Neurosciences Commons^™

Kdm6b Variants May Contribute To The Pathophysiology Of Human Cerebral Folate Deficiency, Xiao Han, Xuanye Cao, Robert M Cabrera, Paula Andrea Pimienta Ramirez, Cuilian Zhang, Vincent T Ramaekers, Richard H Finnell, Yunping Lei

Faculty, Staff and Students Publications

(1) Background: The genetic etiology of most patients with cerebral folate deficiency (CFD) remains poorly understood. KDM6B variants were reported to cause neurodevelopmental diseases; however, the association between KDM6B and CFD is unknown; (2) Methods: Exome sequencing (ES) was performed on 48 isolated CFD cases. The effect of KDM6B variants on KDM6B protein expression, Histone H3 lysine 27 epigenetic modification and FOLR1 expression were examined in vitro. For each patient, serum FOLR1 autoantibodies were measured; (3) Results: Six KDM6B variants were identified in five CFD patients, which accounts for 10% of our CFD cohort cases. Functional experiments indicated that these …

White Matter Correlates Of Domain-Specific Working Memory, Autumn Horne, Junhua Ding, Tatiana T Schnur, Randi C Martin

Faculty, Staff and Student Publications

Prior evidence suggests domain-specific working memory (WM) buffers for maintaining phonological (i.e., speech sound) and semantic (i.e., meaning) information. The phonological WM buffer's proposed location is in the left supramarginal gyrus (SMG), whereas semantic WM has been related to the left inferior frontal gyrus (IFG), the middle frontal gyrus (MFG), and the angular gyrus (AG). However, less is known about the white matter correlates of phonological and semantic WM. We tested 45 individuals with left hemisphere brain damage on single word processing, phonological WM, and semantic WM tasks and obtained T1 and diffusion weighted neuroimaging. Virtual dissections were performed for …

Xcvatr: Detection And Characterization Of Variant Impact On The Embeddings Of Single -Cell And Bulk Rna-Sequencing Samples, Arif Harmanci, Akdes Serin Harmanci, Tiemo J Klisch, Akash J Patel

Duncan NRI Faculty and Staff Publications

Background: RNA-sequencing has become a standard tool for analyzing gene activity in bulk samples and at the single-cell level. By increasing sample sizes and cell counts, this technique can uncover substantial information about cellular transcriptional states. Beyond quantification of gene expression, RNA-seq can be used for detecting variants, including single nucleotide polymorphisms, small insertions/deletions, and larger variants, such as copy number variants. Notably, joint analysis of variants with cellular transcriptional states may provide insights into the impact of mutations, especially for complex and heterogeneous samples. However, this analysis is often challenging due to a prohibitively high number of variants and …

Empowering Nurses To Recognize Post-Stroke Depression In The African American Community, Deidra Frisbie, Robin Simon

Doctor of Nursing Practice Projects

African Americans (AA) have the highest prevalence of stroke and death compared to other racial groups in the United States. Post-stroke depression (PSD) affects approximately 1/3 of all stroke patients and is underdiagnosed in the African American community.

Aim: By using a mHealth mobile app and a Psychiatry provider list at discharge, PSD can be identified, and interventions initiated, thus decreasing the sequela of PSD in AA.

Methods: Nurses were provided education on PSD, expressions of depression in African-Americans, cultural humility, implicit bias, and the importance of the nurse's role in developing a therapeutic relationship.

Results: Quantitative analysis revealed the …

Frequency And Burden Of Neurological Manifestations Upon Hospital Presentation In Covid-19 Patients: Findings From A Large Brazilian Cohort, Milena Soriano Marcolino, Fernando Anschau, Luciane Kopittke, Magda Carvalho Pires, Izabela Guimarães Barbosa, Daniella Nunes Pereira, Lucas Emanuel Ferreira Ramos, Luís Fernando Israel Assunção, André Soares De Moura Costa, Matheus Carvalho Alves Nogueira, Helena Duani, Karina Paula Medeiros Prado Martins, Leila Beltrami Moreira, Carla Thais Cândida Alves Da Silva, Neimy Ramos De Oliveira, Patricia Klarmann Ziegelmann, Milton Henriques Guimarães-Júnior, Mauro Oscar Soares De Souza Lima, Rubia Laura Oliveira Aguiar, Luanna Silva Monteiro Menezes, Talita Fischer Oliveira, Maíra Dias Souza, Bárbara Lopes Farace, Christiane Corrêa Rodrigues Cimini, Amanda De Oliveira Maurílio, Silvana Mangeon Mereilles Guimarães, Silvia Ferreira Araújo, Guilherme Fagundes Nascimento, Daniel Vitório Silveira, Karen Brasil Ruschel, Thainara Conceição De Oliveira, Alexandre Vargas Schwarzbold, Luiz Antônio Nasi, Maiara Anschau Floriani, Veridiana Baldon Dos Santos, Carolina Marques Ramos, Joice Coutinho De Alvarenga, Ana Luiza Bahia Alves Scotton, Euler Roberto Fernandes Manenti, Gabriela Petry Crestani, Joanna D'Arc Lyra Batista, Daniela Ponce, Juliana Machado-Rugolo, Adriana Falangola Benjamin Bezerra, Petrônio José De Lima Martelli, Heloisa Reniers Vianna, Luís César De Castro, Cássia Regina Gotler Medeiros, Giovanna Grunewald Vietta, Elayne Crestani Pereira, José Miguel Chatkin, Mariana Frizzo De Godoy, Polianna Delfino-Pereira, Antonio Lucio Teixeira

Faculty, Staff and Student Publications

BACKGROUND: Scientific data regarding the prevalence of COVID-19 neurological manifestations and prognosis in Latin America countries is still lacking. Therefore, the study aims to understand neurological manifestations of SARS-CoV 2 infection and outcomes in the Brazilian population.

METHODS: This study is part of the Brazilian COVID-19 Registry, a multicentric cohort, including data from 37 hospitals. For the present analysis, patients were grouped according to the presence of reported symptoms (i.e., headache; anosmia and ageusia; syncope and dizziness) vs. clinically-diagnosed neurological manifestations (clinically-defined neurological syndrome: neurological signs or diagnoses captured by clinical evaluation) and matched with patients without neurological manifestations by …

Tiam1-Mediated Synaptic Plasticity Underlies Comorbid Depression-Like And Ketamine Antidepressant-Like Actions In Chronic Pain, Qin Ru, Yungang Lu, Ali Bin Saifullah, Francisco A Blanco, Changqun Yao, Juan P Cata, De-Pei Li, Kimberley F Tolias, Lingyong Li

Faculty, Staff and Students Publications

Chronic pain often leads to depression, increasing patient suffering and worsening prognosis. While hyperactivity of the anterior cingulate cortex (ACC) appears to be critically involved, the molecular mechanisms underlying comorbid depressive symptoms in chronic pain remain elusive. T cell lymphoma invasion and metastasis 1 (Tiam1) is a Rac1 guanine nucleotide exchange factor (GEF) that promotes dendrite, spine, and synapse development during brain development. Here, we show that Tiam1 orchestrates synaptic structural and functional plasticity in ACC neurons via actin cytoskeleton reorganization and synaptic N-methyl-d-aspartate receptor (NMDAR) stabilization. This Tiam1-coordinated synaptic plasticity underpins ACC hyperactivity and drives chronic pain-induced depressive-like behaviors. …

Detection Of Stroke With Retinal Microvascular Density And Self-Supervised Learning Using Oct-A And Fundus Imaging, Samiksha Pachade, Ivan Coronado, Rania Abdelkhaleq, Juntao Yan, Sergio Salazar-Marioni, Amanda Jagolino, Charles Green, Mozhdeh Bahrainian, Roomasa Channa, Sunil A Sheth, Luca Giancardo

Faculty, Staff and Student Publications

Acute cerebral stroke is a leading cause of disability and death, which could be reduced with a prompt diagnosis during patient transportation to the hospital. A portable retina imaging system could enable this by measuring vascular information and blood perfusion in the retina and, due to the homology between retinal and cerebral vessels, infer if a cerebral stroke is underway. However, the feasibility of this strategy, the imaging features, and retina imaging modalities to do this are not clear. In this work, we show initial evidence of the feasibility of this approach by training machine learning models using feature engineering …

Contributions Of Semantic And Phonological Working Memory To Narrative Language Independent Of Single Word Production: Evidence From Acute Stroke, Rachel Zahn, Tatiana T Schnur, Randi C Martin

Faculty, Staff and Student Publications

Neuropsychological case studies have provided evidence that individuals with semantic, but not phonological, working memory (WM) deficits have difficulty producing phrases containing several content words. These findings supported the claim of a phrasal scope of planning at the grammatical formulation stage of production, where semantic WM supports the maintenance of lexical-semantic representations as they are inserted into slots in phrasal constituents. Recent narrative production results for individuals at the acute stage of stroke supported the role for semantic WM in phrasal elaboration while suggesting a role for phonological WM at a subsequent phonological encoding stage in supporting fluent, rapid speech. …

Rna Editing Of Microtubule-Associated Protein Tau Circular Rnas Promotes Their Translation And Tau Tangle Formation, Justin Ralph Welden, Giorgi Margvelani, Karol Andrea Arizaca Maquera, Bhavani Gudlavalleti, Sandra C. Miranda Sardón, Alexandre Rosa Campos, Noémie Robil, Daniel C. Lee, Alvaro G. Hernandez, Wang-Xia Wang, Jing Di, Pierre De La Grange, Peter T. Nelson, Stefan Stamm

Sanders-Brown Center on Aging Faculty Publications

Aggregation of the microtubule-associated protein tau characterizes tauopathies, including Alzheimer’s disease and frontotemporal lobar degeneration (FTLD-Tau). Gene expression regulation of tau is complex and incompletely understood. Here we report that the human tau gene (MAPT) generates two circular RNAs (circRNAs) through backsplicing of exon 12 to either exon 7 (12→7 circRNA) or exon 10 (12→10 circRNA). Both circRNAs lack stop codons. The 12→7 circRNA contains one start codon and is translated in a rolling circle, generating a protein consisting of multimers of the microtubule-binding repeats R1–R4. For the 12→10 circRNA, a start codon can be introduced by two …

Genetic Expression Changes And Pathologic Findings Associated With Hyperhomocysteinemia In Human Autopsy Brain Tissue, Erica M. Weekman, Zachary Winder, Colin B. Rogers, Erin L. Abner, Tiffany L. Sudduth, Ela Patel, Adam J. Dugan, Shuling X. Fister, Brandi Wasek, Peter T. Nelson, Gregory A. Jicha, Teodoro Bottiglieri, David W. Fardo, Donna M. Wilcock

Sanders-Brown Center on Aging Faculty Publications

Introduction: Vascular contributions to cognitive impairment and dementia (VCID) are a leading cause of dementia. An underappreciated, modifiable risk factor for VCID is hyperhomocysteinemia (HHcy), defined by elevated levels of plasma homocysteine, most often due to impaired B vitamin absorption in aged persons. Studies aimed at identifying neuropathologic features and gene expression profiles associated with HHcy have been lacking.

Methods: A subset of research volunteers from the University of Kentucky Alzheimer’s Disease Research Center longitudinal cohort came to autopsy and had ante mortem plasma homocysteine levels available. Brain tissue and blood plasma drawn closest to death were used to measure …

Nursing Considerations For Post-Traumatic Amnesia After A Traumatic Brain Injury, Hannah Grant

Senior Honors Theses

A period known as post-traumatic amnesia (PTA) often follows a traumatic brain injury (TBI). PTA is characterized by anterograde and retrograde amnesia, confusion, disorientation, and agitation. The duration and severity of PTA is a key indicator of the long-term prognosis after a TBI, so proper assessment and nursing care of a PTA patient is crucial. TBIs range from mild to severe, but primarily affect the fronto-temporal lobes. In PTA, both neural lesions and white matter damage within the parahippocampal region can cause PTA. A nurse must perform a thorough assessment of a TBI patient, but, since PTA is a key …

Active Dna Demethylation Promotes Cell Fate Specification And The Dna Damage Response, Dongpeng Wang, Wei Wu, Elsa Callen, Raphael Pavani, Nicholas Zolnerowich, Srikanth Kodali, Dali Zong, Nancy Wong, Santiago Noriega, William J Nathan, Gabriel Matos-Rodrigues, Raj Chari, Michael J Kruhlak, Ferenc Livak, Michael Ward, Keith Caldecott, Bruno Di Stefano, André Nussenzweig

Faculty, Staff and Students Publications

Neurons harbor high levels of single-strand DNA breaks (SSBs) that are targeted to neuronal enhancers, but the source of this endogenous damage remains unclear. Using two systems of postmitotic lineage specification-induced pluripotent stem cell-derived neurons and transdifferentiated macrophages-we show that thymidine DNA glycosylase (TDG)-driven excision of methylcytosines oxidized with ten-eleven translocation enzymes (TET) is a source of SSBs. Although macrophage differentiation favors short-patch base excision repair to fill in single-nucleotide gaps, neurons also frequently use the long-patch subpathway. Disrupting this gap-filling process using anti-neoplastic cytosine analogs triggers a DNA damage response and neuronal cell death, which is dependent on TDG. …

Apoe Genetics Influence Murine Gut Microbiome, Diana J. Zajac, Stefan J. Green, Lance A. Johnson, Steven Estus

Sanders-Brown Center on Aging Faculty Publications

Apolipoprotein E (APOE) alleles impact pathogenesis and risk for multiple human diseases, making them primary targets for disease treatment and prevention. Previously, we and others reported an association between APOE alleles and the gut microbiome. Here, we evaluated effects of APOE heterozygosity and tested whether these overall results extended to mice maintained under ideal conditions for microbiome analyses. To model human APOE alleles, this study used APOE targeted replacement (TR) mice on a C57Bl/6 background. To minimize genetic drift, homozygous APOE3 mice were crossed to homozygous APOE2 or homozygous APOE4 mice prior to the study, and the resulting …

Single Low-Dose Targeted Bevacizumab Infusion In Adult Patients With Steroid-Refractory Radiation Necrosis Of The Brain: A Phase Ii Open-Label Prospective Clinical Trial, Shervin R. Dashti, Robert J. Kadner, Bradley S. Folley, Jason P. Sheehan, Dong Y. Han, Richard J. Kryscio, Mary B. Carter, Lisa B. E. Shields, Brian M. Plato, Renato V. La Rocca, Aaron C. Spalding, Tom L. Yao, Justin F. Fraser

Sanders-Brown Center on Aging Faculty Publications

OBJECTIVE There is an unmet need for safe and rapidly effective therapies for refractory brain radiation necrosis (RN). The aim of this prospective single-arm phase II trial was to evaluate the safety and efficacy of a single low-dose targeted bevacizumab infusion after blood-brain barrier disruption (BBBD) in adult patients with steroid-refractory brain RN.

METHODS Ten adults with steroid-refractory, imaging-confirmed brain RN were enrolled between November 2016 and January 2018 and followed for 12 months after treatment. Bevacizumab 2.5 mg/kg was administered as a one-time targeted intra-arterial infusion immediately after BBBD. Primary outcomes included safety and > 25% decrease in lesion volume. …

Author Correction: Entorhinal Cortex Directs Learning-Related Changes In Ca1 Representations, Christine Grienberger, Jeffrey C Magee

Faculty, Staff and Students Publications

No abstract provided.

Reorganization Of The Functional Connectome From Rest To A Visual Perception Task In Schizophrenia And Bipolar Disorder, Philipp Riedel, Junghee Lee, Christopher G Watson, Amy M Jimenez, Eric A Reavis, Michael F Green

Faculty, Staff and Student Publications

Functional connectome organization is altered in schizophrenia (SZ) and bipolar disorder (BD). However, it remains unclear whether network reorganization during a task relative to rest is also altered in these disorders. This study examined connectome organization in patients with SZ (N = 43) and BD (N = 42) versus healthy controls (HC; N = 39) using fMRI data during a visual object-perception task and at rest. Graph analyses were conducted for the whole-brain network using indices selected a priori: three reflecting network segregation (clustering coefficient, local efficiency, modularity), two reflecting integration (characteristic path length, global efficiency). Group differences were limited …

A Minimal Role For Synonymous Variation In Human Disease, Ryan S Dhindsa, Quanli Wang, Dimitrios Vitsios, Oliver S Burren, Fengyuan Hu, James E Dicarlo, Leonid Kruglyak, Daniel G Macarthur, Matthew E Hurles, Slavé Petrovski

Duncan NRI Faculty and Staff Publications

Synonymous mutations change the DNA sequence of a gene without affecting the amino acid sequence of the encoded protein. Although some synonymous mutations can affect RNA splicing, translational efficiency, and mRNA stability, studies in human genetics, mutagenesis screens, and other experiments and evolutionary analyses have repeatedly shown that most synonymous variants are neutral or only weakly deleterious, with some notable exceptions. Based on a recent study in yeast, there have been claims that synonymous mutations could be as important as nonsynonymous mutations in causing disease, assuming the yeast findings hold up and translate to humans. Here, we argue that there …

Propranolol Modulates Cerebellar Circuit Activity And Reduces Tremor., Joy Zhou, Meike E Van Der Heijden, Luis E Salazar Leon, Tao Lin, Lauren N Miterko, Dominic J Kizek, Ross M Perez, Matea Pavešković, Amanda M Brown, Roy V Sillitoe

Duncan NRI Faculty and Staff Publications

Tremor is the most common movement disorder. Several drugs reduce tremor severity, but no cures are available. Propranolol, a β-adrenergic receptor blocker, is the leading treatment for tremor. However, the in vivo circuit mechanisms by which propranolol decreases tremor remain unclear. Here, we test whether propranolol modulates activity in the cerebellum, a key node in the tremor network. We investigated the effects of propranolol in healthy control mice and Car8^wdl/wdl mice, which exhibit pathophysiological tremor and ataxia due to cerebellar dysfunction. Propranolol reduced physiological tremor in control mice and reduced pathophysiological tremor in Car8^wdl/wdl mice to control levels. …

Neurobehavioral Deficits And A Progressive Ictogenesis In The Tetrodotoxin Model Of Epileptic Spasms, John T Le, Carlos J Ballester-Rosado, James D Frost, John W Swann

Duncan NRI Faculty and Staff Publications

Objective: Our goal was to determine whether animals with a history of epileptic spasms have learning and memory deficits. We also used continuous (24/7) long-term electroencephalographic (EEG) recordings to evaluate the evolution of epileptiform activity in the same animals over time.

Methods: Object recognition memory and object location memory tests were undertaken, as well as a matching to place water maze test that evaluated working memory. A retrospective analysis was undertaken of long-term video/EEG recordings from rats with epileptic spasms. The frequency and duration of the ictal events of spasms were quantified.

Results: Rats with a history of epileptic spasms …

Development Of Myelinating Glia: An Overview, Carlo D Cristobal, Hyun Kyoung Lee

Duncan NRI Faculty and Staff Publications

Myelin is essential to nervous system function, playing roles in saltatory conduction and trophic support. Oligodendrocytes (OLs) and Schwann cells (SCs) form myelin in the central and peripheral nervous systems respectively and follow different developmental paths. OLs are neural stem-cell derived and follow an intrinsic developmental program resulting in a largely irreversible differentiation state. During embryonic development, OL precursor cells (OPCs) are produced in distinct waves originating from different locations in the central nervous system, with a subset developing into myelinating OLs. OPCs remain evenly distributed throughout life, providing a population of responsive, multifunctional cells with the capacity to remyelinate …

Seizure Count Forecasting To Aid Diagnostic Testing In Epilepsy, Emily T Wang, Sharon Chiang, Stephen Cleboski, Vikram R Rao, Marina Vannucci, Zulfi Haneef

Faculty, Staff and Students Publications

Objective: Epilepsy monitoring unit (EMU) admissions are critical for presurgical evaluation of drug-resistant epilepsy but may be nondiagnostic if an insufficient number of seizures are recorded. Seizure forecasting algorithms have shown promise for estimating the likelihood of seizures as a binary event in individual patients, but methods to predict how many seizures will occur remain elusive. Such methods could increase the diagnostic yield of EMU admissions and help patients mitigate seizure-related morbidity. Here, we evaluated the performance of a state-space method that uses prior seizure count data to predict future counts.

Methods: A Bayesian negative-binomial dynamic linear model (DLM) was …

Implementation Of Systematic Safety Checklists In A Neurocritical Care Unit: A Quality Improvement Study, César E Escamilla-Ocañas, Gabriel Torrealba-Acosta, Pitchaiah Mandava, Muhammad Suhaib Qasim, Bárbara Gutiérrez-Flores, Eric Bershad, Mohammad Hirzallah, Chethan P Venkatasubba Rao, Rahul Damani

Faculty, Staff and Students Publications

Background and objectives: Structured and systematised checklists have been shown to prevent complications and improve patient care. We evaluated the implementation of systematic safety checklists in our neurocritical care unit (NCCU) and assessed its effect on patient outcomes.

Design/methods: This quality improvement project followed a Plan-Do-Study-Act (PDSA) methodology. A checklist for medication reconciliation, thromboembolic prophylaxis, glycaemic control, daily spontaneous awakening, breathing trial, diet, catheter/lines duration monitoring and antibiotics de-escalation was implemented during daily patient rounds. Main outcomes included the rate of new infections, mortality and NCCU-length of stay (LOS). Intervened patients were compared with historical controls after propensity score and …

K27m In Canonical And Noncanonical H3 Variants Occurs In Distinct Oligodendroglial Cell Lineages In Brain Midline Gliomas, Selin Jessa, Abdulshakour Mohammadnia, Ashot S Harutyunyan, Maud Hulswit, Srinidhi Varadharajan, Hussein Lakkis, Nisha Kabir, Zahedeh Bashardanesh, Steven Hébert, Damien Faury, Maria C Vladoiu, Samantha Worme, Marie Coutelier, Brian Krug, Augusto Faria Andrade, Manav Pathania, Andrea Bajic, Alexander G Weil, Benjamin Ellezam, Jeffrey Atkinson, Roy W R Dudley, Jean-Pierre Farmer, Sebastien Perreault, Benjamin A Garcia, Valérie Larouche, Mathieu Blanchette, Livia Garzia, Aparna Bhaduri, Keith L Ligon, Pratiti Bandopadhayay, Michael D Taylor, Stephen C Mack, Nada Jabado, Claudia L Kleinman

Faculty, Staff and Students Publications

Canonical (H3.1/H3.2) and noncanonical (H3.3) histone 3 K27M-mutant gliomas have unique spatiotemporal distributions, partner alterations and molecular profiles. The contribution of the cell of origin to these differences has been challenging to uncouple from the oncogenic reprogramming induced by the mutation. Here, we perform an integrated analysis of 116 tumors, including single-cell transcriptome and chromatin accessibility, 3D chromatin architecture and epigenomic profiles, and show that K27M-mutant gliomas faithfully maintain chromatin configuration at developmental genes consistent with anatomically distinct oligodendrocyte precursor cells (OPCs). H3.3K27M thalamic gliomas map to prosomere 2-derived lineages. In turn, H3.1K27M ACVR1-mutant pontine gliomas uniformly mirror early ventral …

Hdac2 In Primary Sensory Neurons Constitutively Restrains Chronic Pain By Repressing Α2Δ-1 Expression And Associated Nmda Receptor Activity, Jixiang Zhang, Shao-Rui Chen, Meng-Hua Zhou, Daozhong Jin, Hong Chen, Li Wang, Ronald A Depinho, Hui-Lin Pan

Faculty, Staff and Student Publications

α2δ-1 (encoded by the Cacna2d1 gene) is a newly discovered NMDA receptor-interacting protein and is the therapeutic target of gabapentinoids (e.g., gabapentin and pregabalin) frequently used for treating patients with neuropathic pain. Nerve injury causes sustained α2δ-1 upregulation in the dorsal root ganglion (DRG), which promotes NMDA receptor synaptic trafficking and activation in the spinal dorsal horn, a hallmark of chronic neuropathic pain. However, little is known about how nerve injury initiates and maintains the high expression level of α2δ-1 to sustain chronic pain. Here, we show that nerve injury caused histone hyperacetylation and diminished enrichment of histone deacetylase-2 (HDAC2), …

The Association Of Gabapentin Initiation And Neurocognitive Changes In Older Adults With Normal Cognition, Gyeon Oh, Daniela Claudia Moga, David W. Fardo, Erin L. Abner

Sanders-Brown Center on Aging Faculty Publications

Background: Gabapentin is increasingly prescribed to older adults, which raises concerns about its potential to cause neurocognitive changes. Therefore, we aimed to examine the association of gabapentin use with neurocognitive changes (i.e., cognitive decline, functional status decline, and motor function change) in older adults.

Methods: We conducted a retrospective cohort study using the National Alzheimer’s Coordinating Center Uniform Data Set (UDS; September 2005-March 2021 data freeze). From the eligible sample (≥age 65 years), we identified cognitively normal new-users of gabapentin and the visit they initiated gabapentin (i.e., index visit). Initiators were matched to randomly selected nonusers on year …

Notch Missense Mutations In Drosophila Reveal Functions Of Specific Egf-Like Repeats In Notch Folding, Trafficking, And Signaling, Hilman Nurmahdi, Mao Hasegawa, Elzava Yuslimatin Mujizah, Takeshi Sasamura, Mikiko Inaki, Shinya Yamamoto, Tomoko Yamakawa, Kenji Matsuno

Duncan NRI Faculty and Staff Publications

Notch signaling plays various roles in cell-fate specification through direct cell–cell interactions. Notch receptors are evolutionarily conserved transmembrane proteins with multiple epidermal growth factor (EGF)-like repeats. Drosophila Notch has 36 EGF-like repeats, and while some play a role in Notch signaling, the specific functions of most remain unclear. To investigate the role of each EGF-like repeat, we used 19 previously identified missense mutations of Notch with unique amino acid substitutions in various EGF-like repeats and a transmembrane domain; 17 of these were identified through a single genetic screen. We assessed these mutants’ phenotypes in the nervous system and hindgut during …

Influence Of Data Sampling Methods On The Representation Of Neural Spiking Activity In Vivo, Meike E Van Der Heijden, Amanda M Brown, Roy V Sillitoe

Duncan NRI Faculty and Staff Publications

No abstract provided.

Region-Specific Denoising Identifies Spatial Co-Expression Patterns And Intra-Tissue Heterogeneity In Spatially Resolved Transcriptomics Data, Linhua Wang, Mirjana Maletic-Savatic, Zhandong Liu

Duncan NRI Faculty and Staff Publications

Spatially resolved transcriptomics is a relatively new technique that maps transcriptional information within a tissue. Analysis of these datasets is challenging because gene expression values are highly sparse due to dropout events, and there is a lack of tools to facilitate in silico detection and annotation of regions based on their molecular content. Therefore, we develop a computational tool for detecting molecular regions and region-based Missing value Imputation for Spatially Transcriptomics (MIST). We validate MIST-identified regions across multiple datasets produced by 10x Visium Spatial Transcriptomics, using manually annotated histological images as references. We benchmark MIST against a spatial k-nearest neighboring …

Uncovering The Biological Basis Of Control Energy: Structural And Metabolic Correlates Of Energy Inefficiency In Temporal Lobe Epilepsy, Xiaosong He, Lorenzo Caciagli, Linden Parkes, Jennifer Stiso, Teresa M. Karrer, Jason Z. Kim, Zhixin Lu, Tommaso Menara, Fabio Pasqualetti, Michael R. Sperling, Joseph I. Tracy, Dani S. Bassett

Department of Neurology Faculty Papers

Network control theory is increasingly used to profile the brain's energy landscape via simulations of neural dynamics. This approach estimates the control energy required to simulate the activation of brain circuits based on structural connectome measured using diffusion magnetic resonance imaging, thereby quantifying those circuits' energetic efficiency. The biological basis of control energy, however, remains unknown, hampering its further application. To fill this gap, investigating temporal lobe epilepsy as a lesion model, we show that patients require higher control energy to activate the limbic network than healthy volunteers, especially ipsilateral to the seizure focus. The energetic imbalance between ipsilateral and …

Two Neuronal Peptides Encoded From A Single Transcript Regulate Mitochondrial Complex Iii In Drosophila, Justin A Bosch, Berrak Ugur, Israel Pichardo-Casas, Jordan Rabasco, Felipe Escobedo, Zhongyuan Zuo, Ben Brown, Susan Celniker, David A Sinclair, Hugo J Bellen, Norbert Perrimon

Duncan NRI Faculty and Staff Publications

Naturally produced peptides (<100 amino acids) are important regulators of physiology, development, and metabolism. Recent studies have predicted that thousands of peptides may be translated from transcripts containing small open-reading frames (smORFs). Here, we describe two peptides in Drosophila encoded by conserved smORFs, Sloth1 and Sloth2. These peptides are translated from the same bicistronic transcript and share sequence similarities, suggesting that they encode paralogs. Yet, Sloth1 and Sloth2 are not functionally redundant, and loss of either peptide causes animal lethality, reduced neuronal function, impaired mitochondrial function, and neurodegeneration. We provide evidence that Sloth1/2 are highly expressed in neurons, imported to mitochondria, and regulate mitochondrial complex III assembly. These results suggest that phenotypic analysis of smORF genes in Drosophila can provide a wealth of information on the biological functions of this poorly characterized class of …