett P Banks, Eleonora Bartoli

Faculty, Staff and Students Publications

The ability to override prepotent actions is critical to control impulses and adjust behavior depending on goals and contextual needs. In this study, we investigate the inhibitory control abilities of a patient diagnosed with Klüver-Bucy Syndrome following a left temporal resection. The patient presented with disruptive hypersexuality symptoms akin to compulsions, leading to the inability to control and suppress inappropriate actions. The patient was recruited for the current research study while undergoing intracranial monitoring for epilepsy, to investigate the cognitive and neural processes underlying the patient's inhibitory control symptoms. We formulated the hypothesis that a reactive inhibitory control deficit emerges …

Cognitive Reserve Predicts Baseline Tau Burden In The Us Pointer Trial Imaging Cohort, Valory N Pavlik, Chris J Weber, Joseph C Masdeu, Laura D Baker, Melissa M Yu, Michele York, Rachel A Whitmer, Susan M Landau, Theresa M Harrison, Tomas M Holland, Laura Lovato

Faculty, Staff and Students Publications

Introduction: Higher cognitive reserve (CR) is associated with reduced dementia risk. We hypothesized that higher CR is associated with less baseline Alzheimer's disease (AD) pathology in the U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) cohort.

Methods: A subsample of participants underwent amyloid beta and tau positron emission tomography imaging. Regression analysis was used to model the association between educational attainment (EA) as a CR proxy measure, amyloid positivity, and entorhinal cortex (ERC) and meta-temporal region of interest (meta-ROI) tau standardized uptake value ratio (SUVR).

Results: In 911 participants with complete imaging data, higher …

Epdevatlas: Mapping Gabaergic Cells And Microglia In The Early Postnatal Mouse Brain, Josephine K. Liwang, Fae N. Kronman, Hyun-Jae Pi, Yuan-Ting Wu, Daniel J. Vanselow, Steffy B. Manjila, Deniz Parmaksiz, Donghui Shin, Yoav Ben-Simon, Michael Taormina, Sharon W. Way, Hongkui Zeng, Bosiljka Tasic, Lydia Ng, Yongsoo Kim

School of Graduate Studies Faculty Publications

During development, brain regions follow encoded growth trajectories. Compared to classical brain growth charts, high-definition growth charts could quantify regional volumetric growth and constituent cell types, improving our understanding of typical and pathological brain development. Here, we create high-resolution 3D atlases of the early postnatal mouse brain, using Allen CCFv3 anatomical labels, at postnatal days (P) 4, 6, 8, 10, 12, and 14, and determine the volumetric growth of different brain regions. We utilize 11 different cell type-specific transgenic animals to validate and refine anatomical labels. Moreover, we reveal region-specific density changes in γ-aminobutyric acid-producing (GABAergic) neurons, cortical layer-specific cell …

Microglia Sensing Of Peripheral Signals That Bridge The Brain And Body, Claire E Young, Melanie A Samuel

Faculty, Staff and Students Publications

Microglia are the resident immune cell of the brain, and alterations in microglia signaling have been implicated in many neurodegenerative disorders. While microglia responses to central cues and other brain cell types are well documented, studies are increasingly investigating the impact of peripherally derived signals on microglia function. A diverse array of peripheral cues, including dietary components, hormones, and bacteria metabolites and components from the microbiome cross the blood brain barrier and directly influence microglia state through ligand-receptor interactions. This review highlights the complexity of brain-body interactions from the perspective of microglia function and proposes the idea that microglia could …

Injectable Microparticle-Nanoliposome Hydrogel For Extended Release Of Small Hydrophilic Molecules, Gil Aizik, Wonmin Choi, Claire A Ostertag-Hill, Matthew Torre, Daniel S Kohane

Duncan NRI Faculty and Staff Publications

Achieving sustained local release of small hydrophilic drugs is challenging and is particularly important when the drugs are toxic. To address these challenges, we developed a hybrid system comprising drug-containing microparticles embedded within a nanoliposomal hydrogel matrix. This system forms through salt-induced gelation using physiologically relevant sodium chloride concentrations (0.9%), allowing for microparticle encapsulation without harsh chemical processes. In vitro, the hybrid system exhibited a slower release of encapsulated cargo compared to microparticles or hydrogel alone. In vivo proof of principle was provided with tetrodotoxin (TTX), a small hydrophilic and ultrapotent local anesthetic, which can cause systemic toxicity if the …

The Fast And The Very Fast: High-Frequency Oscillations In Alzheimer's Disease, Manuel Silva-Pérez, Jeannie Chin

Faculty, Staff and Students Publications

Alzheimer's disease increases the risk of developing epilepsy together with cognitive decline. Early diagnosis or prediction of parameters associated with epileptic activity can greatly help in managing disease outcomes. Network hyperexcitability is a candidate of interest as a neurophysiological biomarker of Alzheimer's disease. High-frequency oscillations are increasingly recognized as potential biomarkers of hyperexcitability and epileptic activity. However, they have not yet been identified in Alzheimer's disease. In this study, we measured high-frequency oscillations via magnetoencephalography recordings in Alzheimer's disease patients with and without epileptic activity, as part of a Phase 2a randomized, double blind clinical trial of the efficacy of …

Generative Modeling For Interpretable Anomaly Detection In Medical Imaging: Applications In Failure Detection And Data Curation, Mckell E Woodland, Mais Altaie, Caleb S O'Connor, Austin H Castelo, Olubunmi C Lebimoyo, Aashish C Gupta, Joshua P Yung, Paul E Kinahan, Clifton D Fuller, Eugene J Koay, Bruno C Odisio, Ankit B Patel, Kristy K Brock

Faculty, Staff and Students Publications

This work aims to leverage generative modeling-based anomaly detection to enhance interpretability in AI failure detection systems and to aid data curation for large repositories. For failure detection interpretability, this retrospective study utilized 3339 CT scans (525 patients), divided patient-wise into training, baseline test, and anomaly (having failure-causing attributes—e.g., needles, ascites) test datasets. For data curation, 112,120 ChestX-ray14 radiographs were used for training and 2036 radiographs from the Medical Imaging and Data Resource Center for testing, categorized as baseline or anomalous based on attribute alignment with ChestX-ray14. StyleGAN2 networks modeled the training distributions. Test images were reconstructed with backpropagation and …

Intracranial Neural Biomarkers Of Psychiatric Symptoms And Their Utility For Guiding Neuromodulation Therapy: A Systematic Review, Katherine E Kabotyanski, Nicole R Provenza, Sameer A Sheth

Faculty, Staff and Students Publications

The quest to develop and improve neuromodulatory therapies for treatment-resistant psychiatric disorders has been fueled by the discovery of intracranial neural biomarkers of symptom dimensions. These neural correlates shed light on the underlying neurophysiology of the disorder and may even be useful in guiding therapy delivery. This systematic review summarizes recent efforts in this field relating neural activity to behavior and symptomatology. For years, the majority of these neurobehavioral relationships had been studied in the hospital or clinic environment. Recent technological advances in implanted neuromodulation devices that permit not only stimulation, but also intracranial neural recording have enabled this research …

Advancements In Prenatal Genetic Screening And Testing: Emerging Technologies And Evolving Applications, Mona M Makhamreh, Mei Ling Chong, Ignatia B Van Den Veyver

Duncan NRI Faculty and Staff Publications

Advancements in genomic technologies have transformed prenatal genetic testing, offering more accurate, comprehensive, and noninvasive approaches to reproductive care. This review provides an in-depth overview of current methodologies and emerging innovations, including expanded carrier screening (ECS), cell-free DNA (cfDNA) testing, chromosomal microarray analysis (CMA), and sequencing-based diagnostics. We highlight how next-generation sequencing (NGS) technologies have revolutionized carrier screening and fetal genome analysis, enabling detection of a broad spectrum of genetic conditions. The clinical implementation of cfDNA has expanded from common aneuploidies to include copy number variants (CNVs), and single-gene disorders. Diagnostic testing has similarly evolved, with genome sequencing outperforming traditional …

Biliverdin Reductase A Is A Major Determinant Of Protective Nrf2 Signaling, Chirag Vasavda, Ruchita Kothari, Navneet Ammal Kaidery, Suwarna Chakraborty, Sunil Jamuna Tripathi, Ryan S Dhindsa, Cristina Ricco, Shruthi Shanmukha, Samaneh Saberi, Julia E Lefler, Priyanka Kothari, Kalyani Chaubey, Adele M Snowman, Michael C Ostrowski, Eugenio Barone, Lakshminarayan M Iyer, L Aravind, Sudarshana M Sharma, Andrew A Pieper, Bobby Thomas, Solomon H Snyder, Bindu D Paul

Duncan NRI Faculty and Staff Publications

Biliverdin reductase A (BVRA), the terminal enzyme in heme catabolism, generates the neuroprotective and lipophilic antioxidant bilirubin. Here, we identify a nonenzymatic role for BVRA in redox regulation. Through phylogenetic, genetic, biochemical, and enzymatic assays, we found that BVRA exerts critical nonenzymatic antioxidant activity. Transcriptomic analyses further revealed that BVRA physically and genetically interacts with nuclear factor erythroid-derived factor-like 2 (NRF2), a major transcriptional regulator of cellular redox signaling. ChIP-seq and RNA-seq analyses reveal that BVRA and NRF2 coordinate the expression of antioxidant genes, many of which are typically dysregulated in neurodegenerative conditions such as Alzheimer's disease. Thus, this noncanonical …

Atg Conjugation-Dependent/Independent Mechanisms Underlie Lysosomal Stress-Induced Tfeb Regulation, Shiori Akayama, Takayuki Shima, Tatsuya Kaminishi, Mengying Cui, Jlenia Monfregola, Kohei Nishino, Andrea Ballabio, Hidetaka Kosako, Tamotsu Yoshimori, Shuhei Nakamura

Duncan NRI Faculty and Staff Publications

TFEB, a master regulator of autophagy and lysosomal biogenesis, is activated by several cellular stresses including lysosomal damage, but its underlying mechanism is unclear. TFEB activation during lysosomal damage depends on the ATG conjugation system, which mediates lipidation of ATG8 proteins. Here, we newly identify ATG conjugation-independent TFEB regulation that precedes ATG conjugation-dependent regulation, designated Modes I and II, respectively. We reveal unique regulators of TFEB in each mode: APEX1 in Mode I and CCT7 and/or TRIP6 in Mode II. APEX1 interacts with TFEB independently of the ATG conjugation system, and is required for TFEB stability, while both CCT7 and …

Traumatic Brain Injury In Pregnancy: A Single Level I Trauma Center Experience, Hector Fuentes Plata, Nisha K Dabhi, Shankar P Gopinath, Spyridoula Tsetsou

Faculty, Staff and Students Publications

Traumatic brain injury (TBI) is less common in pregnancy than in the general population; however, it poses significant challenges in diagnosis and management. These include the potential teratogenicity of medications, radiation exposure from imaging modalities, physiological changes associated with pregnancy, and obstetric complications that may arise. Although there are general guidelines for trauma in the obstetric patient, they are not specific to TBI, and most recommendations are based on low-level evidence or institutional experiences.

We conducted a retrospective review of the hospital trauma registry over a 10-year period. We included all the patients admitted to our neurosurgical intensive care unit …

Hydrogen Sulfide Inhibits Recruitment Of Monocyte-Derived Tumor Associated Macrophages In Glioblastoma By Downregulating Cxcl12, Joseph Camarano, Morgan Roque, Gabrielle Gahn, Stephen Garrett Whipple, Danielle Terrell, Charles Ronkon, Jamie Toms, Anthony Sin, Bharat Guthikonda, Khatri Latha, Yuhui Yang, Xinggui Shen, Christopher G Kevil, Ganesh Rao, Sungho Lee

Faculty, Staff and Students Publications

Tumor associated macrophages (TAMs) directly contribute to the dismal prognosis of glioblastoma by preventing anti-tumor immunity and promoting tumor invasion and angiogenesis. Inhibiting TAM infiltration is a potential therapeutic strategy in glioblastoma, with several chemokine antagonists in early clinical development. Hydrogen sulfide, a gasotransmitter that regulates microglial accumulation in a wide range of CNS diseases, may be a novel therapeutic target to prevent TAM recruitment in glioblastoma. In this study, hydrogen sulfide concentrations were directly measured from 14 isocitrate dehydrogenase (IDH)-wildtype glioblastoma surgical samples and compared against overall survival as well as expression of TAM markers and chemokines. Effects of …

Carbonic Anhydrase Inhibition Sensitizes Group 3 Medulloblastoma To Radiotherapy, Cory M Richman, Alexandra Rasnitsyn, Borja L Holgado, Maria Vladoiu, Namal Abeysundara, Sandra Majo, Sara Chabi, Lucie J Taunay, Hiromichi Suzuki, Ichiyo Shibahara, Joonas Haapasalo, Jonelle G Pallotta, Tajana Douglas, Kaitlin Kharas, Kyle Juraschka, Oliver Ocsenas, Sachin A Kumar, Kristiina Nordfors, Ana Guerreiro Stücklin, Raul A Suarez, Jiao Zhang, Xiaochong Wu, Craig Daniels, Livia Garzia, Jüri Reimand, Olivier Saulnier, Thomas E Merchant, Celio Pouponnot, David R Raleigh, Michael D Taylor, Pasqualino De Antonellis

Faculty, Staff and Students Publications

Group 3 (G3) medulloblastoma constitutes the most aggressive molecular subgroup, and nearly all patients present with metastases upon recurrence. Treatment for newly diagnosed medulloblastoma relies on a combination of maximal safe surgical resection, followed by chemotherapy and ionizing radiation, and no therapies have been shown to confer a survival benefit at the time of recurrence. Given the limited therapeutic options available for patients with medulloblastoma, especially at recurrence, and the incomplete understanding of the molecular mechanisms underlying resistance to treatment, we sought to uncover actionable targets and biomarkers that could help refine patient selection and treatment of newly diagnosed medulloblastoma …

Refining The Utility Of Late Amniocentesis In High-Risk Pregnancies, Roni Zemet, Ronald J Wapner, Ignatia B Van Den Veyver

Duncan NRI Faculty and Staff Publications

No abstract provided.

Kmt2d Temporally Activates Neuronal Transcriptional Factor Genes To Mediate Cerebellar Granule Cell Differentiation, Shilpa S Dhar, Kyung-Pil Ko, Jinho Jang, Calena Brown-Abel, Tao Lin, Sharad Awasthi, Kaifu Chen, Roy V Sillitoe, Jae-Il Park, Min Gyu Lee

Duncan NRI Faculty and Staff Publications

Spatiotemporal gene expression is the fundamental feature of cellular differentiation, including neuron differentiation. The epigenetic mechanism underlying spatiotemporal gene regulation during in vivo neuron differentiation remains largely unknown. Granule cells (GCs) constitute the vast majority of neurons in the cerebellum, which contains most of neurons in the brain. Here, we show that

Adsl Deficiency Is A Secondary Mitochondrial Disease Affecting Organelle Homeostasis And Erk2/Akt Signaling In A Linear Genotype-Phenotype Relation, Matteo Bordi, Beatrice Testa, Claudia Compagnucci, Fiorella Colasuonno, Francesca Cipressa, Elisabetta Betterini, Andrea Mancini, Claudia Carsetti, Illari Salvatori, Caterina Ferraina, Ming Yang, Rossella De Cegli, Eugenio Del Prete, Chiara Veroni, Salvatore Rizza, Sofia Mauri, Elena Ziviani, Marina Macchiaiolo, Davide Vecchio, Filippo Maria Panfili, Teresa Rizza, Gerrit Weber, Rosalba Carrozzo, Alberto Ferri, Silvia Campello, Andrea Ballabio, Christian Frezza, Gianluca Cestra, Marco Tartaglia, Andrea Bartuli, Francesco Cecconi

Duncan NRI Faculty and Staff Publications

Adenylosuccinate lyase deficiency (ADSLd) is a rare autosomal recessive purine metabolism disorder with several clinical manifestations. While toxic substrate accumulation is a known hallmark, no additional molecular mechanisms have been established. Here, we show that ADSLd is associated with mitochondrial dysfunction, including increased fragmentation, impaired respiration, and reduced ATP production. The severity of mitochondrial impairment correlates with ADSLd pathology, especially in mitochondria-dependent tissues. We also identify defects in mitochondrial dynamics and transport linked to ERK2 and AKT suppression. Notably, overexpressing constitutively active ERK2 or supplementing purine intermediates partially rescues the mitochondrial phenotype. These findings suggest an alternative disease mechanism and …

Repeat Selective Dorsal Rhizotomy For Residual Spasticity: Illustrative Case, Elizabeth Ledbetter, Aloysia L Schwabe, Heather Sgro, Sarah Slocum, Nisha Gadgil

Faculty, Staff and Students Publications

Background: Selective dorsal rhizotomy (SDR) is typically a one-time surgical procedure supported by intense rehabilitation to improve ambulatory capability in children with spastic cerebral palsy (CP).

Observations: The authors present the unique case of a teenager with spastic diplegic CP who had undergone L2-S1 SDR as a child and presented with residual focal spasticity in the right plantar flexors. He underwent revision SDR at the right L5 and S1 levels in addition to decompression of canal stenosis. Postoperatively, he had notable improvement in his gait with relief of preoperative right knee and foot pain, improved ease of ambulation, and improved …

Cerebellar Dysfunction In A Mouse Model Of Childhood-Onset Manganese-Induced Dystonia Parkinsonism, Alexander N Rodichkin, Amanda M Brown, Pavani Devabathini, Jennifer L Mcglothan, Si Chen, Ajith Pattammattel, Yong S Chu, Tao Lin, Daniel D Pontow, Karam Abilmouna, Ritishka Kapoor, Sarah E Hardin, Yulia Pushkar, Roy V Sillitoe, Tomás R Guilarte

Duncan NRI Faculty and Staff Publications

Humans with pathogenic variants of the manganese (Mn) transporter gene SLC39A14 exhibit highly elevated brain Mn concentrations and childhood-onset dystonia-parkinsonism. Here we show that Slc39a14-knockout (KO) mice, a preclinical model of the disease with elevated Mn concentrations in the CB, express deficits in physiological tremor implicating cerebellar (CB) dysfunction. Imaging of intracellular Mn in Purkinje cells (PCs) using synchrotron-based X-ray fluorescence microscopy confirmed highly elevated Mn concentrations in the PCs of Slc39a14-KO mice. To determine biological pathways altered in the CB of Slc39a14-KO mice relative to wildtype (WT), we performed RNA sequencing and discovered significant upregulation of pathways and genes …

Determining The Effects Of An Hiv Infective Model On The Development Of Neuropathic Pain In Alzheimer’S Disease Model Mice., Ayesha Usman, Megan W. Szobody, Jose Rios, Mohammed Alnoud, Khalid Benamar

Research Colloquium

The purpose of this study is to determine the effect of the Human Immunodeficiency virus (HIV) in producing neuropathic pain in an Alzheimer’s Disease (AD) mouse model. HIV-1 envelope glycoprotein gp120 is correlated with increased release of thermal hyperalgesia and mechanical allodynia mediators from astrocytes and glial cells in rodents, producing the identifiable symptoms of neuropathic pain. Similarly, studies show that 45.8% of AD patients experience chronic pain. The production of an HIV/AD comorbid mouse model will be useful in determining important pathological pathways for neuropathic pain and is vital to future studies in therapeutic approaches to these conditions. Two …

Wernicke’S Encephalopathy With Classic Triad And Normal Mri In A Young Woman Following Rapid-Sequence Bariatric And Biliary Surgery, Hugo Zamarron, Nina Mourao, Roberto A. Cruz Saldana

Research Colloquium

Background: Wernicke’s encephalopathy is a life-threatening neurological disorder caused by thiamine deficiency, most commonly associated with alcoholism. However, postoperative nutritional deficiencies in young patients undergoing bariatric procedures are increasingly recognized. This case is unique due to the rapid succession of bariatric and cholecystectomy surgeries, development of classic Wernicke’s symptoms with a normal MRI, and diagnostic delay due to overlapping differential diagnoses including intracranial hypotension and myelopathy.

Case Presentation: A 22-year-old woman with class III obesity underwent sleeve gastrectomy in July 2022, followed by significant weight loss and persistent intractable vomiting. Due to suspected gallbladder disease, she underwent a cholecystectomy in …

Corticobasal Syndrome With Mixed Pathology In The Absence Of Grn Mutation: A Clinico-Pathological Case Of Ftld-Tdp With Coexisting Alzheimer’S And Lewy Body Pathology, Hugo Zamarron, David Irwin, Jeffery Phillips, Edward Lee, Matthew Tisdall, Corey Mcmillan

Research Colloquium

Background: Corticobasal syndrome (CBS) is a neurodegenerative disorder characterized by often asymmetric fronto-pariteal and extra-pyramidal features that is traditionally associated with tauopathy, but pathological findings are heterogenous, including other forms of frontotemporal lobar degeneration (FTLD) and mixed pathologies of aging. We present clinical, radiographic, and histopathologic features of asymmetry in a unique patient with CBS and underlying FTLD with TDP-43 pathology (FTLD-TDP), co-occurring with other age-related pathologies.

Case Presentation: A 76-year-old man presented with progressive cognitive and motor dysfunction including asymmetric parkinsonism, left-sided dystonia and rigidity, apraxia, visuospatial impairment, and a subtle social disorder including apathy and social withdrawal. The …

Bilateral Small Vessel Strokes In A Young Male With Coccidioidal Meningitis And Suspected Cns Vasculitis, Hugo Zamarron, Ahsan Ali

Research Colloquium

Background: Cerebral small vessel strokes in young, otherwise healthy adults without traditional vascular risk factors are rare and warrant further investigation. Central nervous system (CNS) vasculitis is an uncommon etiology that may be triggered by infections, including fungal pathogens. This case is notable for a suspected primary CNS vasculitis manifesting as bilateral deep infarcts in the setting of Coccidioidal meningitis. It highlights the importance of considering fungal infections and vasculitis in the differential diagnosis of stroke in younger patients.

Case Presentation: A 32-year-old previously healthy male presented with fever, headache, and was diagnosed with aseptic meningitis. He was later readmitted …

Blue-Shifted Ancyromonad Channelrhodopsins For Multiplex Optogenetics, Elena G Govorunova, Oleg A Sineshchekov, Hai Li, Yueyang Gou, Hongmei Chen, Shuyuan Yang, Yumei Wang, Stephen Mitchell, Alyssa Palmateer, Leonid S Brown, François St-Pierre, Mingshan Xue, John L Spudich

Duncan NRI Faculty and Staff Publications

Light-gated ion channels from protists (channelrhodopsins or ChRs) are optogenetic tools widely used for controlling neurons and cardiomyocytes. Multiplex optogenetic applications require spectrally separated molecules, which are difficult to engineer without disrupting channel function. Scanning numerous sequence databases, we identified three naturally blue-shifted ChRs from ancyromonads. They form a separate branch on the phylogenetic tree and contain residue motifs characteristic of anion ChRs (ACRs). However, only two conduct chloride, whereas the closely related Nutomonas longa homolog generates inward cation currents in mammalian cells under physiological conditions, significantly exceeding those by previously known tools with similar spectral maxima (peak absorption at …

Structural Basis For Mtorc1 Activation On The Lysosomal Membrane, Zhicheng Cui, Alessandra Esposito, Gennaro Napolitano, Andrea Ballabio, James H Hurley

Duncan NRI Faculty and Staff Publications

The mechanistic target of rapamycin complex 1 (mTORC1) integrates growth factor (GF) and nutrient signals to stimulate anabolic processes connected to cell growth and inhibit catabolic processes such as autophagy1,2. GF signalling through the tuberous sclerosis complex regulates the lysosomally localized small GTPase RAS homologue enriched in brain (RHEB)3. Direct binding of RHEB-GTP to the mTOR kinase subunit of mTORC1 allosterically activates the kinase by inducing a large-scale conformational change4. Here we reconstituted mTORC1 activation on membranes by RHEB, RAGs and Ragulator. Cryo-electron microscopy showed that RAPTOR and mTOR interact directly with the membrane. Full engagement of the membrane anchors …