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Macrophages Respond Rapidly To Ototoxic Injury Of Lateral Line Hair Cells But Are Not Required For Hair Cell Regeneration, Mark E Warchol, Angela Schrader, Lavinia Sheets

Open Access Publications

The sensory organs of the inner ear contain resident populations of macrophages, which are recruited to sites of cellular injury. Such macrophages are known to phagocytose the debris of dying cells but the full role of macrophages in otic pathology is not understood. Lateral line neuromasts of zebrafish contain hair cells that are nearly identical to those in the inner ear, and the optical clarity of larval zebrafish permits direct imaging of cellular interactions. In this study, we used larval zebrafish to characterize the response of macrophages to ototoxic injury of lateral line hair cells. Macrophages migrated into neuromasts within …

A Single Amino Acid Change To Taq Dna Polymerase Enables Faster Pcr, Reverse Transcription And Strand-Displacement, Wayne M Barnes, Zhian Zhang, Milko B Kermekchiev

Open Access Publications

A change of an aspartic acid to asparagine of Taq (

Blood Biomarkers For Detection Of Brain Injury In Covid-19 Patients, Steven T. Dekosky, Lawrence Lewis, Stacey House, Et Al.

Open Access Publications

No abstract provided.

Upregulation Of 5′‑Terminal Oligopyrimidine Mrna Translation Upon Loss Of The Arf Tumor Suppressor, Kyle A. Cottrell, Ryan C. Chiou, Jason D. Weber

Open Access Publications

No abstract provided.

Postural Directionality And Head Tremor In Cervical Dystonia, Qiyu Chen, Jeanne P Vu, Elizabeth Cisneros, Casey N Benadof, Zheng Zhang, Richard L Barbano, Christopher G Goetz, Joseph Jankovic, Hyder A Jinnah, Joel S Perlmutter, Mark I Appelbaum, Glenn T Stebbins, Cynthia L Comella, David A Peterson

Open Access Publications

Background: Although abnormal head and neck postures are defining features of cervical dystonia (CD), head tremor (HT) is also common. However, little is known about the relationship between abnormal postures and HT in CD.

Methods: We analyzed clinical data and video recordings from 185 patients enrolled by the Dystonia Coalition. We calculated the likelihood of their HT and HT type ("regular" vs. "jerky") given directionality of abnormal head postures, disease duration, sex, and age.

Results: Patients with retrocollis were more likely to have HT than patients with anterocollis (X

Discussion: We found that HT is more likely for CD patients …

Community Health Behaviors And Geographic Variation In Early-Onset Colorectal Cancer Survival Among Women, Andreana N. Holowatyj, Marvin E. Langston, Yunan Han, Richard Viskochil, Jose Perea, Yin Cao, Charles R. Rogers, Christopher H. Lieu, Justin X. Moore

Open Access Publications

No abstract provided.

Determinants Of Mammographic Breast Density By Race Among A Large Screening Population, Justin X. Moore, Yunan Han, Catherine Appleton, Graham Colditz, Adetunji T. Toriola

Open Access Publications

Background: Because of the mixed reports from smaller studies, we examined associations of race with mammographic breast density and evaluated racial differences in the determinants of breast density.

Methods: Participants included 37 839 women (23 166 non-Hispanic white and 14 673 African American) receiving screening mammograms at the Joanne Knight Breast Health Center at Washington University School of Medicine from June 2010 to December 2015. Mammographic breast density was assessed using the Breast Imaging Reporting and Data System (5th edition). To determine the association of race and participant characteristics with mammographic breast density, we used multivariable polytomous logistic regression models …

An Atypical Brct-Brct Interaction With The Xrcc1 Scaffold Protein Compacts Human Dna Ligase Iiiα Within A Flexible Dna Repair Complex, Michal Hammel, Ishtiaque Rashid, Aleksandr Sverzhinsky, Yasin Pourfarjam, Miaw-Sheue Tsai, Tom Ellenberger, John M. Pascal, In-Kwon Kim, John A. Tainer, Alan E. Tomkinson

Open Access Publications

The XRCC1-DNA ligase IIIα complex (XL) is critical for DNA single-strand break repair, a key target for PARP inhibitors in cancer cells deficient in homologous recombination. Here, we combined biophysical approaches to gain insights into the shape and conformational flexibility of the XL as well as XRCC1 and DNA ligase IIIα (LigIIIα) alone. Structurally-guided mutational analyses based on the crystal structure of the human BRCT-BRCT heterodimer identified the network of salt bridges that together with the N-terminal extension of the XRCC1 C-terminal BRCT domain constitute the XL molecular interface. Coupling size exclusion chromatography with small angle X-ray scattering and multiangle …

The Alzheimer's Biomarker Consortium-Down Syndrome: Rationale And Methodology, Benjamin L Handen, Anne M Fagan, Beau Ances, Et Al

Open Access Publications

Introduction: Adults with Down syndrome (DS) are at exceptionally high risk for Alzheimer's disease (AD), with virtually all individuals developing key neuropathological features by age 40. Identifying biomarkers of AD progression in DS can provide valuable insights into pathogenesis and suggest targets for disease modifying treatments.

Methods: We describe the development of a multi-center, longitudinal study of biomarkers of AD in DS. The protocol includes longitudinal examination of clinical, cognitive, blood and cerebrospinal fluid-based biomarkers, magnetic resonance imaging and positron emission tomography measures (at 16-month intervals), as well as genetic modifiers of AD risk and progression.

Results: Approximately 400 individuals …

Cerebrospinal Fluid Biomarkers Of Alzheimer's Disease In A Cohort Of Adults With Down Syndrome, Rachel L Henson, Eric Doran, Bradley T Christian, Benjamin L Handen, William E Klunk, Florence Lai, Joseph H Lee, H Diana Rosas, Nicole Schupf, Shahid H Zaman, Ira T Lott, Anne M Fagan

Open Access Publications

Introduction: Virtually all individuals with Down syndrome (DS) will develop Alzheimer's disease (AD) pathology by age 40. Cerebrospinal fluid (CSF) biomarkers have characterized AD pathology in cohorts of late-onset AD (LOAD) and autosomal-dominant AD (ADAD). Few studies have evaluated such biomarkers in adults with DS.

Methods: CSF concentrations of amyloid beta (Aβ)40, Aβ42, tau, phospho-tau181 (p-tau), neurofilament light chain (NfL), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase-3-like protein 1 (YKL-40), alpha synuclein (αSyn), neurogranin (Ng), synaptosomal-associated protein 25 (SNAP-25), and visinin-like protein 1 (VILIP-1) were assessed in CSF from 44 adults with DS from the Alzheimer's Biomarker …

Sexually Dimorphic Impact Of The Iron-Regulating Gene, Hfe, On Survival In Glioblastoma, Darya S Nesterova, Vishal Midya, Brad E Zacharia, Elizabeth A Proctor, Sang Y Lee, Lindsay C Stetson, Justin D Lathia, Joshua B Rubin, Kristin A Waite, Michael E Berens, Jill S Barnholtz-Sloan, James R Connor

Open Access Publications

BACKGROUND: The median survival for patients with glioblastoma (GBM), the most common primary malignant brain tumor in adults, has remained approximately 1 year for more than 2 decades. Recent advances in the field have identified GBM as a sexually dimorphic disease. It is less prevalent in females and they have better survival compared to males. The molecular mechanism of this difference has not yet been established. Iron is essential for many biological processes supporting tumor growth and its regulation is impacted by sex. Therefore, we interrogated the expression of a key component of cellular iron regulation, the

METHODS: We analyzed …

Gliomas Display Distinct Sex-Based Differential Methylation Patterns Based On Molecular Subtype, Mette L Johansen, L C Stetson, Vachan Vadmal, Kristin Waite, Michael E Berens, James R Connor, Justin Lathia, Joshua B Rubin, Jill S Barnholtz-Sloan

Open Access Publications

BACKGROUND: Gliomas are the most common type of primary brain tumor and one of many cancers where males are diagnosed with greater frequency than females. However, little is known about the sex-based molecular differences in glioblastomas (GBMs) or lower grade glioma (non-GBM) subtypes. DNA methylation is an epigenetic mechanism involved in regulating gene transcription. In glioma and other cancers, hypermethylation of specific gene promoters downregulates transcription and may have a profound effect on patient outcome. The purpose of this study was to determine if sex-based methylation differences exist in different glioma subtypes.

METHODS: Molecular and clinical data from glioma patients …

Insights Into The Role Of The Jak/Stat Signaling Pathway In Graft-Versus-Host Disease, Ramzi Abboud, Jaebok Choi, Peter Ruminski, Mark A Schroeder, Sena Kim, Camille N Abboud, John F Dipersio

Open Access Publications

Allogeneic hematopoietic transplantation (allo-HCT) is a curative therapy for a variety of hematologic malignancies, primarily through immune-mediated clearance of malignant cells. This graft-

Comparing Sensitivity To Change Using The 6-Item Versus The 17-Item Hamilton Depression Rating Scale In The Guided Randomized Controlled Trial, Boadie W Dunlop, Sagar V Parikh, Anthony J Rothschild, Michael E Thase, Charles Debattista, Charles R Conway, Brent P Forester, Francis M Mondimore, Richard C Shelton, Matthew Macaluso, Jennifer Logan, Paul Traxler, James Li, Holly Johnson, John F Greden

Open Access Publications

BACKGROUND: Previous research suggests that the 17-item Hamilton Depression Rating Scale (HAM-D17) is less sensitive in detecting differences between active treatment and placebo for major depressive disorder (MDD) than is the HAM-D6 scale, which focuses on six core depression symptoms. Whether HAM-D6 shows greater sensitivity when comparing two active MDD treatment arms is unknown.

METHODS: This post hoc analysis used data from the intent-to-treat (ITT) cohort (N = 1541) of the Genomics Used to Improve DEpression Decisions (GUIDED) trial, a rater- and patient-blinded randomized controlled trial. GUIDED compared combinatorial pharmacogenomics-guided care with treatment as usual (TAU) in patients with MDD. …

Humanized Zebrafish Enhance Human Hematopoietic Stem Cell Survival And Promote Acute Myeloid Leukemia Clonal Diversity, Vinothkumar Rajan, Nicole Melong, Wing Hing Wong, Benjamin King, R. Spencer Tong, Nithin Mahajan, Daniel Gaston, Troy Lund, David Rittenberg, Graham Dellaire, Clinton J. V. Campbell, Todd Druley, Jason N. Berman

Open Access Publications

Xenograft models are invaluable tools in establishing the current paradigms of hematopoiesis and leukemogenesis. The zebrafish has emerged as a robust alternative xenograft model but, like mice, lack specific cytokines that mimic the microenvironment found in human patients. To address this critical gap, we generated the first humanized zebrafish that express human hematopoietic-specific cytokines (GM-CSF, SCF, and SDF1α). Termed GSS fish, these zebrafish promote survival, self-renewal and multilineage differentiation of human hematopoietic stem and progenitor cells and result in enhanced proliferation and hematopoietic niche-specific homing of primary human leukemia cells. Using error-corrected RNA sequencing, we determined that patient-derived leukemias transplanted …

Comparison Of Reproducibility, Accuracy, Sensitivity, And Specificity Of Mirna Quantification Platforms, Paula M Godoy, Andrea J Barczak, Peter Dehoff, Srimeenakshi Srinivasan, Alton Etheridge, David Galas, Saumya Das, David J Erle, Louise C Laurent

Open Access Publications

Given the increasing interest in their use as disease biomarkers, the establishment of reproducible, accurate, sensitive, and specific platforms for microRNA (miRNA) quantification in biofluids is of high priority. We compare four platforms for these characteristics: small RNA sequencing (RNA-seq), FirePlex, EdgeSeq, and nCounter. For a pool of synthetic miRNAs, coefficients of variation for technical replicates are lower for EdgeSeq (6.9%) and RNA-seq (8.2%) than for FirePlex (22.4%); nCounter replicates are not performed. Receiver operating characteristic analysis for distinguishing present versus absent miRNAs shows small RNA-seq (area under curve 0.99) is superior to EdgeSeq (0.97), nCounter (0.94), and FirePlex (0.81). …

The Aminoalkylindole Bml-190 Negatively Regulates Chitosan Synthesis Via The Cyclic Amp/Protein Kinase A1 Pathway In Cryptococcus Neoformans, Brian T Maybruck, Woei C Lam, Charles A Specht, Ma Xenia G Ilagan, Maureen J Donlin, Jennifer K Lodge

Open Access Publications

No abstract provided.

The Role Of Glia In Epilepsy, Intellectual Disability, And Other Neurodevelopmental Disorders In Tuberous Sclerosis Complex, Michael Wong

Open Access Publications

BACKGROUND: Tuberous sclerosis complex (TSC) is a genetic disorder characterized by severe neurological manifestations, including epilepsy, intellectual disability, autism, and a range of other behavioral and psychiatric symptoms, collectively referred to as TSC-associated neuropsychiatric disorders (TAND). Various tumors and hamartomas affecting different organs are the pathological hallmarks of the disease, especially cortical tubers of the brain, but specific cellular and molecular abnormalities, such as involving the mechanistic target of rapamycin (mTOR) pathway, have been identified that also cause or contribute to neurological manifestations of TSC independent of gross structural lesions. In particular, while neurons are immediate mediators of neurological symptoms, …

Regional Gene Repression By Dna Double-Strand Breaks In G1 Phase Cells, Caitlin E. Purman, Patrick L. Collins, Sofia I. Porter, Ankita Saini, Harshath Gupta, Barry P. Sleckman, Eugene M. Oltz

Open Access Publications

DNA damage responses (DDR) to double-strand breaks (DSBs) alter cellular transcription programs at the genome-wide level. Through processes that are less well understood, DSBs also alter transcriptional responses locally, which may be important for efficient DSB repair. Here, we developed an approach to elucidate the

Cytogps: A Web-Enabled Karyotype Analysis Tool For Cytogenetics, Zachary B Abrams, Lin Zhang, Lynne V Abruzzo, Nyla A Heerema, Suli Li, Tom Dillon, Ricky Rodriguez, Kevin R Coombes, Philip R O Payne

Open Access Publications

SUMMARY: Karyotype data are the most common form of genetic data that is regularly used clinically. They are collected as part of the standard of care in many diseases, particularly in pediatric and cancer medicine contexts. Karyotypes are represented in a unique text-based format, with a syntax defined by the International System for human Cytogenetic Nomenclature (ISCN). While human-readable, ISCN is not intrinsically machine-readable. This limitation has prevented the full use of complex karyotype data in discovery science use cases. To enhance the utility and value of karyotype data, we developed a tool named CytoGPS. CytoGPS first parses ISCN karyotypes …

Distinct Roles Of Interferon Alpha And Beta In Controlling Chikungunya Virus Replication And Modulating Neutrophil-Mediated Inflammation, Lindsey E Cook, Marissa C Locke, Alissa R Young, Kristen Monte, Matthew L Hedberg, Raeann M Shimak, Kathleen C F Sheehan, Deborah J Veis, Michael S Diamond, Deborah J Lenschow

Open Access Publications

Type I interferons (IFNs) are key mediators of the innate immune response. Although members of this family of cytokines signal through a single shared receptor, biochemical and functional variation exists in response to different IFN subtypes. While previous work has demonstrated that type I IFNs are essential to control infection by chikungunya virus (CHIKV), a globally emerging alphavirus, the contributions of individual IFN subtypes remain undefined. To address this question, we evaluated CHIKV pathogenesis in mice lacking IFN-β (IFN-β knockout [IFN-β-KO] mice or mice treated with an IFN-β-blocking antibody) or IFN-α (IFN regulatory factor 7 knockout [IRF7-KO] mice or mice …

Let-7 Micrornas Regulate Microglial Function And Suppress Glioma Growth Through Toll-Like Receptor 7, Alice Buonfiglioli, David H Gutmann, Et Al

Open Access Publications

Microglia express Toll-like receptors (TLRs) that sense pathogen- and host-derived factors, including single-stranded RNA. In the brain, let-7 microRNA (miRNA) family members are abundantly expressed, and some have recently been shown to serve as TLR7 ligands. We investigated whether let-7 miRNA family members differentially control microglia biology in health and disease. We found that a subset of let-7 miRNA family members function as signaling molecules to induce microglial release of inflammatory cytokines, modulate antigen presentation, and attenuate cell migration in a TLR7-dependent manner. The capability of the let-7 miRNAs to control microglial function is sequence specific, mapping to a let-7 …

The Local Translation Of Kna In Dendritic Projections Of Auditory Neurons And The Roles Of Kna In The Transition From Hidden To Overt Hearing Loss, Jeong Han Lee, Mincheol Kang, Seojin Park, Maria C. Perez-Flores, Xiao-Dong Zhang, Wenying Wang, Michael Anne Gratton, Nipavan Chiamvimonvat, Ebenezer N. Yamoah

Open Access Publications

Local and privileged expression of dendritic proteins allows segregation of distinct functions in a single neuron but may represent one of the underlying mechanisms for early and insidious presentation of sensory neuropathy. Tangible characteristics of early hearing loss (HL) are defined in correlation with nascent hidden hearing loss (HHL) in humans and animal models. Despite the plethora of causes of HL, only two prevailing mechanisms for HHL have been identified, and in both cases, common structural deficits are implicated in inner hair cell synapses, and demyelination of the auditory nerve (AN). We uncovered that Na

Text-Mining Clinically Relevant Cancer Biomarkers For Curation Into The Civic Database, Jake Lever, Martin R Jones, Arpad M Danos, Kilannin Krysiak, Melika Bonakdar, Jasleen K Grewal, Luka Culibrk, Obi L Griffith, Malachi Griffith, Steven J M Jones

Open Access Publications

BACKGROUND: Precision oncology involves analysis of individual cancer samples to understand the genes and pathways involved in the development and progression of a cancer. To improve patient care, knowledge of diagnostic, prognostic, predisposing, and drug response markers is essential. Several knowledgebases have been created by different groups to collate evidence for these associations. These include the open-access Clinical Interpretation of Variants in Cancer (CIViC) knowledgebase. These databases rely on time-consuming manual curation from skilled experts who read and interpret the relevant biomedical literature.

METHODS: To aid in this curation and provide the greatest coverage for these databases, particularly CIViC, we …

Developmental Hypomyelination In Wolfram Syndrome: New Insights From Neuroimaging And Gene Expression Analyses, Amjad Samara, Rachel Rahn, Olga Neyman, Ki Yun Park, Ahmad Samara, Bess Marshall, Joseph Dougherty, Tamara Hershey

Open Access Publications

Wolfram syndrome is a rare multisystem disorder caused by mutations in WFS1 or CISD2 genes leading to brain structural abnormalities and neurological symptoms. These abnormalities appear in early stages of the disease. The pathogenesis of Wolfram syndrome involves abnormalities in the endoplasmic reticulum (ER) and mitochondrial dynamics, which are common features in several other neurodegenerative disorders. Mutations in WFS1 are responsible for the majority of Wolfram syndrome cases. WFS1 encodes for an endoplasmic reticulum (ER) protein, wolframin. It is proposed that wolframin deficiency triggers the unfolded protein response (UPR) pathway resulting in an increased ER stress-mediated neuronal loss. Recent neuroimaging …

Association Of Aspirin Use With Mortality Risk Among Older Adult Participants In The Prostate, Lung, Colorectal, And Ovarian Cancer Screening Trial, Holli A. Loomans-Kropp, Paul Pinsky, Yin Cao, Andrew T. Chan, Asad Umar

Open Access Publications

Importance: Aspirin use has been associated with reduced risk of cancer mortality, particularly of the colorectum. However, aspirin efficacy may be influenced by biological characteristics, such as obesity and age. With the increasing prevalence of obesity and conflicting data regarding the effect of aspirin in older adults, understanding the potential association of aspirin use with cancer mortality according to body mass index (BMI) and age is imperative.

Objectives: To investigate the association of aspirin use with risk of all-cause, any cancer, gastrointestinal (GI) cancer, and colorectal cancer (CRC) mortality among older adults and to perform an exploratory analysis of the …

Sik3 Suppresses Neuronal Hyperexcitability By Regulating The Glial Capacity To Buffer K+ And Water, Hailun Li, Alexandra Russo, Aaron Diantonio

Open Access Publications

Glial regulation of extracellular potassium (K

Disease-Associated Mutations In Niemann-Pick Type C1 Alter Er Calcium Signaling And Neuronal Plasticity, Scott A. Tiscione, Oscar Vivas, Kenneth S. Ginsburg, Donald M. Bers, Daniel S. Ory, Luis F. Santana, Rose E. Dixon, Eamonn J. Dickson

Open Access Publications

Niemann-Pick type C1 (NPC1) protein is essential for the transport of externally derived cholesterol from lysosomes to other organelles. Deficiency of NPC1 underlies the progressive NPC1 neurodegenerative disorder. Currently, there are no curative therapies for this fatal disease. Given the Ca

Association Of Longitudinal Changes In Cerebrospinal Fluid Total Tau And Phosphorylated Tau 181 And Brain Atrophy With Disease Progression In Patients With Alzheimer Disease, Jorge J. Llibre-Guerra, Yan Li, Suzanne E. Schindler, Brian A. Gordon, Anne M. Fagan, John C. Morris, Tammie L.S. Benzinger, Jason Hassenstab, Sarah B. Berman, David M. Holtzman, Chengjie Xiong, Randall J. Bateman, Eric Mcdade

Open Access Publications

Importance: The amyloid/tau/neurodegeneration (A/T/N) framework uses cerebrospinal fluid (CSF) levels of total tau (tTau) as a marker of neurodegeneration and CSF levels of phosphorylated tau 181 (pTau181) as a marker of tau tangles. However, it is unclear whether CSF levels of tTau and pTau181 have similar or different trajectories over the course of Alzheimer disease.

Objectives: To examine the rates of change in CSF levels of tTau and pTau181 across the Alzheimer disease course and how the rates of change are associated with brain atrophy as measured by magnetic resonance imaging.

Design, Setting, and Participants: This cohort study was set …

Tricarboxylic Acid Cycle Enzyme Activities In A Mouse Model Of Methylmalonic Aciduria, Parith Wongkittichote, Gary Cunningham, Marshall L Summar, Elena Pumbo, Patrick Forny, Matthias R Baumgartner, Kimberly A Chapman

Open Access Publications

Methylmalonic acidemia (MMA) is a propionate pathway disorder caused by dysfunction of the mitochondrial enzyme methylmalonyl-CoA mutase (MMUT). MMUT catalyzes the conversion of methylmalonyl-CoA to succinyl-CoA, an anaplerotic reaction which feeds into the tricarboxylic acid (TCA) cycle. As part of the pathological mechanisms of MMA, previous studies have suggested there is decreased TCA activity due to a "toxic inhibition" of TCA cycle enzymes by MMA related metabolites, in addition to reduced anaplerosis. Here, we have utilized mitochondria isolated from livers of a mouse model of MMA (Mut-ko/ki) and their littermate controls (Ki/wt) to examine the amounts and enzyme functions of …