Digital Commons Network^™

Bi-Directional Allosteric Pathway In Nmda Receptor Activation And Modulation, Paula A Bender, Subhajit Chakraborty, Ryan J Durham, Vladimir Berka, Elisa Carrillo, Vasanthi Jayaraman

Faculty, Staff and Student Publications

N-methyl-D-aspartate (NMDA) receptors are ionotropic glutamate receptors involved in learning and memory. NMDA receptors primarily comprise two GluN1 and two GluN2 subunits. The GluN2 subunit dictates biophysical receptor properties, including the extent of receptor activation and desensitization. GluN2A- and GluN2D-containing receptors represent two functional extremes. To uncover the conformational basis of their functional divergence, we utilize single-molecule fluorescence resonance energy transfer to probe the extracellular domains of these receptor subtypes under resting and ligand-bound conditions. We find that the conformational profile of the GluN2 amino-terminal domain correlates with the disparate functions of GluN2A- and GluN2D-containing receptors. Changes at the pre-transmembrane …

Genetic Knock-In Of Eif2ak3 Variants Reveals Differences In Perk Activity In Mouse Liver And Pancreas Under Endoplasmic Reticulum Stress, Shivesh Ghura, Noah R. Beratan, Xinglong Shi, Elena Alvarez-Periel, Sarah E. Bond Newton, Cagla Akay-Espinoza, Kelly L. Jordan-Sciutto

Farber Institute for Neuroscience Staff Papers and Presentations

Common single-nucleotide variants (SNVs) of eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3) slightly increase the risk of disorders in the periphery and the central nervous system. EIF2AK3 encodes protein kinase RNA-like endoplasmic reticulum kinase (PERK), a key regulator of ER stress. Three exonic EIF2AK3 SNVs form the PERK-B haplotype, which is present in 28% of the global population. Importantly, the precise impact of these SNVs on PERK activity remains elusive. In this study, we demonstrate that PERK-B SNVs do not alter PERK expression or basal activity in vitro and in the novel triple knock-in mice expressing the exonic …

Tca Metabolism Regulates Dna Hypermethylation In Lps And Mycobacterium Tuberculosis–Induced Immune Tolerance, Abhimanyu, Santiago Carrero Longlax, Tomoki Nishiguchi, Malik Ladki, Daanish Sheikh, Amera L Martinez, Emily M Mace, Sandra L Grimm, Thaleia Caldwell, Alexandra Portillo Varela, Rajagopal V Sekhar, Anna M Mandalakas, Mandla Mlotshwa, Sibuse Ginidza, Jeffrey D Cirillo, Robert S Wallis, Mihai G Netea, Reinout Van Crevel, Cristian Coarfa, Andrew R Dinardo

Faculty, Staff and Students Publications

Severe and chronic infections, including pneumonia, sepsis, and tuberculosis (TB), induce long-lasting epigenetic changes that are associated with an increase in all-cause postinfectious morbidity and mortality. Oncology studies identified metabolic drivers of the epigenetic landscape, with the tricarboxylic acid (TCA) cycle acting as a central hub. It is unknown if the TCA cycle also regulates epigenetics, specifically DNA methylation, after infection-induced immune tolerance. The following studies demonstrate that lipopolysaccharide and Mycobacterium tuberculosis induce changes in DNA methylation that are mediated by the TCA cycle. Infection-induced DNA hypermethylation is mitigated by inhibitors of cellular metabolism (rapamycin, everolimus, metformin) and the TCA …

Flagellar Motility Is Mutagenic, Souvik Bhattacharyya, Shelby Lopez, Abhyudai Singh, Rasika M Harshey

Faculty, Staff and Student Publications

Flagella are highly complex rotary molecular machines that enable bacteria to not only migrate to optimal environments but also to promote range expansion, competitiveness, virulence, and antibiotic survival. Flagellar motility is an energy-demanding process, where the sum of its production (biosynthesis) and operation (rotation) costs has been estimated to total ~10% of the entire energy budget of an

Atr Inhibition Radiosensitizes Cells Through Augmented Dna Damage And G2 Cell Cycle Arrest Abrogation, Scott J Bright, Mandira Manandhar, David B Flint, Rishab Kolachina, Mariam Ben Kacem, David Kj Martinus, Broderick X Turner, Ilsa Qureshi, Conor H Mcfadden, Poliana C Marinello, Simona F Shaitelman, Gabriel O Sawakuchi

Faculty, Staff and Student Publications

Ataxia telangiectasia and Rad3-related protein (ATR) is a key DNA damage response protein that facilitates DNA damage repair and regulates cell cycle progression. As such, ATR is an important component of the cellular response to radiation, particularly in cancer cells, which show altered DNA damage response and aberrant cell cycle checkpoints. Therefore, ATR's pharmacological inhibition could be an effective radiosensitization strategy to improve radiotherapy. We assessed the ability of an ATR inhibitor, AZD6738, to sensitize cancer cell lines of various histologic types to photon and proton radiotherapy. We found that radiosensitization took place through persistent DNA damage and abrogated G2 …

Alzheimer’S Disease Risk Gene Cd2ap Is A Dose-Sensitive Determinant Of Synaptic Structure And Plasticity, Matea Pavešković, Ruth B De-Paula, Shamsideen A Ojelade, Evelyne K Tantry, Mikhail Y Kochukov, Suyang Bao, Surabi Veeraragavan, Alexandra R Garza, Snigdha Srivastava, Si-Yuan Song, Masashi Fujita, Duc M Duong, David A Bennett, Philip L De Jager, Nicholas T Seyfried, Mary E Dickinson, Jason D Heaney, Benjamin R Arenkiel, Joshua M Shulman

Duncan NRI Faculty and Staff Publications

CD2-Associated protein (CD2AP) is a candidate susceptibility gene for Alzheimer's disease, but its role in the mammalian central nervous system remains largely unknown. We show that CD2AP protein is broadly expressed in the adult mouse brain, including within cortical and hippocampal neurons, where it is detected at pre-synaptic terminals. Deletion of Cd2ap altered dendritic branching and spine density, and impaired ubiquitin-proteasome system activity. Moreover, in mice harboring either one or two copies of a germline Cd2ap null allele, we noted increased paired-pulse facilitation at hippocampal Schaffer-collateral synapses, consistent with a haploinsufficient requirement for pre-synaptic release. Whereas conditional Cd2ap knockout in …

The Fundamentals Of Antiseizure Medications: A Through Z, Timothy E Welty, Jeannine M Conway, Jacquelyn Bainbridge, Kristen Park, David G Vossler, Archana A Patel, Alica Goldman

Faculty, Staff and Students Publications

Since bromides were first used in 1857 to treat epilepsy, numerous antiseizure medications (ASM) have been developed. Many of these are available for the treatment of epilepsy and status epilepticus today. With so many ASM available, questions arise as to whether all of these medications are needed and when should they be used. As precision medicine begins to play a larger role in determining targeted treatments for specific types of epilepsy, a complete understanding of various medications is needed. Additionally, access to several of these medications can be limited in the United States and are especially limited globally. All these …

2024 Clinical Practice Guideline Update By The Infectious Diseases Society Of America On Complicated Intra-Abdominal Infections: Utility Of Intra-Abdominal Fluid Cultures In Adults, Children, And Pregnant People, Robert A Bonomo, Romney Humphries, Fredrick M Abrahamian, Mary Bessesen, Anthony W Chow, E Patchen Dellinger, Morven S Edwards, Ellie Goldstein, Mary K Hayden, Keith S Kaye, Brian A Potoski, Jesús Rodríguez-Baño, Robert Sawyer, Marion Skalweit, David R Snydman, Pranita D Tamma, Katelyn Donnelly, Jennifer Loveless

Faculty, Staff and Students Publications

This paper is part of a clinical practice guideline update on the risk assessment, diagnostic imaging, and microbiological evaluation of complicated intra-abdominal infections in adults, children, and pregnant people, developed by the Infectious Diseases Society of America. In this paper, the panel provides recommendations for obtaining cultures of intra-abdominal fluid in patients with known or suspected intra-abdominal infection. The panel's recommendations are based on evidence derived from systematic literature reviews and adhere to a standardized methodology for rating the certainty of evidence and strength of recommendation according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach.

Biologic And Clinical Analysis Of Childhood Gamma Delta T-All Identifies Lmo2/Stag2 Rearrangements As Extremely High Risk, Shunsuke Kimura, Chun Shik Park, Lindsey E Montefiori, Ilaria Iacobucci, Petri Pölönen, Qingsong Gao, Elizabeth D Arnold, Andishe Attarbaschi, Anthony Brown, Barbara Buldini, Kenneth J Caldwell, Yunchao Chang, Chelsey Chen, Cheng Cheng, Zhongshan Cheng, John Choi, Valentino Conter, Kristine R Crews, Hester A De Groot-Kruseman, Takao Deguchi, Mariko Eguchi, Hannah E Muhle, Sarah Elitzur, Gabriele Escherich, Burgess B Freeman, Zhaohui Gu, Katie Han, Keizo Horibe, Toshihiko Imamura, Sima Jeha, Motohiro Kato, Kean H Chiew, Tanya Khan, Michal Kicinski, Stefan Köhrer, Steven M Kornblau, Rishi S Kotecha, Chi-Kong Li, Yen-Chun Liu, Franco Locatelli, Selina M Luger, Elisabeth M Paietta, Atsushi Manabe, Hanne V Marquart, Riccardo Masetti, Mellissa Maybury, Pauline Mazilier, Jules P P Meijerink, Sharnise Mitchell, Takako Miyamura, Andrew S Moore, Koichi Oshima, Katarzyna Pawinska-Wasikowska, Rob Pieters, Mollie S Prater, Shondra M Pruett-Miller, Ching-Hon Pui, Chunxu Qu, Michaela Reiterova, Noemi Reyes, Kathryn G Roberts, Jacob M Rowe, Atsushi Sato, Kjeld Schmiegelow, Martin Schrappe, Shuhong Shen, Szymon Skoczeń, Orietta Spinelli, Jan Stary, Michael Svaton, Masatoshi Takagi, Junko Takita, Yanjing Tang, David T Teachey, Paul G Thomas, Daisuke Tomizawa, Jan Trka, Elena Varotto, Tiffaney L Vincent, Jun J Yang, Allen E J Yeoh, Yinmei Zhou, Martin Zimmermann, Hiroto Inaba, Charles G Mullighan

Faculty, Staff and Student Publications

Acute lymphoblastic leukemia expressing the gamma delta T-cell receptor (γδ T-ALL) is a poorly understood disease. We studied 200 children with γδ T-ALL from 13 clinical study groups to understand the clinical and genetic features of this disease. We found age and genetic drivers were significantly associated with outcome. γδ T-ALL diagnosed in children under 3 years of age was extremely high-risk and enriched for genetic alterations that result in both LMO2 activation and STAG2 inactivation. Mechanistically, using patient samples and isogenic cell lines, we show that inactivation of STAG2 profoundly perturbs chromatin organization by altering enhancer-promoter looping, resulting in …

Cd28 Costimulation Augments Car Signaling In Nk Cells Via The Lck/Cd3Ζ/Zap70 Signaling Axis, Sunil Acharya, Rafet Basar, May Daher, Hind Rafei, Ping Li, Nadima Uprety, Emily Ensley, Mayra Shanley, Bijender Kumar, Pinaki P Banerjee, Luciana Melo Garcia, Paul Lin, Vakul Mohanty, Kun H Kim, Xianli Jiang, Yuchen Pan, Ye Li, Bin Liu, Ana K Nunez Cortes, Chenyu Zhang, Mohsen Fathi, Ali Rezvan, Melisa J Montalvo, Sophia L Cha, Francia Reyes-Silva, Rejeena Shrestha, Xingliang Guo, Kiran Kundu, Alexander Biederstädt, Luis Muniz-Feliciano, Gary M Deyter, Mecit Kaplan, Xin R Jiang, Enli Liu, Antrix Jain, Janos Roszik, Natalie W Fowlkes, Luisa M Solis Soto, Maria G Raso, Joseph D Khoury, Pei Lin, Francisco Vega, Navin Varadarajan, Ken Chen, David Marin, Elizabeth J Shpall, Katayoun Rezvani

Faculty, Staff and Student Publications

Multiple factors in the design of a chimeric antigen receptor (CAR) influence CAR T-cell activity, with costimulatory signals being a key component. Yet, the impact of costimulatory domains on the downstream signaling and subsequent functionality of CAR-engineered natural killer (NK) cells remains largely unexplored. Here, we evaluated the impact of various costimulatory domains on CAR-NK cell activity, using a CD70-targeting CAR. We found that CD28, a costimulatory molecule not inherently present in mature NK cells, significantly enhanced the antitumor efficacy and long-term cytotoxicity of CAR-NK cells both in vitro and in multiple xenograft models of hematologic and solid tumors. Mechanistically, …

Inflammation-Induced Epigenetic Imprinting Regulates Intestinal Stem Cells, Dongchang Zhao, Visweswaran Ravikumar, Tyler J Leach, Daniel Kraushaar, Emma Lauder, Lu Li, Yaping Sun, Katherine Oravecz-Wilson, Evan T Keller, Fengju Chen, Laure Maneix, Robert R Jenq, Robert Britton, Katherine Y King, Ana E Santibanez, Chad J Creighton, Arvind Rao, Pavan Reddy

Faculty, Staff and Students Publications

It remains unknown whether, and how intestinal stem cells (ISC) adapt to inflammatory exposure, and if the adaptation leaves scars will affect their subsequent regeneration. We investigated the consequences of inflammation on Lgr5+ISCs in well-defined clinically relevant models of gastrointestinal acute graft-versus-host disease (GI GVHD). Utilizing single cell transcriptomics, organoid, metabolic, epigenomic and in vivo models we found that Lgr5+ISCs undergo metabolic changes that lead to accumulation of succinate, which reprograms its epigenome. These changes reduced the ability of ISCs to differentiate and regenerate ex vivo in serial organoid cultures and also in vivo following serial transplantation. Furthermore, ISCs demonstrated …

A Ligation-Independent Sequencing Method Reveals Trna-Derived Rnas With Blocked 3′ Termini, Alessandro Scacchetti, Emily J Shields, Natalie A Trigg, Grace S Lee, Jeremy E Wilusz, Colin C Conine, Roberto Bonasio

Faculty, Staff and Students Publications

Despite the numerous sequencing methods available, the diversity in RNA size and chemical modification makes it difficult to capture all RNAs in a cell. We developed a method that combines quasi-random priming with template switching to construct sequencing libraries from RNA molecules of any length and with any type of 3' modifications, allowing for the sequencing of virtually all RNA species. Our ligation-independent detection of all types of RNA (LIDAR) is a simple, effective tool to identify and quantify all classes of coding and non-coding RNAs. With LIDAR, we comprehensively characterized the transcriptomes of mouse embryonic stem cells, neural progenitor …

Advances In Biomedical Research And Treatments: What Is Acceptable?, Michael L. Clancy, Khalid M. Iskandarani, Mitchell C. Mccrea

Journal of Health Ethics

This study investigated the technology acceptance (TA) of twenty-first century biomedical treatments by adults in the United States. A new TA instrument was created, using five distinct levels: (1) Healing and Prevention, (2) Replacement Organs, (3) Enhancements-Medical, (4) Enhancements-Discretionary, and (5) Transhumans. An on-line survey produced 353 usable responses, which showed distinct patterns for each of five biomedical treatment levels. There was clear support for Levels 1–3, but very strong opposition to Levels 4–5. The TA finding draws the line between which human interventions are acceptable versus others that should be prohibited through public policies and medical guidelines.

Shsp Dean's Newsletter, Fall 2024, Robert W. Amler

SHSP Dean’s Newsletter

No abstract provided.

Pparγ/Etv2 Axis Regulates Endothelial-To-Mesenchymal Transition In Pulmonary Hypertension, Dong Hun Lee, Minseong Kim, Sarah S Chang, Raham Lee, Andrew J Jang, Juyoung Kim, Jing Ma, Michael J Passineau, Raymond L Benza, Harry Karmouty-Quintana, Wilbur A Lam, Benjamin T Kopp, Roy L Sutliff, C Michael Hart, Changwon Park, Bum-Yong Kang

Faculty, Staff and Student Publications

Endothelial-to-mesenchymal transition (EndoMT) plays an important role in pulmonary hypertension (PH) but the molecular mechanisms regulating EndoMT remain to be defined. We demonstrate that the axis of the transcription factors PPARγ (Peroxisome Proliferator-Activated Receptor gamma) and ETV2 (ETS variant 2) play important roles in the pathogenesis of PH. Decreased levels of the expression of PPARγ and ETV2 along with reduced endothelial and increased EndoMT markers are consistently observed in lungs and pulmonary artery endothelial cells (PAECs) of idiopathic pulmonary arterial hypertension patients, in hypoxia-exposed mouse lungs, human PAECs, and in induced-EndoMT cells. Etv2 +/- mice spontaneously developed PH and right …

Phenotypic Diversity Of Type Iii Secretion System Activity In Enteropathogenic Escherichia Coli Clinical Isolates, Carmen A Contreras, Tracy H Hazen, Carmen Guadarrama, Ramón Cervantes-Rivera, Theresa J Ochoa, Pablo Vinuesa, David A Rasko, Jose L Puente

Faculty, Staff and Student Publications

Introduction. Enteropathogenic Escherichia coli (EPEC) strains pose a significant threat as a leading cause of severe childhood diarrhoea in developing nations. EPEC pathogenicity relies on the type III secretion system (T3SS) encoded by the locus of enterocyte effacement (LEE), facilitating the secretion and translocation of bacterial effector proteins.

Gap Statement. While the regulatory roles of PerC (plasmid-encoded regulator) and GrlA (global regulator of LEE-activator) in ler expression and LEE gene activation are well-documented in the EPEC prototype strain E2348/69, understanding the variability in LEE gene expression control mechanisms among clinical EPEC isolates remains an area requiring further investigation.

Aim. This …

Cerebellar Deep Brain Stimulation As A Dual-Function Therapeutic For Restoring Movement And Sleep In Dystonic Mice, Luis E Salazar Leon, Linda H Kim, Roy V Sillitoe

Duncan NRI Faculty and Staff Publications

Dystonia arises with cerebellar dysfunction, which plays a key role in the emergence of multiple pathophysiological deficits that range from abnormal movements and postures to disrupted sleep. Current therapeutic interventions typically do not simultaneously address both the motor and non-motor symptoms of dystonia, underscoring the necessity for a multi-functional therapeutic strategy. Deep brain stimulation (DBS) is effectively used to reduce motor symptoms in dystonia, with existing parallel evidence arguing for its potential to correct sleep disturbances. However, the simultaneous efficacy of DBS for improving sleep and motor dysfunction, specifically by targeting the cerebellum, remains underexplored. Here, we test the effect …

Persistent Microbial Infections And Idiopathic Pulmonary Fibrosis – An Insight Into Non-Typeable Haemophilus Influenza Pathogenesis, Dong Hun Lee, Minseong Kim, Sarah S Chang, Raham Lee, Andrew J Jang, Juyoung Kim, Jing Ma, Michael J Passineau, Raymond L Benza, Harry Karmouty-Quintana, Wilbur A Lam, Benjamin T Kopp, Roy L Sutliff, C Michael Hart, Changwon Park, Bum-Yong Kang

Faculty, Staff and Student Publications

Endothelial-to-mesenchymal transition (EndoMT) plays an important role in pulmonary hypertension (PH) but the molecular mechanisms regulating EndoMT remain to be defined. We demonstrate that the axis of the transcription factors PPARγ (Peroxisome Proliferator-Activated Receptor gamma) and ETV2 (ETS variant 2) play important roles in the pathogenesis of PH. Decreased levels of the expression of PPARγ and ETV2 along with reduced endothelial and increased EndoMT markers are consistently observed in lungs and pulmonary artery endothelial cells (PAECs) of idiopathic pulmonary arterial hypertension patients, in hypoxia-exposed mouse lungs, human PAECs, and in induced-EndoMT cells. Etv2 +/- mice spontaneously developed PH and right …

Ketamine For Acute Pain After Trauma: A Pragmatic, Randomized Clinical Trial, James M Klugh, Thaddeus J Puzio, Michael W Wandling, Chelsea J Guy-Frank, Charles Green, Paulina B Sergot, Samuel J Prater, Julius Balogh, Christopher T Stephens, Charles E Wade, Lillian S Kao, John A Harvin

Faculty, Staff and Student Publications

Background: Non-narcotic intravenous medications may be a beneficial adjunct to oral multimodal pain regimens (MMPRs) which reduce but do not eliminate opioid exposure and prescribing after trauma. We hypothesized that the addition of a subdissociative ketamine infusion (KI) to a standardized oral MMPR reduces inpatient opioid exposure.

Methods: Eligible adult trauma patients admitted to the intermediate or intensive care unit were randomized upon admission to our institutional MMPR per usual care (UC) or UC plus subdissociative KI for 24 hours to 72 hours after arrival. The primary outcome was morphine milligram equivalents per day (MME/d) and secondary outcomes included total …

Galectin 3-Binding Protein (Lgals3bp) Depletion Attenuates Hepatic Fibrosis By Reducing Transforming Growth Factor-Β1 (Tgf-Β1) Availability And Inhibits Hepatocarcinogenesis, Dae-Hwan Kim, Minjeong Sung, Myong-Suk Park, Eun-Gene Sun, Sumin Yoon, Kyung Hyun Yoo, Kamalakannan Radhakrishnan, Sung Yun Jung, Woo-Kyun Bae, Sang-Hee Cho, Ik-Joo Chung

Faculty, Staff and Students Publications

Background: Increased Galectin 3-binding protein (LGALS3BP) serum levels have been used to assess hepatic fibrosis stages and the severity of hepatocellular carcinoma (HCC). Considering the crucial role of transforming growth factor-β1 (TGF-β1) in the emergence of these diseases, the present study tested the hypothesis that LGALS3BP regulates the TGF-β1 signaling pathway.

Methods: The expression levels of LGALS3BP and TGFB1 were analyzed in patients with metabolic dysfunction-associated steatohepatitis (MASH) and HCC. Multiple omics techniques, such as RNA-sequencing, transposase-accessible chromatin-sequencing assay, and liquid chromatography-tandem mass spectrometry proteomics, were used to identify the regulatory mechanisms for the LGALS3BP-TGF-β1 axis. The effects of altered …

Targeting Snai1-Mediated Colorectal Cancer Chemoresistance And Stemness By Sphingosine Kinase 2 Inhibition, Harinarayanan Janakiraman, Zachary Gao, Yun Zhu, Jiangling Dong, Scott A Becker, Alhaji Janneh, Besim Ogretmen, E Ramsay Camp

Faculty, Staff and Students Publications

BACKGROUND: Epithelial-to-mesenchymal transition (EMT), cancer stem cells (CSCs), and colorectal cancer (CRC) therapy resistance are closely associated. Prior reports have demonstrated that sphingosine-1-phosphate (S1P) supports stem cells and maintains the CSC phenotype. We hypothesized that the EMT inducer SNAI1 drives S1P signaling to amplify CSC self-renewal capacity and chemoresistance.

METHODS: CRC cell lines with or without ectopic expression of SNAI1 were used to study the role of S1P signaling as mediators of cancer stemness and 5-fluorouracil (5FU) chemoresistance. The therapeutic ability of sphingosine kinase 2 (SPHK2) was assessed using siRNA and ABC294640, a SPHK2 inhibitor. CSCs were isolated from patient-derived …

Changes In Conjunctival Mononuclear Phagocytes And Suppressive Activity Of Regulatory Macrophages In Desiccation Induced Dry Eye, Jehan Alam, Ebru Yaman, Cintia S De Paiva, De-Quan Li, Gerda Cristal Villalba Silva, Zhen Zuo, Stephen C Pflugfelder

Faculty, Staff and Students Publications

Purpose: To evaluate the effects of dry eye on conjunctival immune cell number and transcriptional profiles with attention to mononuclear phagocytes.

Methods: Expression profiling was performed by single-cell RNA sequencing on sorted conjunctival immune cells from non-stressed and C57BL/6 mice subjected to desiccating stress (DS). Monocle 3 modeled cell trajectory, scATAC-seq assessed chromatin accessibility and IPA identified canonical pathways. Inflammation and goblet cells were measured after depletion of MRC1+ MΦs with mannosylated clodronate liposomes.

Results: Mononuclear phagocytes (monocytes, MΦs, DCs) comprised 72 % of immune cells and showed the greatest changes with DS. Distinct DS induced gene expression patterns were …

Tau Is Required For Glial Lipid Droplet Formation And Resistance To Neuronal Oxidative Stress, Lindsey D Goodman, Isha Ralhan, Xin Li, Shenzhao Lu, Matthew J Moulton, Ye-Jin Park, Pinghan Zhao, Oguz Kanca, Ziyaneh S Ghaderpour Taleghani, Julie Jacquemyn, Joshua M Shulman, Kanae Ando, Kai Sun, Maria S Ioannou, Hugo J Bellen

Duncan NRI Faculty and Staff Publications

The accumulation of reactive oxygen species (ROS) is a common feature of tauopathies, defined by Tau accumulations in neurons and glia. High ROS in neurons causes lipid production and the export of toxic peroxidated lipids (LPOs). Glia uptake these LPOs and incorporate them into lipid droplets (LDs) for storage and catabolism. We found that overexpressing Tau in glia disrupts LDs in flies and rat neuron-astrocyte co-cultures, sensitizing the glia to toxic, neuronal LPOs. Using a new fly tau loss-of-function allele and RNA-mediated interference, we found that endogenous Tau is required for glial LD formation and protection against neuronal LPOs. Similarly, …

Evaluation Of Vancomycin Dose Needed To Achieve 24-Hour Area Under The Concentration-Time Curve To Minimum Inhibitory Concentration Ratio Greater Than Or Equal To 400 Using Pharmacometric Approaches In Pediatric Intensive Care Patients, Dawoon Jung, Omayma A Kishk, Adnan T Bhutta, Ginny E Cummings, Hana M El Sahly, Manpreet K Virk, Brady S Moffett, Jennifer L Morris Daniel, Amy Watanabe, Nicholas Fishbane, Karen L Kotloff, Kenan Gu, Varduhi Ghazaryan, Jogarao V S Gobburu, Ayse Akcan-Arikan, James D Campbell

Faculty, Staff and Students Publications

OBJECTIVES: To investigate which independent factor(s) have an impact on the pharmacokinetics of vancomycin in critically ill children, develop an equation to predict the 24-hour area under the concentration-time curve from a trough concentration, and evaluate dosing regimens likely to achieve a 24-hour area under the concentration-time curve to minimum inhibitory concentration ratio (AUC24/MIC) greater than or equal to 400.

DESIGN: Prospective population pharmacokinetic study of vancomycin.

SETTING: Critically ill patients in quaternary care PICUs.

PATIENTS: Children 90 days old or older to younger than 18 years who received IV vancomycin treatment, irrespective of the indication for use, in the …

Isolated Psychiatric Symptoms In Children With Anti-N-Methyl-D Aspartate Receptor Encephalitis, Grace Gombolay, J Nicholas Brenton, Jennifer H Yang, Coral M Stredny, Ryan Kammeyer, Kristen S Fisher, Alexander J Sandweiss, Timothy A Erickson, Varun Kannan, Catherine Otten, Claude Steriade, Ngochanh Vu, Jonathan D Santoro, Karla Robles-Lopez, Robert Goodrich, Scott Otallah, Janetta Arellano, Andrew Christiana, Morgan Morris, Mark P Gorman, Alexandra B Kornbluh, Ilana Kahn, Leigh Sepeta, Yike Jiang, Eyal Muscal, Kristy O Murray, Manikum Moodley, Duriel Hardy

Faculty, Staff and Students Publications

Background: Isolated psychiatric symptoms can be the initial symptom of pediatric anti-N-methyl-d-aspartate (NMDA) receptor autoimmune encephalitis (pNMDARE). Here we report on the prevalence of isolated psychiatric symptoms in pNMDARE. We also assess whether initial neurodiagnostic tests (brain magnetic resonance imaging [MRI], electroencephalography [EEG], and/or cerebrospinal fluid [CSF] white blood cell count) are abnormal in children with isolated psychiatric symptoms and pNMDARE.

Methods: This multicenter retrospective cohort study from CONNECT (Conquering Neuroinflammation and Epilepsies Consortium) from 14 institutions included children under age 18 years who were diagnosed with pNMDARE. Descriptive statistics using means, medians, and comparisons for continuous versus discrete data …

Pkmyt1 Is A Marker Of Treatment Response And A Therapeutic Target For Cdk4/6 Inhibitor-Resistance In Er+ Breast Cancer, Anran Chen, Beom-Jun Kim, Aparna Mitra, Craig T Vollert, Jonathan T Lei, Diana Fandino, Meenakshi Anurag, Matthew V Holt, Xuxu Gou, Jacob B Pilcher, Matthew P Goetz, Donald W Northfelt, Susan G Hilsenbeck, C Gary Marshall, Marc L Hyer, Robert Papp, Shou-Yun Yin, Carmine De Angelis, Rachel Schiff, Suzanne A W Fuqua, Cynthia X Ma, Charles E Foulds, Matthew J Ellis

Faculty, Staff and Students Publications

Endocrine therapies (ET) with cyclin-dependent kinase 4/6 (CDK4/6) inhibition are the standard treatment for estrogen receptor-α-positive (ER+) breast cancer, however drug resistance is common. In this study, proteogenomic analyses of patient-derived xenografts (PDXs) from patients with 22 ER+ breast cancer demonstrated that protein kinase, membrane-associated tyrosine/threonine one (PKMYT1), a WEE1 homolog, is estradiol (E2) regulated in E2-dependent PDXs and constitutively expressed when growth is E2-independent. In clinical samples, high PKMYT1 mRNA levels associated with resistance to both ET and CDK4/6 inhibition. The PKMYT1 inhibitor lunresertib (RP-6306) with gemcitabine selectively and synergistically reduced the viability of ET and palbociclib-resistant ER+ breast …

Aging Skeletal Muscle: Influence Of Obesity And Role Of The Exercise Responsive Nuclear Receptor Nor-1, Hector G. Paez

Alternative Theses and Dissertations (AETDs)

Skeletal muscle mass and function are critical components of overall health and quality of life. Advanced age is associated with skeletal muscle disease characterized by a loss of muscle mass, function, and quality. Indeed, low muscle mass and function is associated with poor disease outcomes and greater mortality, greater incidence of falls, and a high fiscal and societal cost. Aging contributes to a decline in skeletal muscle health through several intrinsic and extrinsic mechanisms including impaired nutrient sensing, mitochondrial dysfunction, inflammation, physical inactivity, and proteostatic imbalance. Obesity, an increasingly prominent public health concern, is becoming more common in the elderly …

The Fallacy Of Electronic Cigarettes For Tobacco Dependence, Harold J Farber, Carlos Rábade Castedo, Carlos A Jimenez-Ruiz, Manuel Conrado Pacheco

Faculty, Staff and Students Publications

No abstract provided.

Perspectives On Hand Hygiene In Belizean Healthcare Facilities During The Covid-19 Pandemic: A Qualitative Evaluation With Healthcare Workers, Kelsey Mcdavid, Christina Craig, Anh N Ly, Nicholas Bivens, Francis Morey, Russell Manzanero, Gerhaldine Morazan, Ella Hawes, Alexandra Medley, Kristy Murray, Matthew Lozier

Faculty, Staff and Students Publications

The World Health Organization recommends healthcare workers (HCWs) practice hand hygiene (HH) while providing care. Making alcohol-based hand rub (ABHR) available at points of care is recommended during times of high patient volume, such as the COVID-19 pandemic. In low- and middle-income countries, such as Belize, there may be limited access to HH materials within healthcare facilities (HCF). This paper examines the motivators and barriers to HH among HCWs in the 11 largest public healthcare facilities in Belize and HCWs' experiences with an intervention. In 2021, focus group discussions (FGDs) gathered HCWs' HH perceptions and preferences. An intervention was then …

Addressing Platelet Insecurity – A National Call To Action, Eric A Gehrie, Pampee P Young, Sridhar V Basavaraju, Arthur W Bracey, Andrew P Cap, Liz Culler, Nancy M Dunbar, Mary Homer, Iris Isufi, Rob Macedo, Tanya Petraszko, Glenn Ramsey, Christopher A Tormey, Richard M Kaufman, Edward L Snyder

Faculty, Staff and Students Publications

No abstract provided.