Medicine and Health Sciences Commons^™

Intrinsic Disorder-Based Emergence In Cellular Biology: Physiological And Pathological Liquid-Liquid Phase Transitions In Cells, April L. Darling, Boris Zaslavsky, Vladimir N. Uversky

Molecular Medicine Faculty Publications

The visible outcome of liquid-liquid phase transitions (LLPTs) in cells is the formation and disintegration of various proteinaceous membrane-less organelles (PMLOs). Although LLPTs and related PMLOs have been observed in living cells for over 200 years, the physiological functions of these transitions (also known as liquid-liquid phase separation, LLPS) are just starting to be understood. While unveiling the functionality of these transitions is important, they have come into light more recently due to the association of abnormal LLPTs with various pathological conditions. In fact, several maladies, such as various cancers, different neurodegenerative diseases, and cardiovascular diseases, are known to be …

Evolutionary Analyses Of Sequence And Structure Space Unravel The Structural Facets Of Sod1, Sourav Chowdury, Dwipanjan Sanyal, Sagnik Sen, Vladimir N. Uversky, Ujjwal Maulik, Krishnananda Chattopadhyay

Molecular Medicine Faculty Publications

Superoxide dismutase (SOD) is the primary enzyme of the cellular antioxidant defense cascade. Misfolding, concomitant oligomerization, and higher order aggregation of human cytosolic SOD are linked to amyotrophic lateral sclerosis (ALS). Although, with two metal ion cofactors SOD1 is extremely robust, the de-metallated apo form is intrinsically disordered. Since the rise of oxygen-based metabolism and antioxidant defense systems are evolutionary coupled, SOD is an interesting protein with a deep evolutionary history. We deployed statistical analysis of sequence space to decode evolutionarily co-varying residues in this protein. These were validated by applying graph theoretical modelling to understand the impact of the …

Driving Forces Of Liquid–Liquid Phase Separation In Biological Systems, Boris Y. Zaslavsky, Luisa A. Ferreira, Vladimir N. Uversky

Molecular Medicine Faculty Publications

Analysis of liquid–liquid phase separation in biological systems shows that this process is similar to the phase separation observed in aqueous two-phase systems formed by nonionic polymers, proteins, and polysaccharides. The emergence of interfacial tension is a necessary condition of phase separation. The situation in this regard is similar to that of phase separation in mixtures of partially miscible solvents. It is suggested that the evaluation of the effects of biological macromolecules on the solvent properties of aqueous media and the measurement of the interfacial tension as a function of these solvent properties may be more productive for gaining insights …

Zika And Flavivirus Shell Disorder: Virulence And Fetal Morbidity, Gerard Kian-Meng Goh, A. Keith Dunker, James A. Foster, Vladimir N. Uversky

Molecular Medicine Faculty Publications

Zika virus (ZIKV) was first discovered in 1947 in Africa. Since then, sporadic ZIKV infections of humans have been reported in Africa and Asia. For a long time, this virus was mostly unnoticed due to its mild symptoms and low fatality rates. However, during the 2015–2016 epidemic in Central and South America, when millions of people were infected, it was discovered that ZIKV causes microcephaly in the babies of mothers infected during pregnancy. An examination of the M and C proteins of the ZIKV shell using the disorder predictor PONDR VLXT revealed that the M protein contains relatively high disorder …

Supramolecular Fuzziness Of Intracellular Liquid Droplets: Liquid–Liquid Phase Transitions, Membrane-Less Organelles, And Intrinsic Disorder, Vladimir N. Uversky

Molecular Medicine Faculty Publications

Cells are inhomogeneously crowded, possessing a wide range of intracellular liquid droplets abundantly present in the cytoplasm of eukaryotic and bacterial cells, in the mitochondrial matrix and nucleoplasm of eukaryotes, and in the chloroplast’s stroma of plant cells. These proteinaceous membrane-less organelles (PMLOs) not only represent a natural method of intracellular compartmentalization, which is crucial for successful execution of various biological functions, but also serve as important means for the processing of local information and rapid response to the fluctuations in environmental conditions. Since PMLOs, being complex macromolecular assemblages, possess many characteristic features of liquids, they represent highly dynamic (or …

Rational Discovery Of Antimetastatic Agents Targeting The Intrinsically Disordered Region Of Mbd2, Min Young Kim, Insung Na, Ji Sook Kim, Seung Han Son, Sungwoo Choi, Seol Eui Lee, Ji-Hun Kim, Kiseok Jang, Gil Alterovitz, Yu Chen, Arjant Van Der Vaar, Hyung-Sik Won, Vladimir N. Uversky, Chul Geun Kim

Molecular Medicine Faculty Publications

Although intrinsically disordered protein regions (IDPRs) are commonly engaged in promiscuous protein-protein interactions (PPIs), using them as drug targets is challenging due to their extreme structural flexibility. We report a rational discovery of inhibitors targeting an IDPR of MBD2 that undergoes disorder-to-order transition upon PPI and is critical for the regulation of the Mi-2/NuRD chromatin remodeling complex (CRC). Computational biology was essential for identifying target site, searching for promising leads, and assessing their binding feasibility and off-target probability. Molecular action of selected leads inhibiting the targeted PPI of MBD2 was validated in vitro and in cell, followed by confirming their …

Experimental Insight Into The Structural And Functional Roles Of The ‘Black’ And ‘Gray’ Clusters In Recoverin, A Calcium Binding Protein With Four Ef-Hand Motifs, Sergei E. Permyakov, Alisa S. Vologzhannikova, Ekaterina L. Nemashkalova, Alexei S. Kazakov, Alexander I. Denesyuk, Konstantin Denessiouk, Viktoriia E. Baksheeva, Andrey A. Zamyatnin Jr., Eugene Yu. Zernii, Vladimir N. Uversky, Eugene A. Permyakov

Molecular Medicine Faculty Publications

Recently, we have found that calcium binding proteins of the EF-hand superfamily (i.e., a large family of proteins containing helix-loop-helix calcium binding motif or EF-hand) contain two types of conserved clusters called cluster I (‘black’ cluster) and cluster II (‘grey’ cluster), which provide a supporting scaffold for the Ca2+ binding loops and contribute to the hydrophobic core of the EF-hand domains. Cluster I is more conservative and mostly incorporates aromatic amino acids, whereas cluster II includes a mix of aromatic, hydrophobic, and polar amino acids of different sizes. Recoverin is EF-hand Ca2+-binding protein containing two ‘black’ clusters comprised of F35, …

Intrinsic Disorder Of The Baf Complex: Roles In Chromatin Remodeling And Disease Development, Nashwa El Hadidy, Vladimir N. Uversky

Molecular Medicine Faculty Publications

The two-meter-long DNA is compressed into chromatin in the nucleus of every cell, which serves as a significant barrier to transcription. Therefore, for processes such as replication and transcription to occur, the highly compacted chromatin must be relaxed, and the processes required for chromatin reorganization for the aim of replication or transcription are controlled by ATP-dependent nucleosome remodelers. One of the most highly studied remodelers of this kind is the BRG1- or BRM-associated factor complex (BAF complex, also known as SWItch/sucrose non-fermentable (SWI/SNF) complex), which is crucial for the regulation of gene expression and differentiation in eukaryotes. Chromatin remodeling complex …

Many-To-One Binding By Intrinsically Disordered Protein Regions, Wei-Lun Alterovitz, Eshel Faraggi, Christopher J. Oldfield, Jingwei Meng, Bin Xue, Fei Huang, Pedro Romero, Andrzej Kloczkowski, Vladimir N. Uversky, A. Keith Dunker

Molecular Medicine Faculty Publications

Disordered binding regions (DBRs), which are embedded within intrinsically disordered proteins or regions (IDPs or IDRs), enable IDPs or IDRs to mediate multiple protein-protein interactions. DBR-protein complexes were collected from the Protein Data Bank for which two or more DBRs having different amino acid sequences bind to the same (100% sequence identical) globular protein partner, a type of interaction herein called many-to-one binding. Two distinct binding profiles were identified: independent and overlapping. For the overlapping binding profiles, the distinct DBRs interact by means of almost identical binding sites (herein called “similar”), or the binding sites contain both common and divergent …

Intrinsically Disordered Proteins In Chronic Diseases, Prakash Kulkarni, Vladimir N. Uversky

Molecular Medicine Faculty Publications

No abstract provided.

Hiv Vaccine Mystery And Viral Shell Disorder, Gerard Kian-Meng Goh, A. Keith Dunker, James A. Foster, Vladimir N. Uversky

Molecular Medicine Faculty Publications

Hundreds of billions of dollars have been spent for over three decades in the search for an effective human immunodeficiency virus (HIV) vaccine with no success. There are also at least two other sexually transmitted viruses, for which no vaccine is available, the herpes simplex virus (HSV) and the hepatitis C virus (HCV). Traditional textbook explanatory paradigm of rapid mutation of retroviruses cannot adequately address the unavailability of vaccine for many sexually transmissible viruses, since HSV and HCV are DNA and non-retroviral RNA viruses, respectively, whereas effective vaccine for the horsefly-transmitted retroviral cousin of HIV, equine infectious anemia virus (EIAV), …

On The Need To Develop Guidelines For Characterizing And Reporting Intrinsic Disorder In Proteins, Michael Vincent, Vladimir N. Uversky, Santiago Schnell

Molecular Medicine Faculty Publications

Since the early 2000s, numerous computational tools have been created and used to predict intrinsic disorder in proteins. At present, the output from these algorithms is difficult to interpret in the absence of standards or references for comparison. There are many reasons to establish a set of standard-based guidelines to evaluate computational protein disorder predictions. This viewpoint explores a handful of these reasons, including standardizing nomenclature to improve communication, rigor and reproducibility, and making it easier for newcomers to enter the field. An approach for reporting predicted disorder in single proteins with respect to whole proteomes is discussed. The suggestions …

Ifi16, A Nuclear Innate Immune Dna Sensor, Mediates Epigenetic Silencing Of Herpesvirus Genomes By Its Association With H3k9 Methyltransferases Suv39h1 And Glp, Arunava Roy, Anandita Ghosh, Binod Kumar, Bala Chandran

Molecular Medicine Faculty Publications

IFI16, an innate immune DNA sensor, recognizes the nuclear episomal herpes viral genomes and induces the inflammasome and interferon-β responses. IFI16 also regulates cellular transcription and act as a DNA virus restriction factor. IFI16 knockdown disrupted the latency of Kaposi’s sarcoma associated herpesvirus (KSHV) and induced lytic transcripts. However, the mechanism of IFI16’s transcription regulation is unknown. Here, we show that IFI16 is in complex with the H3K9 methyltransferase SUV39H1 and GLP and recruits them to the KSHV genome during de novo infection and latency. The resulting depositions of H3K9me2/me3 serve as a docking site for the heterochromatin-inducing HP1α protein …

Cyclized Ndga Modifies Dynamic Α-Synuclein Monomers Preventing Aggregation And Toxicity, Malcolm J. Daniels, J. Brucker Nourse, Hanna Kim, Valerio Sainati, Marco Schiavina, Maria Grazia Murrali, Buyan Pan, John J. Ferrie, Conor M. Haney, Rani Moons, Neal S. Gould, Antonino Natalello, Rita Grandori, Frank Sobott, E. James Petersson, Elizabeth Rhoades, Roberta Pierattelli, Isabella Felli, Vladimir N. Uversky, Kim A. Caldwell, Guy A. Caldwell, Edward S. Krol, Harry Ischiropoulos

Molecular Medicine Faculty Publications

Growing evidence implicates α-synuclein aggregation as a key driver of neurodegeneration in Parkinson’s disease (PD) and other neurodegenerative disorders. Herein, the molecular and structural mechanisms of inhibiting α-synuclein aggregation by novel analogs of nordihydroguaiaretic acid (NDGA), a phenolic dibenzenediol lignan, were explored using an array of biochemical and biophysical methodologies. NDGA analogs induced modest, progressive compaction of monomeric α-synuclein, preventing aggregation into amyloid-like fibrils. This conformational remodeling preserved the dynamic adoption of α-helical conformations, which are essential for physiological membrane interactions. Oxidation-dependent NDGA cyclization was required for the interaction with monomeric α-synuclein. NDGA analog-pretreated α-synuclein did not aggregate even without …

Intrinsically Disordered Proteins And Their “Mysterious” (Meta)Physics, Vladimir N. Uversky

Molecular Medicine Faculty Publications

Recognition of the natural abundance and functional importance of intrinsically disordered proteins (IDPs), and protein hybrids that contain both intrinsically disordered protein regions (IDPRs) and ordered regions, is changing protein science. IDPs and IDPRs, i.e., functional proteins and protein regions without unique structures, can often be found in all organisms, and typically play vital roles in various biological processes. Disorder-based functionality complements the functions of ordered proteins and domains. However, by virtue of their existence, IDPs/IDPRs, which are characterized by remarkable conformational flexibility and structural plasticity, break multiple rules established over the years to explain structure, folding, and functionality of …

Small Heat Shock Proteins, Big Impact On Protein Aggregation In Neurodegenerative Disease, Jack M. Webster, April L. Darling, Vladimir N. Uversky, Laura J. Blair

Molecular Medicine Faculty Publications

Misfolding, aggregation, and aberrant accumulation of proteins are central components in the progression of neurodegenerative disease. Cellular molecular chaperone systems modulate proteostasis, and, therefore, are primed to influence aberrant protein-induced neurotoxicity and disease progression. Molecular chaperones have a wide range of functions from facilitating proper nascent folding and refolding to degradation or sequestration of misfolded substrates. In disease states, molecular chaperones can display protective or aberrant effects, including the promotion and stabilization of toxic protein aggregates. This seems to be dependent on the aggregating protein and discrete chaperone interaction. Small heat shock proteins (sHsps) are a class of molecular chaperones …

Life In Phases: Intra- And Inter- Molecular Phase Transitions In Protein Solutions, Vladimir N. Uversky, Alexey V. Finkelstein

Molecular Medicine Faculty Publications

Proteins, these evolutionarily-edited biological polymers, are able to undergo intramolecular and intermolecular phase transitions. Spontaneous intramolecular phase transitions define the folding of globular proteins, whereas binding-induced, intra- and inter- molecular phase transitions play a crucial role in the functionality of many intrinsically-disordered proteins. On the other hand, intermolecular phase transitions are the behind-the-scenes players in a diverse set of macrosystemic phenomena taking place in protein solutions, such as new phase nucleation in bulk, on the interface, and on the impurities, protein crystallization, protein aggregation, the formation of amyloid fibrils, and intermolecular liquid–liquid or liquid–gel phase transitions associated with the biogenesis …

Preoperative Mental Health Scores And Achieving Patient Acceptable Symptom State Are Predictive Of Return To Work After Arthroscopic Rotator Cuff Repair, Anirudh K. Gowd, Gregory L. Cvetanovich, Joseph N. Liu, Benedict U. Nwachukwu, Brandon C. Cabarcas, Brian J. Cole, Brian Forsythe, Anthony A. Romeo, Nikhil N. Verma

Orthopaedics and Sports Medicine Faculty Publications

Background: The incidence of rotator cuff repairs has risen dramatically over the past 10 years, most notably in the working-class population. Return to work (RTW) is a valuable outcome measure to set patient expectations before surgery.

Purpose: To establish the rate of RTW after rotator cuff repair with respect to stratified levels of occupational demand (sedentary, light, moderate, and heavy) and to identify clinical factors significantly associated with postoperative RTW.

Study Design: Cohort study; Level of evidence, 3.

Methods: Patients who received rotator cuff repair between 2014 and 2017 were queried from a prospectively maintained institutional registry. Work status was …

Eukaryotic Initiation Factor 3, Subunit C Silencing Inhibits Cell Proliferation And Promotes Apoptosis In Human Ovarian Cancer Cells, Fang Wen, Zhang-Ying Wu, Lei Nie, Qi-Zhu Zhang, Yuan-Kun Qin, Zun-Lun Zhou, Jin-Jian Wu, Xing Zhao, Jun Tan, Darrell Sawmiller, Dan Zi

Psychiatry & Behavioral Neurosciences Faculty Publications

Ovarian cancer remains the leading cause of death among all gynaecological cancers, illustrating the urgent need to understand the molecular mechanisms involved in this disease. Eukaryotic initiation factor 3c (EIF3c) plays an important role in protein translation and cancer cell growth and proliferation, but its role in human ovarian cancer is unclear. Our results showed that EIF3c silencing significantly up-regulated 217 and down-regulated 340 genes. Ingenuity Pathway Analysis (IPA) indicated that the top differentially expressed genes are involved in ‘Classical Pathways’, ‘Diseases and Functions’ and ‘Networks’, especially those involved in signalling and cellular growth and proliferation. In addition, eIF3c silencing …

A Case Report Of Extensive Cerebral Venous Sinus Thrombosis As A Presenting Sign Of Relapsing Nephrotic Syndrome, Janet K. Lee, Kathleen Murray, Swetha Renati

Neurology Faculty Publications

Nephrotic syndrome is defined by three characteristic features including proteinuria of >3 g in 24 hours, hypoalbuminemia of less than 3 g/dL, and peripheral edema. Multiple nephropathies can result in nephrotic syndrome. Most commonly, minimal change disease is seen in children under the age of 10, while adults are more commonly found to have membranous nephropathy. Hypercoagulability and thrombotic sequela can be seen in nephrotic syndrome, regardless of underlying etiology, and thrombosis is most commonly seen in deep veins of the lower extremities and renal veins. Our case identifies an adult with previously diagnosed and treated for minimal change disease …

Safety, Pharmacodynamics, And Potential Benefit Of Omaveloxolone In Friedreich Ataxia, David R. Lynch, Jennifer Farmer, Lauren Hauser, Ian A. Blair, Qing Qing Wang, Clementina Mesaros, Nathaniel Snyder, Sylvia Boesch, Melanie Chin, Martin B. Delatycki, Paola Giunti, Angela Goldsberry, Chad Hoyle, Michael G. Mcbride, Wolfgang Nachbauer, Megan O'Grady, Susan Perlman, S. H. Subramony, George R. Wilmot, Theresa A. Zesiewicz, Colin Meyer

Neurology Faculty Publications

Objective Previous studies have demonstrated that suppression of Nrf2 in Friedreich ataxia tissues contributes to excess oxidative stress, mitochondrial dysfunction, and reduced ATP production. Omaveloxolone, an Nrf2 activator and NF-kB suppressor, targets dysfunctional inflammatory, metabolic, and bioenergetic pathways. The dose-ranging portion of this Phase 2 study assessed the safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia patients (NCT02255435).

Methods Sixty-nine Friedreich ataxia patients were randomized 3:1 to either omaveloxolone or placebo administered once daily for 12 weeks. Patients were randomized in cohorts of eight patients, at dose levels of 2.5–300 mg/day.

Results Omaveloxolone was well tolerated, and adverse …

Central Pain Mimicking Trigeminal Neuralgia As A Result Of Lateral Medullary Ischemic Stroke, Abinayaa Ravichandran, Kareem S. Elsayed, Hussam A. Yacoub

Neurology Faculty Publications

Background. Central pain mimicking trigeminal neuralgia (TN) as a result of lateral medullary infarction or Wallenberg syndrome has been rarely reported. Case Report. We discuss a patient who presented with a lateral medullary infarct and shortly after developed facial pain mimicking TN. We also elaborate on the anatomical pathway of the trigeminal nerve explaining facial pain as a result of a lateral medullary lesion. Discussion. Clinicians should be aware of this typical complication of lateral medullary infarct in order to attain proper management and work-up.

Protocol For Arest: Apixaban For Early Prevention Of Recurrent Embolic Stroke And Hemorrhagic Transformation—A Randomized Controlled Trial Of Early Anticoagulation After Acute Ischemic Stroke In Atrial Fibrillation, David Z. Rose, John N. Meriwether, Michael G. Fradley, Swetha Renati, Ryan C. Martin, Thomas Kasprowicz, Aarti Patel, Maxim Mokin, Ryan Murtagh, Kevin Kip, Andrea C. Bozeman, Tara Mctigue, Nicholas Hilker, Bonnie Kirby, Natasha Wick, Nhi Tran, W. Scott Burgin, Arthur J. Labovitz

Neurology Faculty Publications

Background: Optimal timing to initiate anticoagulation after acute ischemic stroke (AIS) from atrial fibrillation (AF) is currently unknown. Compared to other stroke etiologies, AF typically provokes larger infarct volumes and greater concern of hemorrhagic transformation, so seminal randomized trials waited weeks to months to begin anticoagulation after initial stroke. Subsequent data are limited and non-randomized. Guidelines suggest anticoagulation initiation windows between 3 and 14 days post-stroke, with Class IIa recommendations, and level of evidence B in the USA and C in Europe.

Aims: This open-label, parallel-group, multi-center, randomized controlled trial AREST (Apixaban for Early Prevention of Recurrent Embolic Stroke and …

Pathophysiology Of Ganglioside Gm1 In Ischemic Stroke: Ganglioside Gm1: A Critical Review, Wenchao Zhang, Paul R. Krafft, Tianlong Wang, John H. Zhang, Li Li, Jiping Tang

Neurosurgery and Brain Repair Faculty Publications

Ganglioside GM1 is a member of the ganglioside family which has been used in many countries and is thought of as a promising alternative treatment for preventing several neurological diseases, including cerebral ischemic injury. The therapeutic effects of GM1 have been proved both in neonates and in adults following ischemic brain damage; however, its clinical efficacy in patients with ischemic stroke is still uncertain. This review examines the recent knowledge of the neuroprotective properties of GM1 in ischemic stroke, collected in the past two decades. We conclude that GM1 may have potential for stroke treatment, although we need to be …

Microrna-133a And Myocardial Infarction, Yi Xiao, Jiling Zhao, Julian P. Tuazon, Cesar V. Borlongan, Guolong Yu

Neurosurgery and Brain Repair Faculty Publications

Myocardial infarction (MI) is the leading cause of morbidity and mortality in the world. The infarcted heart displays typical cell death cascades characterized by a loss of cells and fibrotic scarring in the myocardium. Cardiac hypertrophy and fibrosis largely contribute to ventricular wall thickening and stiffening, altogether defining an adverse cardiac remodeling that ultimately leads to impaired cardiac function and subsequent heart failure. Finding a strategy to promote therapeutic, instead of detrimental, cardiac remodeling may pose as a potent MI treatment. Accumulating evidence shows that microRNAs (miRNAs) may play an essential role in cardiovascular diseases. In particular, microRNA-133a (miR-133a) is …

Prophylactic Treatment Of Hyperbaric Oxygen Treatment Mitigates Inflammatory Response Via Mitochondria Transfer, Trenton Lippert, Cesar V. Borlongan

Neurosurgery and Brain Repair Faculty Publications

No abstract provided.

Gutting The Brain Of Inflammation: A Key Role Of Gut Microbiome In Human Umbilical Cord Blood Plasma Therapy In Parkinson's Disease Model, Jea-Young Lee, Julian P. Tuazon, Jared Ehrhart, Paul R. Sanberg, Cesar V. Borlongan

Neurosurgery and Brain Repair Faculty Publications

Current therapies for Parkinson's disease (PD), including L-3,4-dihydroxyphenylalanine (L-DOPA), and clinical trials investigating dopaminergic cell transplants, have generated mixed results with the eventual induction of dyskinetic side effects. Although human umbilical cord blood (hUCB) stem/progenitor cells present with no or minimal capacity of differentiation into mature dopaminergic neurons, their transplantation significantly attenuates parkinsonian symptoms likely via bystander effects, specifically stem cell graft-mediated secretion of growth factors, anti-inflammatory cytokines, or synaptic function altogether promoting brain repair. Recognizing this non-cell replacement mechanism, we examined here the effects of intravenously transplanted combination of hUCB-derived plasma into the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced rat model of PD. …

Concise Review: Stem Cell Therapy For Stroke Patients: Are We There Yet?, Cesar V. Borlongan

Neurosurgery and Brain Repair Faculty Publications

Four decades of preclinical research demonstrating survival, functional integration, and behavioral effects of transplanted stem cells in experimental stroke models have provided ample scientific basis for initiating limited clinical trials of stem cell therapy in stroke patients. Although safety of the grafted cells has been overwhelmingly documented, efficacy has not been forthcoming. Two recently concluded stroke clinical trials on mesenchymal stem cells (MSCs) highlight the importance of strict adherence to the basic science findings of optimal transplant regimen of cell dose, timing, and route of delivery in enhancing the functional outcomes of cell therapy. Echoing the Stem Cell Therapeutics as …

A Hallmark Clinical Study Of Cord Blood Therapy In Adults With Ischemic Stroke, Paul R. Sanberg, Jared Ehrhart

Neurosurgery and Brain Repair Faculty Publications

The therapeutic application of human umbilical cord blood cells has been an area of great interest for at least the last 25 years. Currently, cord blood cells are approved for reconstitution of the bone marrow following myeloablation in both young and old patients with myeloid malignancies and other blood cancers. Translational studies investigating alternative uses of cord blood have also shown that these cells not only stimulate neurogenesis in the aged brain but are also potentially therapeutic in the treatment of adult neurodegenerative disorders including amyotrophic lateral sclerosis, Alzheimer’s disease, ischemic stroke, traumatic brain injury, and Parkinson’s disease. Recent advances …

Immunomodulation With Human Umbilical Cord Blood Stem Cells Ameliorates Ischemic Brain Injury – A Brain Transcriptome Profiling Analysis, Maple L. Shiao, Ce Yuan, Andrew T. Crane, Joseph P. Voth, Mario Juliano, Laura L. Hocum Stone, Zhenghong Nan, Ying Zhang, Nicole Kuzmin-Nichols, Paul R. Sanberg, Andrew W. Grande, Walter C. Low

Neurosurgery and Brain Repair Faculty Publications

Our group previously demonstrated that administration of a CD34-negative fraction of human non- hematopoietic umbilical cord blood stem cells (UCBSC) 48 h after ischemic injury could reduce infarct volume by 50% as well as significantly ameliorate neurological deficits. In the present study, we explored possible mechanisms of action using next generation RNA sequencing to analyze the brain transcriptome profiles in rats with ischemic brain injury following UCBSC therapy. Two days after ischemic injury, rats were treated with UCBSC. Five days after administration, total brain mRNA was then extracted for RNAseq analysis using Illumina Hiseq 2000. We found 275 genes that …