Digital Commons Network^™

Site-Specific Effects Of Neurosteroids On Gaba(A) Receptor Activation And Desensitization, Yusuke Sugasawa, Wayland W.L. Cheng, John R. Bracamontes, Zi-Wei Chen, Lei Wang, Allison L. Germann, Spencer R. Pierce, Thomas C. Senneff, Kathiresan Krishnan, David E. Reichert, Douglas F. Covey, Gustav Akk, Alex S. Evers

Open Access Publications

This study examines how site-specific binding to three identified neurosteroid-binding sites in the α

Validation Of A Parkinson Disease Predictive Model In A Population-Based Study, Irene M. Faust, Brad A. Racette, Susan Searles Nielsen

Open Access Publications

No abstract provided.

Lung Secretoglobin Scgb1a1 Influences Alveolar Macrophage-Mediated Inflammation And Immunity, Min Xu, Wei Yang, Xuanchuan Wang, Deepak Kumar Nayak

Open Access Publications

Alveolar macrophage (AM) is a mononuclear phagocyte key to the defense against respiratory infections. To understand AM's role in airway disease development, we examined the influence of Secretoglobin family 1a member 1 (SCGB1A1), a pulmonary surfactant protein, on AM development and function. In a murine model, high-throughput RNA-sequencing and gene expression analyses were performed on purified AMs isolated from mice lacking in

A Novel Method For High-Dimensional Anatomical Mapping Of Extra-Axial Cerebrospinal Fluid: Application To The Infant Brain, Mahmoud Mostapha, Sun Hyung Kim, Alan C Evans, Stephen R Dager, Annette M Estes, Robert C Mckinstry, Kelly N Botteron, Guido Gerig, Stephen M Pizer, Robert T Schultz, Heather C Hazlett, Joseph Piven, Jessica B Girault, Mark D Shen, Martin A Styner

Open Access Publications

Cerebrospinal fluid (CSF) plays an essential role in early postnatal brain development. Extra-axial CSF (EA-CSF) volume, which is characterized by CSF in the subarachnoid space surrounding the brain, is a promising marker in the early detection of young children at risk for neurodevelopmental disorders. Previous studies have focused on global EA-CSF volume across the entire dorsal extent of the brain, and not regionally-specific EA-CSF measurements, because no tools were previously available for extracting local EA-CSF measures suitable for localized cortical surface analysis. In this paper, we propose a novel framework for the localized, cortical surface-based analysis of EA-CSF. The proposed …

Characterization Of The Complete Mitochondrial Genomes Of Two Sibling Species Of Parasitic Roundworms, Haemonchus Contortus And Teladorsagia Circumcincta, Nikola Palevich, Paul H Maclean, Young-Jun Choi, Makedonka Mitreva

Open Access Publications

No abstract provided.

Phase I Study Of Vemurafenib In Children With Recurrent Or Progressive Brafv600e Mutant Brain Tumors: Pacific Pediatric Neuro-Oncology Consortium Study (Pnoc-002), Theodore Nicolaides, Karen Gauvain, Et Al

Open Access Publications

No abstract provided.

Tourette Syndrome Research Highlights From 2019, Andreas Hartmann, Yulia Worbe, Kevin J Black

Open Access Publications

This is the sixth yearly article in the Tourette Syndrome Research Highlights series, summarizing research from 2019 relevant to Tourette syndrome and other tic disorders. The highlights from 2020 is being drafted on the Authorea online authoring platform; readers are encouraged to add references or give feedback on our selections comments feature on this page. After the calendar year ends, this article is submitted as the annual update for the Tics collection F1000Research.

Tictimer Web: Software For Measuring Tic Suppression Remotely, Jonathan K Black, Jonathan M Koller, Kevin J. Black

Open Access Publications

Woods and Himle developed a standardized tic suppression paradigm (TSP) for the experimental setting, to quantify the effects of intentional tic suppression in Tourette syndrome. We previously provided a computer program to facilitate recording tic occurrence and to automate reward delivery during the several experimental conditions of the TSP. The present article describes a web-based program that performs the same functions. Implementing this program on the web allows research sessions to be performed remotely, in tandem with a video calling program. Relevant data for each session, such as the timing of tics and dispensed rewards, are stored in plain text …

Assessment Of Potential Risk Factors For The Development Of Persistent Postural-Perceptual Dizziness: A Case-Control Pilot Study, Aaron Trinidade, Paula Harman, Jon Stone, Jeffrey P Staab, Joel A Goebel

Open Access Publications

No abstract provided.

Apurinic/Apyrimidinic Endonuclease 1 Restricts The Internalization Of Bacteria Into Human Intestinal Epithelial Cells Through The Inhibition Of Rac1, Gerco Den Hartog, Lindsay D Butcher, Amber L Ablack, Laura A Pace, Jailal N G Ablack, Richard Xiong, Soumita Das, Thaddeus S Stappenbeck, Lars Eckmann, Peter B Ernst, Sheila E Crowe

Open Access Publications

Pathogenic intestinal bacteria lead to significant disease in humans. Here we investigated the role of the multifunctional protein, Apurinic/apyrimidinic endonuclease 1 (APE1), in regulating the internalization of bacteria into the intestinal epithelium. Intestinal tumor-cell lines and primary human epithelial cells were infected with

Rna Based Approaches To Profile Oncogenic Pathways From Low Quantity Samples To Drive Precision Oncology Strategies, Anja Van De Stolpe, Wim Verhaegh, Jean-Yves Blay, Cynthia X Ma, Patrick Pauwels, Mark Pegram, Hans Prenen, Dirk De Ruysscher, Nabil F Saba, Susan F Slovin, Karen Willard-Gallo, Hatim Husain

Open Access Publications

Precision treatment of cancer requires knowledge on active tumor driving signal transduction pathways to select the optimal effective targeted treatment. Currently only a subset of patients derive clinical benefit from mutation based targeted treatment, due to intrinsic and acquired drug resistance mechanisms. Phenotypic assays to identify the tumor driving pathway based on protein analysis are difficult to multiplex on routine pathology samples. In contrast, the transcriptome contains information on signaling pathway activity and can complement genomic analyses. Here we present the validation and clinical application of a new knowledge-based mRNA-based diagnostic assay platform (OncoSignal) for measuring activity of relevant signaling …

Ige And T Cell Reactivity To A Comprehensive Panel Of Cockroach Allergens In Relation To Disease, Anna Pomés, Véronique Schulten, Jill Glesner, Ricardo Da Silva Antunes, Aaron Sutherland, Leonard B Bacharier, Avraham Beigelman, Paula Busse, April Frazier, Alessandro Sette

Open Access Publications

IgE sensitization to cockroach allergens is associated with development of allergic diseases, such as asthma. To understand the relevance of different cockroach allergens for diagnosis and immunotherapy, a comprehensive analysis of IgE antibody levels and T cell reactivity to an expanded set of cockroach allergens and their relationship to disease was performed in a cohort of USA cockroach sensitized patients. IgE antibody levels to recombinant chitinase and hemocyanin were measured for 23 subjects by custom-made ImmunoCAPs and compared with IgE levels to eight cockroach allergens we previously reported for the same cohort.

Affinity-Restricted Memory B Cells Dominate Recall Responses To Heterologous Flaviviruses, Rachel Wong, Julia A. Belk, Jennifer Govero, Jennifer L. Uhrlaub, Dakota Reinartz, Haiyan Zhao, John M. Errico, Lucas D'Souza, Tyler J. Ripperger, Janko Nikolich-Zugich, Mark J. Shlomchik, Ansuman T. Satpathy, Daved H. Fremont, Michael S. Diamond, Deepta Bhattacharya

Open Access Publications

No abstract provided.

Intensive Teenage Activity Is Associated With Greater Muscle Hyperintensity On T1w Magnetic Resonance Imaging In Adults With Dysferlinopathy, Ursula Moore, Alan Pestronk, Et Al

Open Access Publications

Practice of sports during childhood or adolescence correlates with an earlier onset and more rapidly progressing phenotype in dysferlinopathies. To determine if this correlation relates to greater muscle pathology that persists into adulthood, we investigated the effect of exercise on the degree of muscle fatty replacement measured using muscle MRI. We reviewed pelvic, thigh and leg T1W MRI scans from 160 patients with genetically confirmed dysferlinopathy from the Jain Foundation International clinical outcomes study in dysferlinopathy. Two independent assessors used the Lamminen-Mercuri visual scale to score degree of fat replacement in each muscle. Exercise intensity for each individual was defined …

Direct Tumor Visual Feedback During Free Breathing In 0.35t Mrgrt, Taeho Kim, Benjamin C Lewis, Alex Price, Thomas Mazur, H Michael Gach, Justin C Park, Bin Cai, Erin Wittland, Lauren Henke, Hyun Kim, Sasa Mutic, Olga Green

Open Access Publications

To present a tumor motion control system during free breathing using direct tumor visual feedback to patients in 0.35 T magnetic resonance-guided radiotherapy (MRgRT). We present direct tumor visualization to patients by projecting real-time cine MR images on an MR-compatible display system inside a 0.35 T MRgRT bore. The direct tumor visualization included anatomical images with a target contour and an auto-segmented gating contour. In addition, a beam-status sign was added for patient guidance. The feasibility was investigated with a six-patient clinical evaluation of the system in terms of tumor motion range and beam-on time. Seven patients without visual guidance …

Krasg12c Inhibition With Sotorasib In Advanced Solid Tumors, David S. Hong, Ramaswamy Govindan, Et Al

Open Access Publications

No abstract provided.

Consumptive Coagulopathy Of Severe Yellow Fever Occurs Independently Of Hepatocellular Tropism And Massive Hepatic Injury, Adam L. Bailey, Liang-I Kang, Luiz Gonzaga Francisco De Assis Barros D'Elia Zanella, Cássia G. T. Silveira, Yeh-Li Ho, Lander Foquet, Greg Bial, Broc T. Mccune, Amaro Nunes Duarte-Neto, Archana Thomas, Hans-Peter Raué, Kathleen Byrnes, Esper G. Kallas, Mark K. Slifka, Michael S. Diamond

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.

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 …

A Recommended "Minimum Data Set" Framework For Sd-Oct Retinal Image Acquisition And Analysis From The Atlas Of Retinal Imaging In Alzheimer's Study (Arias), Jessica Alber, Gregory Van Stavern, Et Al

Open Access Publications

Introduction: We propose a minimum data set framework for the acquisition and analysis of retinal images for the development of retinal Alzheimer's disease (AD) biomarkers. Our goal is to describe methodology that will increase concordance across laboratories, so that the broader research community is able to cross-validate findings in parallel, accumulate large databases with normative data across the cognitive aging spectrum, and progress the application of this technology from the discovery stage to the validation stage in the search for sensitive and specific retinal biomarkers in AD.

Methods: The proposed minimum data set framework is based on the Atlas of …

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 …

A Qualitative Study Of Older Adults' Perspectives On Initiating Exercise And Mindfulness Practice, Diana C Parra, Julie Loebach Wetherell, Alexandria Van Zandt, Ross C Brownson, Janardan Abhishek, Eric J Lenze

Open Access Publications

BACKGROUND: Mindfulness practice and exercise are ways by which older adults can improve and maintain their physical, emotional and cognitive health.

METHODS: This single-site qualitative study gathered insights of older adults' perceptions about initiating and maintaining mindfulness and exercise practices. We carried out focus groups with 41 adults aged 65-85 who had recently initiated Mindfulness Based Stress Reduction (MBSR), structured exercise, or their combination as part of participation in a clinical trial. We used a semi-structured interview to ask them open-ended questions regarding the benefits, barriers and facilitators of participating in mindfulness and/or exercise interventions. The interview also included questions …

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 …

Immunomodulatory Activity Of Humanized Anti-Il-7r Monoclonal Antibody Rn168 In Subjects With Type 1 Diabetes, Kevan C Herold, Jing Hughes, Janet B Mcgill, Et Al

Open Access Publications

BACKGROUND: The cytokine IL-7 is critical for T cell development and function. We performed a Phase Ib study in patients with type 1 diabetes (T1D) to evaluate how blockade of IL-7 would affect immune cells and relevant clinical responses.

METHODS: Thirty-seven subjects with T1D received s.c. RN168, a monoclonal antibody that blocks the IL -7 receptor α (IL7Rα) in a dose-escalating study.

RESULTS: Between 90% and 100% IL-7R occupancy and near-complete inhibition of pSTAT5 was observed at doses of RN168 1 mg/kg every other week (Q2wk) and greater. There was a significant decline in CD4+ and CD8+ effector and central …

Dosimetric Feasibility Of Utilizing The Viewray Magnetic Resonance Guided Linac System For Image-Guided Spine Stereotactic Body Radiation Therapy, Gage Redler, Tynan Stevens, Jochen Cammin, Martha Malin, Olga Green, Sasa Mutic, Sean Pitroda, Bulent Aydogan

Open Access Publications

INTRODUCTION: Spine stereotactic body radiation therapy (SBRT) achieves favorable outcomes compared to conventional radiotherapy doses/fractionation. The spinal cord is the principal dose-limiting organ-at-risk (OAR), and safe treatment requires precise immobilization/localization. Therefore, image guidance is paramount to successful spine SBRT. Conventional X-ray imaging and alignment to surrogate bony anatomy may be inadequate, whereas magnetic resonance imaging (MRI) directly visualizes the dose-limiting cord. This work assessed the dosimetric capability of the ViewRay (ViewRay Inc. Oakwood Village, OH) magnetic resonance (MR) guided linac (MR-Linac) for spine SBRT.

METHODS: Eight spine SBRT patients without orthopedic hardware who were previously treated on a TrueBeam using …

Gantenerumab Reduces Amyloid-Β Plaques In Patients With Prodromal To Moderate Alzheimer's Disease: A Pet Substudy Interim Analysis, Gregory Klein, Paul Delmar, Nicola Voyle, Sunita Rehal, Carsten Hofmann, Danielle Abi-Saab, Mirjana Andjelkovic, Smiljana Ristic, Guoqiao Wang, Randall Bateman, Geoffrey A Kerchner, Monika Baudler, Paulo Fontoura, Rachelle Doody

Open Access Publications

BACKGROUND: We previously investigated low doses (105 or 225 mg) of gantenerumab, a fully human monoclonal antibody that binds and removes aggregated amyloid-β by Fc receptor-mediated phagocytosis, in the SCarlet RoAD (SR) and Marguerite RoAD (MR) phase 3 trials. Several lines of evidence suggested that higher doses may be necessary to achieve clinical efficacy. We therefore designed a positron emission tomography (PET) substudy to evaluate the effect of gantenerumab uptitrated to 1200 mg every 4 weeks on amyloid-β plaques as measured using florbetapir PET in patients with prodromal to moderate Alzheimer's disease (AD).

METHODS: A subset of patients enrolled in …

Assessing Somatization In Urologic Chronic Pelvic Pain Syndrome, C S North, B A Hong, H H Lai, D H Alpers

Open Access Publications

BACKGROUND: This study examined the prevalence of somatization disorder in Urological Chronic Pelvic Pain Syndrome (UCPPS) and the utility of two self-report symptom screening tools for assessment of somatization in patients with UCPPS.

METHODS: The study sample included 65 patients with UCPPS who enrolled in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Study at Washington University. Patients completed the PolySymptomatic PolySyndromic Questionnaire (PSPS-Q) (n = 64) and the Patient Health Questionnaire-15 Somatic Symptom Severity Scale (PHQ-15) (n = 50). Review of patient medical records found that only 47% (n = 30) contained sufficient documentation to assess …

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 …