Digital Commons Network^™

Multi-Omics Delineate Growth Factor Network Underlying Exercise Effects In An Alzheimer’S Mouse Model, Xin Li, Chaozhong Liu, Wenbo Li, Guantong Qi, Yanwan Dai, Chaohao Gu, Yuxiang Sun, Wenjun Zhou, Veronica C Ciliberto, Jing Liang, Udhaya Kumar S, Dongyin Guan, Zhaoyong Hu, Hui Zheng, Zhandong Liu, Hu Chen, Ying-Wooi Wan, Zheng Sun

Duncan NRI Faculty and Staff Publications

Introduction: Physical exercise is a primary defense against age-related cognitive decline and Alzheimer's disease (AD).

Methods: We conducted single-nucleus transcriptomic and chromatin accessibility analyses (snRNA-seq and snATAC-seq) on the hippocampus of mice carrying mutations in the amyloid precursor protein gene (APPNL-G-F) following prolonged voluntary wheel-running exercise.

Results: Exercise mitigates amyloid-induced changes in transcriptome and chromatin accessibility through cell type-specific regulatory networks converging on growth factor signaling, particularly the epidermal growth factor receptor (EGFR) signaling. The beneficial effects of exercise on neurocognition can be blocked by pharmacological inhibition of EGFR and its downstream PI3K signaling. Exercise leads to elevated levels of …

Reevaluating Anti-Inflammatory Therapy: Targeting Senescence To Balance Anti-Cancer Efficacy And Vascular Disease, Bernardo Casso-Chapa, Norma Alicia Vazquez González, Nhat-Tu Le, Nicolas L Palaskas, Kevin T Nead, Lydia P Eutsey, Venkata S K Samanthapudi, Abigail M Osborn, Jonghae Lee, Gilbert Mejia, Oanh Hoang, Steven H Lin, Anita Deswal, Joerg Herrmann, Guangyu Wang, James L Kirkland, Sunil Krishnan, Xander H T Wehrens, Eduardo N Chini, Syed Wamique Yusuf, Cezar A Iliescu, Abhishek Jain, Jared K Burks, Erin Seeley, Philip L Lorenzi, Khanh M Chau, Keila C Ostos-Mendoza, Isabella M Grumbach, Paul S Brookes, Nordin M J Hanssen, Menno P J De Winther, Laurent Yvan-Charvet, Sivareddy Kotla, Keri Schadler, Jun-Ichi Abe

The Brown Foundation: Institute of Molecular Medicine

Modulating immune function is a critical strategy in cancer and atherosclerosis treatments. For cancer, boosting or maintaining the immune system is crucial to prevent tumor growth. However, in vascular disease, mitigating immune responses can decrease inflammation and slow atherosclerosis progression. Anti-inflammatory therapy, therefore, presents a unique dilemma for cancer survivors: while it may decrease cardiovascular risk, it might also promote cancer growth and metastasis by suppressing the immune response. Senescence presents a potentially targetable solution to this challenge; senescence increases the risk of both cancer therapy resistance and vascular disease. Exercise, notably, shows promise in delaying this premature senescence, potentially …

Quantitative Profiling Ph Heterogeneity Of Acidic Endolysosomal Compartments Using Fluorescence Lifetime Imaging Microscopy, Dinghuan Deng, Youchen Guan, Ayse Sena Mutlu, Baiping Wang, Shihong Max Gao, Hui Zheng, Meng C Wang

Center on Aging Staff Publications

The endolysosomal system plays a crucial role in maintaining cellular homeostasis and promoting organism fitness. The pH of its acidic compartments is a crucial parameter for proper function, and it is dynamically influenced by both intracellular and environmental factors. Here, we present a method based on fluorescence lifetime imaging microscopy (FLIM) for quantitatively analyzing the pH profiles of acidic endolysosomal compartments in diverse types of primary mammalian cells and in live organism Caenorhabditis elegans. This FLIM-based method exhibits high sensitivity in resolving subtle pH differences, thereby revealing heterogeneity within a cell and across cell types. This method enables rapid …

Decreased Voluntary Alcohol Intake And Ventral Striatal Epigenetic And Transcriptional Remodeling In Male Acss2 Ko Mice, Gabor Egervari, Greg Donahue, Natalia A Quijano Cardé, Desi C Alexander, Connor Hogan, Jessica K Shaw, Erica M Periandri, Vanessa Fleites, Mariella De Biasi, Shelley L Berger

2020-Current year OA Pubs

Metabolic-epigenetic interactions are emerging as key pathways in regulating alcohol-related transcriptional changes in the brain. Recently, we have shown that this is mediated by the metabolic enzyme Acetyl-CoA synthetase 2 (Acss2), which is nuclear and chromatin-bound in neurons. Mice lacking ACSS2 fail to deposit alcohol-derived acetate onto histones in the brain and show no conditioned place preference for ethanol reward. Here, we further explored the role of this pathway during voluntary alcohol intake. We found that Acss2 KO mice consume significantly less alcohol in a model of binge drinking, an effect primarily driven by males. Genome-wide transcriptional profiling of 7 …

Impact Of Mass Drug Administration With Ivermectin, Diethylcarbamazine, And Albendazole For Lymphatic Filariasis On Hookworm And Strongyloides Stercoralis Infections In Papua New Guinea, Jannet A. Tobon Ramos, Tobias Maure, Lenore Carias, Daphne Lew, Charles Goss, Anna Samuel, Livingstone Tavul, Peter U. Fischer, Gary J. Weil, Moses Laman, Leanne J. Robinson, William Pomat, Christopher L. King

2020-Current year OA Pubs

BACKGROUND: Persons with lymphatic filariasis (LF) are often co-infected with soil-transmitted helminths. A single co-administered dose of ivermectin/diethylcarbamazine/albendazole (IDA) is recommended by WHO for mass drug administration (MDA) for LF instead of diethylcarbamazine/albendazole (DA) in Papua New Guinea (PNG). We compared the effectiveness of a single round of MDA with IDA or DA on hookworm and strongyloidiasis in PNG.

METHODOLOGY/PRINCIPAL FINDINGS: This study was conducted as part of a cluster randomized trial of MDA with IDA versus DA for LF in individuals willing to provide stool and blood samples at baseline and 12 months after MDA. Participants from 23 villages …

Spatial Proteomics Of Onchocerca Volvulus With Pleomorphic Neoplasms Shows Local And Systemic Dysregulation Of Protein Expression, Lucia S. Di Maggio, Kerstin Fischer, Bruce A. Rosa, Devyn Yates, Byoung-Kyu Cho, Jessica Lukowski, Antonia Zamacona Calderon, Minsoo Son, Young Ah Goo, Nicholas O. Opoku, Gary J. Weil, Makedonka Mitreva, Peter U. Fischer

2020-Current year OA Pubs

Onchocerca volvulus is the agent of onchocerciasis (river blindness) and targeted by WHO for elimination though mass drug administration with ivermectin. A small percentage of adult female worms develop pleomorphic neoplasms (PN) which occur more frequently after ivermectin treatment. Worms with PN have a lower life expectancy and improved understanding of proteins expressed in PN and their impact on different tissues could help elucidate the mechanisms of macrofilaricidal activity of ivermectin. Within paraffin embedded nodules removed after ivermectin treatment, we detected 24 (5.6%) O. volvulus females with PN. To assess the protein inventory of the PN and identify proteins potentially …

Integrative Analysis Of The 3d Genome And Epigenome In Mouse Embryonic Tissues, Miao Yu, Yang E Li, Et Al.

2020-Current year OA Pubs

While a rich set of putative cis-regulatory sequences involved in mouse fetal development have been annotated recently on the basis of chromatin accessibility and histone modification patterns, delineating their role in developmentally regulated gene expression continues to be challenging. To fill this gap, here we mapped chromatin contacts between gene promoters and distal sequences across the genome in seven mouse fetal tissues and across six developmental stages of the forebrain. We identified 248,620 long-range chromatin interactions centered at 14,138 protein-coding genes and characterized their tissue-to-tissue variations and developmental dynamics. Integrative analysis of the interactome with previous epigenome and transcriptome datasets …

Rest And Rinse: Sleeping Rhythms Drive Brain Detox, Leon C D Smyth, Benjamin A Plog, Jonathan Kipnis

2020-Current year OA Pubs

Sleep is a major driver of waste clearance from the brain, but the mechanisms underpinning brain cleansing during sleep, which are also important for immunological functions, are poorly understood. Recent mouse work by Hauglund et al. shows how oscillatory surges in norepinephrine (NE) during sleep drive vascular pulsation and cerebrospinal fluid (CSF) movement to cleanse the brain.

Genetically Engineered Brain Organoids Recapitulate Spatial And Developmental States Of Glioblastoma Progression, Matthew Ishahak, Rowland H Han, Devi Annamalai, Timothy Woodiwiss, Colin Mccornack, Ryan T Cleary, Patrick A Desouza, Xuan Qu, Sonika Dahiya, Albert H Kim, Jeffrey R Millman

2020-Current year OA Pubs

Glioblastoma (GBM) is an aggressive form of brain cancer that is highly resistant to therapy due to significant intra-tumoral heterogeneity. The lack of robust in vitro models to study early tumor progression has hindered the development of effective therapies. Here, this study develops engineered GBM organoids (eGBOs) harboring GBM subtype-specific oncogenic mutations to investigate the underlying transcriptional regulation of tumor progression. Single-cell and spatial transcriptomic analyses revealed that these mutations disrupt normal neurodevelopment gene regulatory networks resulting in changes in cellular composition and spatial organization. Upon xenotransplantation into immunodeficient mice, eGBOs form tumors that recapitulate the transcriptional and spatial landscape …

Endothelial Cell Piezo1 Promotes Vascular Smooth Muscle Cell Differentiation On Large Arteries, Javier Abello, Ying Yin, Yonghui Zhao, Josh Maurer, Jihui Lee, Cherokee Bodell, Jahmiera Richee, Zarek Burton, Megan E Goeckel, Michelle Lin, Carmen M Halabi, Rajan Sah, Amber N Stratman, Et Al.

2020-Current year OA Pubs

Vascular stabilization is a mechanosensitive process, in part driven by blood flow. Here, we demonstrate the involvement of the mechanosensitive ion channel, Piezo1, in promoting arterial accumulation of vascular smooth muscle cells (vSMCs) during zebrafish development. Using a series of small molecule antagonists or agonists to temporally regulate Piezo1 activity, we identified a role for the Piezo1 channel in regulating klf2a, a blood flow responsive transcription factor, expression levels and altered targeting of vSMCs between arteries and veins. Increasing Piezo1 activity suppressed klf2a and increased vSMC association with the cardinal vein, while inhibition of Piezo1 activity increased klf2a levels and …

Sacubitril/Valsartan Attenuates Inflammation And Myocardial Fibrosis In Takotsubo-Like Cardiomyopathy, Jiangying Kuang, Zhiyi Jia, Tou Kun Chong, Jian Chen, Kan Liu, Xin Wang, Zhaohua Li, Jing Zhang, Yanru Kong, Lin Deng, Martin Cadieras, Yuanyuan Sun, Rong Sun, Qinghua Lu, Yusheng Liu

2020-Current year OA Pubs

BACKGROUND: Takotsubo syndrome (TTS) primarily manifests as a cardiomyopathy induced by physical or emotional stress, remains a poorly understood condition with no established treatments. In this study, we investigated the potential of sacubitril/valsartan (sac/val) to increase the survival of TTS patients and reduce inflammation and myocardial fibrosis in experimental models.

AIM: This study aimed to evaluate whether sac/val could improve survival rates in TTS patients, mitigate cardiac remodeling in vivo, and explore its anti-inflammatory and antifibrotic mechanisms in vitro.

METHODS: Clinical cases from the Chinese Takotsubo syndrome (ChiTTS) registry were analyzed to assess patient survival rates. In addition, we used …

Convergence On Camk4: A Key Modulator Of Autism-Associated Signaling Pathways In Neurons, Jacqueline Kaiser, Alana Risteska, Abbey G Muller, Haoxiong Sun, Bethany Lei, Kevin Nay, Anthony R Means, Margot A Cousin, David H Drewry, Jonathan S Oakhill, Bruce E Kemp, Anthony J Hannan, Michael Berk, Mark A Febbraio, Andrew L Gundlach, Elisa L Hill-Yardin, John W Scott

Faculty, Staff and Students Publications

Although the precise underlying cause(s) of autism spectrum disorder remain unclear, more than 1000 rare genetic variations are associated with the condition. For many people living with profound autism, this genetic heterogeneity has impeded the identification of common biological targets for therapy development for core and comorbid traits that include significant impairments in social communication and repetitive and restricted behaviors. A substantial number of genes associated with autism encode proteins involved in signal transduction and synaptic transmission that are critical for brain development and function. CAMK4 is an emerging risk gene for autism spectrum disorder that encodes the CaMK4 (calcium/calmodulin-dependent …

Thalamic Deep Brain Stimulation Improves Movement In A Cerebellar Model Of Lesion-Based Status Dystonicus, Megan X Nguyen, Amanda M Brown, Tao Lin, Roy V Sillitoe, Jason S Gill

Faculty, Staff and Students Publications

Dystonia is the third most common movement disorder and an incapacitating co-morbidity in a variety of neurologic conditions. Dystonia can be caused by genetic, degenerative, idiopathic, and acquired etiologies, which are hypothesized to converge on a "dystonia network" consisting of the basal ganglia, thalamus, cerebellum, and cerebral cortex. In acquired dystonia, focal lesions to subcortical network regions lead to dystonia that can be difficult to manage with canonical treatments, including deep brain stimulation (DBS). While studies in animal models have begun to parse the contribution of individual nodes in the dystonia network, how acquired injury to the cerebellar outflow tracts …

Altered Thermal Preference By Preoptic Estrogen Receptor Alpha Neurons In Postpartum Females, Nan Zhang, Meng Yu, Qianru Zhao, Bing Feng, Yue Deng, Jonathan C Bean, Qingzhuo Liu, Benjamin P Eappen, Yang He, Kristine M Conde, Hailan Liu, Yongjie Yang, Longlong Tu, Mengjie Wang, Yongxiang Li, Na Yin, Hesong Liu, Junying Han, Darah Ave Threat, Nathan Xu, Taylor Smiley, Pingwen Xu, Lulu Chen, Tianshu Zeng, Yanlin He, Chunmei Wang

Faculty, Staff and Students Publications

OBJECTIVE: This study aims to investigate how reproductive experience (RE) alters thermal preference and thermoregulation in female mice, with a focus on estrogen receptor alpha (ERα)-expressing neurons in the preoptic area (POA).

METHODS: Thermal preference and body temperature were measured in female mice with and without RE, and virgin female mice with selective deletion of ERα from the POA (ERα

RESULTS: We showed that female mice prefer a cooler environment starting from late pregnancy and persisting long term postpartum. Female mice with RE (>4 weeks post-weaning) displayed lower body temperature and a lower thermal preferred temperature, and lost preference …

Visible Light Polarization-Sensitive Optical Coherence Tomography With Balanced Detection, Bahar Baradaran, Adam J Black, Sarah R Heilbronner, Taner Akkin

Faculty, Staff and Students Publications

Significance: We introduce a visible-light polarization-sensitive optical coherence tomography (PS-OCT) system that operates in the spectral domain with balanced detection (BD) capability. While the BD improves the signal-to-noise ratio (SNR), the use of shorter wavelengths improves spatial resolution and birefringence sensitivity.

Aim: We aim to implement a new optical design, characterize its performance, and investigate the imaging potential for biological tissues.

Approach: The design utilizes a unique interferometer and a custom spectrometer that captures four highly aligned spectra with a single area/multi-line camera. Each pair of spectral lines is highly aligned, and their subtraction yields balanced detected spectra of the …

Fructose Induces Inflammatory Activation In Macrophages And Microglia Through The Nutrient-Sensing Ghrelin Receptor, Zheng Shen, Zeyu Liu, Hongying Wang, Danilo Landrock, Ji Yeon Noh, Qun Sophia Zang, Chih-Hao Lee, Yuhua Z Farnell, Zheng Chen, Yuxiang Sun

Faculty, Staff and Student Publications

High fructose corn syrup (HFCS) is a commonly used sweetener in soft drinks and processed foods, and HFCS exacerbates inflammation when consumed in excess. Fructose, a primary component of HFCS; however, it is unclear whether fructose directly activates inflammatory signaling. Growth hormone secretagogue receptor (GHSR) is a receptor of the nutrient‐sensing hormone ghrelin. We previously reported that GHSR ablation mitigates HFCS‐induced inflammation in adipose tissue and liver, shifting macrophages toward an anti‐inflammatory spectrum. Since inflammation is primarily governed by innate immune cells, such as macrophages in the peripheral tissues and microglia in the brain, this study aims to investigate whether …

Androgen Receptor Ubiquitination Links Kctd13 To Genitourinary Tract Defects, Ahmed Chahdi, Carolina Jorgez, Jill A Rosenfeld, Neetu Neetu, Abhishek Seth

Faculty, Staff and Students Publications

The potassium channel tetramerization domain containing 13 (KCTD13) protein is a substrate-specific adapter for cullin3-based E3 ubiquitin ligase. Patients with copy number variants at this locus exhibit genitourinary tract anomalies. In this study, we show that decreased androgen receptor (AR) protein level correlated with increased AR ubiquitination in the testis of Kctd13-deficient mice, suggesting that KCTD13 inhibits AR ubiquitination. KCTD13 increased CUL3-dependent AR ubiquitination but had no effect on CUL3 binding to AR, confirming the role of KCTD13 as an adaptor of CUL3 ligase. Recombinant KCTD13 directly binds to recombinant AR, and the BTB domain of KCTD13 is critical for …

Chemogenetic Activation Of Microglial Gi Signaling Decreases Microglial Surveillance And Impairs Neuronal Synchronization, Shunyi Zhao, Lingxiao Wang, Dimitrios Kleidonas, Fangfang Qi, Yue Liang, Jiaying Zheng, Anthony D Umpierre, Long-Jun Wu

Faculty, Staff and Student Publications

Microglia actively survey the brain and dynamically interact with neurons to maintain brain homeostasis. Microglial Gi protein-coupled receptors (Gi-GPCRs) play a critical role in microglia-neuron communications. However, the impact of temporally activating microglial Gi signaling on microglial dynamics and neuronal activity in the homeostatic brain remains largely unknown. In this study, we used Gi-based designer receptors exclusively activated by designer drugs (Gi-DREADD) to selectively and temporally modulate microglial Gi signaling pathway. By integrating this chemogenetic approach with in vivo two-photon imaging, we observed that exogenous activation of microglial Gi signaling transiently inhibited microglial process dynamics, reduced neuronal activity, and impaired …

Muscle-Specific Errγ Activation Mitigates Muscle Atrophy After Acl Injury, Aiping Lu, Katie J Sikes, Ping Guo, Matthieu Huard, Shelbi Green, Kelly Santangelo, Jacob Singer, Ashley Groesbeck, Scott Tashman, Vihang A Narkar, Johnny Huard

Faculty, Staff and Student Publications

Anterior cruciate ligament (ACL) injury adversely affects skeletal muscle, leading to muscle atrophy and weakness, significantly impacting clinical outcomes. This study aimed to determine if estrogen-related receptor gamma (ERRγ) overexpression in skeletal muscle could mitigate muscle atrophy after ACL injury. An animal model with selective overexpression of ERRγ in skeletal muscle (ERR-gamma transgenic mice, TG) and WT control mice were used for this study. All the mice received a mechanical ACL rupture and were euthanized at 4- and 8-week post-injury. Muscle histology, atrophy, and function were evaluated and compared between the TG and WT mice. Muscle-specific ERRγ activation in TG …

Norovirus Co-Opts Ninj1 For Selective Protein Secretion, Jaewon Song, Wandy L Beatty, Anthony Orvedahl, Et Al.

2020-Current year OA Pubs

Plasma membrane rupture by Ninjurin-1 (NINJ1) executes programmed cell death, releasing large cellular damage-associated molecular patterns (DAMPs). However, the regulation and selectivity of NINJ1-mediated DAMP release remain unexplored. Here, we uncover that murine norovirus (MNoV) strategically co-opts NINJ1 to selectively release the intracellular viral protein NS1, while NINJ1-mediated plasma membrane rupture simultaneously bulk-releases various cellular DAMPs. Host caspase-3 cleaves the precursor NS1/2, leading to NS1 secretion via an unconventional pathway. An unbiased CRISPR screen identifies NINJ1 as an essential factor for NS1 secretion. During infection, NINJ1 is recruited to the viral replication site, where it oligomerizes and forms speckled bodies, …

Myelin-Reactive Cd8+ T Cells Influence Conventional Dendritic Cell Subsets Towards A Mature And Regulatory Phenotype In Experimental Autoimmune Encephalomyelitis, Mohit Upadhye, Connor R Wilhelm, Kai J Rogers, Chakrapani Vemulawada, Nicholas Borcherding, Alexander W Boyden, Kevin L Legge, Nitin J Karandikar

2020-Current year OA Pubs

Multiple sclerosis (MS), an autoimmune demyelinating disease of the central nervous system, is modeled in mice as experimental autoimmune encephalomyelitis (EAE). While CD4

Inhibition Of Il-6 Trans-Signaling Promotes Post-Stroke Functional Recovery In A Sex And Dose-Dependent Manner, Cassandra Hall, Dustin T Nguyen, Kate Mendoza, Chunfeng Tan, Anjali Chauhan

Faculty, Staff and Student Publications

Introduction: Elevated circulating IL-6 levels are associated with poorer outcomes after stroke, and increased serum IL-6 levels are linked to a higher risk of stroke. IL-6 binds to soluble IL-6 receptors (sIL-6R) and subsequently to ubiquitously expressed gp130, initiating proinflammatory trans-signaling. This study tested the hypothesis that inhibiting IL-6 trans-signaling by administering soluble (s) gp130 improves long-term functional outcomes in young mice after stroke.

Methods: Recombinant mouse gp130Fc chimera (sgp130) was administered one hour after middle cerebral artery occlusion (MCAO) followed by twice-weekly administration for 2 weeks in mice (8-15 weeks old). Behavioral assessments were done on days 7 and …

Ultrasound-Triggered Release Of Vancomycin From A Novel Spinal Device: Antibiotic Release And Efficacy In Vivo, Lauren J. Delaney, Priscilla Machado, Ji-Bin Liu, Rachel Evans, Asia Winslow, Neil Zhao, Christopher K. Kepler, Rajkishen Narayanan, Teeto Ezeonu, Viren Soni, Gagan Kaushal, Rachel Hilliard, Thomas P. Schaer, Noreen J. Hickok, Flemming Forsberg

Department of Orthopaedic Surgery Faculty Papers

Post-surgical spinal infection occurs in up to 20 % of patients, despite aggressive peri-operative antibiotic treatments. To improve prophylaxis, we have designed and evaluated an ultrasound-activated prophylactic antibiotic release system to combat post-surgical bacterial survival. Polylactic acid (PLA) clips (1 cm³) were 3D-printed with an interior reservoir (0.8 cm³) for carrying drug payload, specifically vancomycin (VAN). Under IACUC approval, clips were surgically implanted into the spines of sheep (n = 9) and swine (n = 2) by removing the spinous process at several levels of the lumbar spine. In the sheep, clips were insonated and the …

Loss Of Mucin 2 And Mhc Ii Molecules Causes Rare Resistance To Murine Rv Infection, Carolyn Bomidi, Faith M Sawyer, Noah Shroyer, Margaret Conner, Mary K Estes, Sarah E Blutt

Faculty, Staff and Students Publications

Enteric pathogen rotavirus (RV) primarily infects mature enterocytes at the tips of the intestinal villi; however, the role of secretory Paneth and goblet cells in RV pathogenesis remains unappreciated. Atoh1 knockout mice (Atoh1cKO) were used to conditionally delete Paneth, goblet, and enteroendocrine cells in the epithelium to investigate the role of secretory cells in RV infection. Unexpectedly, the number of infected enterocytes and the amount of RV shedding in the stool were greatly decreased following secretory cell deletion. Resistance to RV infection persisted for 7 days after virus inoculation, and Atoh1 knockout mice co-housed with infected wild-type mice were uninfected, …

The Hao-Fountain Syndrome Protein Usp7 Regulates Neuronal Connectivity In The Brain Via A Novel P53-Independent Ubiquitin Signaling Pathway, Hao Chen, Cole J Ferguson, Dylan C Mitchell, Isabel Risch, Amanda Titus, Joao A Paulo, Andrew Hwang, Loren K Beck, Tsen-Hsuan Lin, Sheng-Kwei Song, Carla M Yuede, Hiroko Yano, Obi L Griffith, Malachi Griffith, Steven P Gygi, Azad Bonni, Albert H Kim, Et Al.

2020-Current year OA Pubs

Mutation or deletion of the deubiquitinase USP7 causes Hao-Fountain syndrome (HAFOUS), which is characterized by speech delay, intellectual disability, and aggressive behavior and highlights important unknown roles of USP7 in the nervous system. Here, we conditionally delete USP7 in glutamatergic neurons in the mouse forebrain, triggering disease-relevant phenotypes, including sensorimotor deficits, impaired cognition, and aggressive behavior. Although USP7 deletion induces p53-dependent neuronal apoptosis, most behavioral abnormalities in USP7 conditional knockout mice persist following p53 loss. Strikingly, USP7 deletion perturbs the synaptic proteome and dendritic spinogenesis independent of p53. Integrated proteomics and biochemical analyses identify the RNA splicing factor Ppil4 as …

Phospho-Relay Feedback Loops Control Egress Vs. Intracellular Development In Toxoplasma Gondii, Ja E Claywell, Yong Fu, L David Sibley

2020-Current year OA Pubs

The intracellular parasite Toxoplasma gondii alternates between a motile invasive and a quiescent intracellular replicative form, yet how these transitions are regulated is unknown. A positive feedback loop involving protein kinase G (PKG) and calcium-dependent PKs (CDPKs) controls motility, invasion, and egress by Toxoplasma gondii, while PKA isoform c1 (PKAc1) counteracts this pathway. Shortly after invasion, PKAc1 is activated by cyclic AMP (cAMP) produced by adenylate cyclases, leading to the suppression of the PKG/CDPK pathway. PKAc1 further activates phosphodiesterase 2, which selectively consumes cAMP, thus forming a negative feedback loop, causing transient activation of PKAc1. Perturbation of cyclic GMP (cGMP) …

Plant-Based, Fast-Food, Western-Contemporary, And Animal-Based Dietary Patterns And Risk Of Premature Aging In Adult Survivors Of Childhood Cancer: A Cross-Sectional Study, Tuo Lan, Mei Wang, Annalynn M Williams, Matthew J Ehrhardt, Jennifer Q Lanctot, Shu Jiang, Kevin R Krull, Gregory T Armstrong, Melissa M Hudson, Graham A Colditz, Leslie L Robison, Kirsten K Ness, Yikyung Park

2020-Current year OA Pubs

BACKGROUND: Although premature aging is a significant concern in adult survivors of childhood cancer, little is known about the role of diet in premature aging in this vulnerable population. Therefore, we examined whether dietary patterns specific to childhood cancer survivors are associated with premature aging.

METHODS: This cross-sectional study included 2904 adult survivors of childhood cancer (mean age = 31 years, SD = 8 years) in the St. Jude Lifetime Cohort. Diet was assessed using a food frequency. Four dietary patterns were identified: (1) plant-based diet pattern high in whole grains, fruit, and vegetables; (2) fast-food diet pattern high in …

Atp-Sensitive Potassium Channels Alter Glycolytic Flux To Modulate Cortical Activity And Sleep, Nicholas J Constantino, Caitlin M Carroll, Holden C Williams, Hemendra J Vekaria, Carla M Yuede, Kai Saito, Patrick W Sheehan, J Andy Snipes, Marcus E Raichle, Erik S Musiek, Patrick G Sullivan, Josh M Morganti, Lance A Johnson, Shannon L Macauley

2020-Current year OA Pubs

Metabolism plays a key role in the maintenance of sleep/wake states. Brain lactate fluctuations are a biomarker of sleep/wake transitions, where increased interstitial fluid (ISF) lactate levels are associated with wakefulness and decreased ISF lactate is required for sleep. ATP-sensitive potassium (K

Mapping Snorna-Target Rna Interactions In An Rna-Binding Protein-Dependent Manner With Chimeric Eclip, Zhuoyi Song, Bongmin Bae, Simon Schnabl, Fei Yuan, Thareendra De Zoysa, Maureen V Akinyi, Charlotte A Le Roux, Karine Choquet, Amanda J Whipple, Eric L Van Nostrand

Faculty, Staff and Students Publications

Background: Small nucleolar RNAs (snoRNAs) are non-coding RNAs that function in ribosome and spliceosome biogenesis, primarily by guiding modifying enzymes to specific sites on ribosomal RNA (rRNA) and spliceosomal RNA (snRNA). However, many orphan snoRNAs remain uncharacterized, with unidentified or unvalidated targets, and studies on additional snoRNA-associated proteins are limited.

Results: We adapted an enhanced chimeric eCLIP approach to comprehensively profile snoRNA-target RNA interactions using both core and accessory snoRNA-binding proteins as baits. Using core snoRNA-binding proteins, we confirmed most annotated snoRNA-rRNA and snoRNA-snRNA interactions in mouse and human cell lines and called novel, high-confidence interactions for orphan snoRNAs. While …

Tifab Modulates Metabolic Pathways In Kmt2a::Mllt3-Induced Aml Through Hnf4a, Yang Wang, Yan Xiu, Qianze Dong, Jinming Zhao, Kelao Neumbo, Masaru Miyagi, Nicholas Borcherding, Lin Fu, Havana De Celis, Nicolas Pintozzi, Daniel T Starczynowski, Chen Zhao

2020-Current year OA Pubs

Tumor necrosis factor (TNF) receptor-associated factor (TRAF)-interacting protein with forkhead-associated domain B (TIFAB), an inhibitor of NF-κB signaling, plays critical roles in hematopoiesis, myelodysplastic neoplasms, and leukemia. We previously demonstrated that Tifab enhances KMT2A::MLLT3-driven acute myeloid leukemia (AML) by either upregulating Hoxa9 or through ubiquitin-specific peptidase 15-mediated downregulation of p53 signaling. In this study, we show that Tifab deletion in KMT2A::MLLT3-induced AML impairs leukemia stem/progenitor cell (LSPC) engraftment, glucose uptake, and mitochondrial function. Gene set enrichment analysis reveals that Tifab deletion downregulates MYC, HOXA9/MEIS1, mTORC1 signaling, and genes involved in glycolysis and oxidative phosphorylation. By comparing genes upregulated in TIFAB-overexpressing …