Digital Commons Network^™

Use Of Leishmania Major Parasites Expressing A Recombinant Trypanosoma Cruzi Antigen As Live Vaccines Against Chagas Disease, Catherine W Cai, Anne O'Shea, Christopher S Eickhoff, Hongjie Guo, Warren G Lewis, Stephen M Beverley, Daniel F Hoft

2020-Current year OA Pubs

INTRODUCTION:

METHODS: We generated recombinant

RESULTS: We demonstrate that mice inoculated with these recombinant TS-expressing

DISCUSSION: Altogether, these data indicate that

Islet Cilia And Glucose Homeostasis, Isabella Melena, Jing W Hughes

2020-Current year OA Pubs

Diabetes is a growing pandemic affecting over ten percent of the U.S. population. Individuals with all types of diabetes exhibit glucose dysregulation due to altered function and coordination of pancreatic islets. Within the critical intercellular space in pancreatic islets, the primary cilium emerges as an important physical structure mediating cell-cell crosstalk and signal transduction. Many events leading to hormone secretion, including GPCR and second-messenger signaling, are spatiotemporally regulated at the level of the cilium. In this review, we summarize current knowledge of cilia action in islet hormone regulation and glucose homeostasis, focusing on newly implicated ciliary pathways that regulate insulin …

Multi-Omics Insights Into The Biological Mechanisms Underlying Statistical Gene-By-Lifestyle Interactions With Smoking And Alcohol Consumption, Timothy D Majarian, Mary F Feitosa, Michael Province, Dabeeru C Rao, Karen Schwander, Yun Ju Sung, C Charles Gu, Et Al.

2020-Current year OA Pubs

Though both genetic and lifestyle factors are known to influence cardiometabolic outcomes, less attention has been given to whether lifestyle exposures can alter the association between a genetic variant and these outcomes. The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium's Gene-Lifestyle Interactions Working Group has recently published investigations of genome-wide gene-environment interactions in large multi-ancestry meta-analyses with a focus on cigarette smoking and alcohol consumption as lifestyle factors and blood pressure and serum lipids as outcomes. Further description of the biological mechanisms underlying these statistical interactions would represent a significant advance in our understanding of gene-environment …

Implicating Genes, Pleiotropy, And Sexual Dimorphism At Blood Lipid Loci Through Multi-Ancestry Meta-Analysis, Stavroula Kanoni, Adam E. Locke, E Warwick Daw, Mary F. Feitosa, Mary K. Wojczynski, Bernhard Banas, Carsten A. Boger, Bettina Jung, D C. Rao, Michael A. Province, Et Al.

2020-Current year OA Pubs

No abstract provided.

Modulation Of Mirisc-Mediated Gene Silencing In Eukaryotes, Courtney F Jungers, Sergej Djuranovic

2020-Current year OA Pubs

Gene expression is regulated at multiple levels in eukaryotic cells. Regulation at the post-transcriptional level is modulated by various

Increased Virus Dissemination Leads To Enhanced Lung Injury But Not Inflammation During Influenza-Associated Secondary Bacterial Infection, Amanda P Smith, Lindey C Lane, Ivan Ramirez Zuniga, David M Moquin, Peter Vogel, Amber M Smith

2020-Current year OA Pubs

Secondary bacterial infections increase influenza-related morbidity and mortality, particularly if acquired after 5-7 d from the viral onset. Synergistic host responses and direct pathogen-pathogen interactions are thought to lead to a state of hyperinflammation, but the kinetics of the lung pathology have not yet been detailed, and identifying the contribution of different mechanisms to disease is difficult because these may change over time. To address this gap, we examined host-pathogen and lung pathology dynamics following a secondary bacterial infection initiated at different time points after influenza within a murine model. We then used a mathematical approach to quantify the increased …

Silver Jubilee: 25 Years Of The First Demonstration Of The Direct Effect Of Phosphate On The Parathyroid Cell, Jordi Bover, Adriana Dusso, Et Al.

2020-Current year OA Pubs

Although phosphorus is an essential element for life, it is not found in nature in its native state but rather combined in the form of inorganic phosphates (PO

Endogenous Opioid Systems Alterations In Pain And Opioid Use Disorder, Jessica A Higginbotham, Tamara Markovic, Nicolas Massaly, Jose A Morón

2020-Current year OA Pubs

Decades of research advances have established a central role for endogenous opioid systems in regulating reward processing, mood, motivation, learning and memory, gastrointestinal function, and pain relief. Endogenous opioid systems are present ubiquitously throughout the central and peripheral nervous system. They are composed of four families, namely the μ (MOPR), κ (KOPR), δ (DOPR), and nociceptin/orphanin FQ (NOPR) opioid receptors systems. These receptors signal through the action of their endogenous opioid peptides β-endorphins, dynorphins, enkephalins, and nociceptins, respectfully, to maintain homeostasis under normal physiological states. Due to their prominent role in pain regulation, exogenous opioids-primarily targeting the MOPR, have been …

Reconstructing Neural Circuits Using Multiresolution Correlated Light And Electron Microscopy, Karl Friedrichsen, Pratyush Ramakrishna, Jen-Chun Hsiang, Katia Valkova, Daniel Kerschensteiner, Josh L Morgan

2020-Current year OA Pubs

Correlated light and electron microscopy (CLEM) can be used to combine functional and molecular characterizations of neurons with detailed anatomical maps of their synaptic organization. Here we describe a multiresolution approach to CLEM (mrCLEM) that efficiently targets electron microscopy (EM) imaging to optically characterized cells while maintaining optimal tissue preparation for high-throughput EM reconstruction. This approach hinges on the ease with which arrays of sections collected on a solid substrate can be repeatedly imaged at different scales using scanning electron microscopy. We match this multiresolution EM imaging with multiresolution confocal mapping of the aldehyde-fixed tissue. Features visible in lower resolution …

Genetic And Transcriptional Contributions To Relapse In Normal Karyotype Acute Myeloid Leukemia, Allegra A Petti, Saad M Khan, Ziheng Xu, Nichole Helton, Catrina C Fronick, Robert Fulton, Sai M Ramakrishnan, Sridhar Nonavinkere Srivatsan, Sharon E Heath, Peter Westervelt, Jacqueline E Payton, Matthew J Walter, Daniel C Link, John Dipersio, Christopher Miller, Timothy J Ley

2020-Current year OA Pubs

To better understand clonal and transcriptional adaptations after relapse in patients with acute myeloid leukemia (AML), we collected presentation and relapse samples from six normal karyotype AML cases. We performed enhanced whole-genome sequencing to characterize clonal evolution, and deep-coverage single-cell RNA sequencing on the same samples, which yielded 142,642 high-quality cells for analysis. Identifying expressed mutations in individual cells enabled us to discriminate between normal and AML cells, to identify coordinated changes in the genome and transcriptome, and to identify subclone-specific cell states. We quantified the coevolution of genetic and transcriptional heterogeneity during AML progression, and found that transcriptional changes …

Creation Of Philadelphia Chromosome By Crispr/Cas9-Mediated Double Cleavages On Bcr And Abl1 Genes As A Model For Initial Event In Leukemogenesis, Minori Tamai, Kenji Kamimoto, Kohei Omachi, Et Al.

2020-Current year OA Pubs

The Philadelphia (Ph) chromosome was the first translocation identified in leukemia. It is supposed to be generated by aberrant ligation between two DNA double-strand breaks (DSBs) at the BCR gene located on chromosome 9q34 and the ABL1 gene located on chromosome 22q11. Thus, mimicking the initiation process of translocation, we induced CRISPR/Cas9-mediated DSBs simultaneously at the breakpoints of the BCR and ABL1 genes in a granulocyte-macrophage colony-stimulating factor (GM-CSF) dependent human leukemia cell line. After transfection of two single guide RNAs (sgRNAs) targeting intron 13 of the BCR gene and intron 1 of the ABL1 gene, a factor-independent subline was …

The Relevance Of Rich Club Regions For Functional Outcome Post-Stroke Is Enhanced In Women, Anna K. Bonkhoff, Laura Heitsch, Chia-Ling Phuah, Et Al.

2020-Current year OA Pubs

No abstract provided.

White Matter Abnormalities In The Hdc Knockout Mouse, A Model Of Tic And Ocd Pathophysiology, Kantiya Jindachomthong, Chengran Yang, Yuegao Huang, Daniel Coman, Maximiliano Rapanelli, Fahmeed Hyder, Joseph Dougherty, Luciana Frick, Christopher Pittenger

2020-Current year OA Pubs

INTRODUCTION: An inactivating mutation in the

MATERIALS AND METHODS: We performed exploratory RNA-seq to identify pathological alterations in several brain regions in

RESULTS: Exploratory RNA-Seq analysis revealed, unexpectedly, that genes associated with oligodendrocytes and with myelin production are upregulated in the dorsal striatum of these mice. This was confirmed by qPCR, immunostaining, and immunoblotting. These results suggest an abnormality in myelination in the striatum. To test this in an intact mouse brain, we performed whole-brain

DISCUSSION: While the DTI literature in individuals with TS is sparse, these results are consistent with findings of disrupted descending cortical projections in patients with …

Clinical And Molecular Characteristics Of A Novel Rare De Novo Variant In Ppp2ca In A Patient With A Developmental Disorder, Autism, And Epilepsy, Iris Verbinnen, Sara S Procknow, Lisa Lenaerts, Sara Reynhout, Aujan Mehregan, Chris Ulens, Veerle Janssens, Katherine A King

2020-Current year OA Pubs

PP2A-related (neuro) developmental disorders are a family of genetic diseases caused by a heterozygous alteration in one of several genes encoding a subunit of type 2A protein phosphatases. Reported affected genes, so far, are

Donor Chimerism And Immune Reconstitution Following Haploidentical Transplantation In Sickle Cell Disease, Yaya Chu, Brenda Grossman, Shalini Shenoy, Et Al

2020-Current year OA Pubs

INTRODUCTION: We previously reported the initial results of a phase II multicenter transplant trial using haploidentical parental donors for children and aolescents with high-risk sickle cell disease achieving excellent survival with exceptionally low rates of graft-versus-host disease and resolution of sickle cell disease symptoms. To investigate human leukocyte antigen (HLA) sensitization, graft characteristics, donor chimerism, and immune reconstitution in these recipients.

METHODS: CD34 cells were enriched using the CliniMACS

RESULTS: HLA antibodies were detected in 7 of 11 (64%) evaluable patients but rarely were against donor antigens. Myeloid engraftment was rapid (100%) at a median of 9 days. At 30 …

A Map Of Neurofilament Light Chain Species In Brain And Cerebrospinal Fluid And Alterations In Alzheimer's Disease, Melissa M Budelier, Yingxin He, Nicolas R Barthelemy, Hong Jiang, Yan Li, Ethan Park, Rachel L Henson, Suzanne E Schindler, David M Holtzman, Randall J Bateman

2020-Current year OA Pubs

Neurofilament light is a well-established marker of both acute and chronic neuronal damage and is increased in multiple neurodegenerative diseases. However, the protein is not well characterized in brain tissue or body fluids, and it is unknown what neurofilament light species are detected by commercial assays and whether additional species exist. We developed an immunoprecipitation-mass spectrometry assay using custom antibodies targeting various neurofilament light domains, including antibodies targeting Coil 1A/1B of the rod domain (HJ30.13), Coil 2B of the rod domain (HJ30.4) and the tail region (HJ30.11). We utilized our assay to characterize neurofilament light in brain tissue and CSF …

Preclinical Antibody-Pet Imaging Of Pd-L1, Emma L Brown, Rachel A Deweerd, Abbey Zidel, Patricia M R Pereira

2020-Current year OA Pubs

Programmed cell death protein-1/ligand-1 (PD-1/PD-L1) blockade, including antibody therapeutics, has transformed cancer treatment. However, a major challenge in the field relates to selecting patients who are likely to respond to immune checkpoint inhibitors. Indeed, biopsy-based diagnostic tests to determine immune checkpoint protein levels do not accurately capture the inherent spatial and temporal heterogeneity of PD-L1 tumor expression. As a result, not all PD-L1-positive tumors respond to immunotherapies, and some patients with PD-L1-negative tumors have shown clinical benefits. In 2018, a first-in-human study of the clinically-approved anti-PD-L1 antibody Atezolizumab labeled with the positron emitter zirconium-89 validated the ability of positron emission …

Job-Exposure Matrix: A Useful Tool For Incorporating Workplace Exposure Data Into Population Health Research And Practice, Alexis Descatha, Marc Fadel, Grace Sembajwe, Susan Peters, Bradley A Evanoff

2020-Current year OA Pubs

Workplace exposures to physical, chemical, and psychosocial factors account for a large burden of chronic diseases. Obtaining useful estimates of current and past workplace exposures is challenging, particularly in large general population studies. Job-exposure matrices (JEMs) are a useful tool for exposure assessment, particularly when no individual level exposure data are available. A JEM provides a cross-tabulation of job titles (sometimes combined with industry) and estimated exposures to workers carrying out these jobs during different time periods. The major limitation of JEMs is that they do not account for individual variation in exposures within the same job. This limitation is …

The Human Myocardium Harbors A Population Of Naive B-Cells With A Distinctive Gene Expression Signature Conserved Across Species, Kevin C Bermea, Nicolas Kostelecky, Sylvie T Rousseau, Chieh-Yu Lin, Luigi Adamo

2020-Current year OA Pubs

INTRODUCTION: Cardiac immunology studies in murine models have identified a sizeable population of myocardial B-cells and have shown that its modulation represents a promising strategy to develop novel therapies for heart failure. However, scarce data on B-cells in the human heart leaves unclear whether findings in rodents are relevant to human biology.

METHODS: We performed immunohistochemical stains to characterize the amount and distribution of B-cells in human hearts, analyzing both fresh and post-mortem tissue. To gain insight into the biology of human myocardial B-cells we analyzed publicly-available spatial transcriptomics and single-cell sequencing datasets of myocardial and peripheral blood mononuclear cells …

Transient Equilibrium Determination Of Dopamine D2/D3 Receptor Densities And Affinities In Brain, Jenny-Ann Phan, Dean F Wong, Natalie H S Chang, Yoshitaka Kumakura, William R Bauer, Albert Gjedde

2020-Current year OA Pubs

Long-term alteration of dopaminergic neurotransmission is known to modulate the D

Impact Of Motile Ciliopathies On Human Development And Clinical Consequences In The Newborn, Rachael Hyland, Steven L. Brody

Open Access Publications

No abstract provided.

Deep Learning Supplants Visual Analysis By Experienced Operators For The Diagnosis Of Cardiac Amyloidosis By Cine-Cmr, Philippe Germain, Armine Vardazaryan, Nicolas Padoy, Aissam Labani, Catherine Roy, Thomas Hellmut Schindler, Soraya El Ghannudi

Open Access Publications

BACKGROUND: Diagnosing cardiac amyloidosis (CA) from cine-CMR (cardiac magnetic resonance) alone is not reliable. In this study, we tested if a convolutional neural network (CNN) could outperform the visual diagnosis of experienced operators.

METHOD: 119 patients with cardiac amyloidosis and 122 patients with left ventricular hypertrophy (LVH) of other origins were retrospectively selected. Diastolic and systolic cine-CMR images were preprocessed and labeled. A dual-input visual geometry group (VGG ) model was used for binary image classification. All images belonging to the same patient were distributed in the same set. Accuracy and area under the curve (AUC) were calculated per frame …

Trial Of Spesolimab For Generalized Pustular Psoriasis, Hervé Bachelez, Milan J Anadkat, Et Al

Open Access Publications

BACKGROUND: Generalized pustular psoriasis (GPP) is a rare, life-threatening, inflammatory skin disease characterized by widespread eruption of sterile pustules. Interleukin-36 signaling is involved in the pathogenesis of this disorder. Spesolimab, a humanized anti-interleukin-36 receptor monoclonal antibody, is being studied for the treatment of GPP flares.

METHODS: In a phase 2 trial, we randomly assigned patients with a GPP flare in a 2:1 ratio to receive a single 900-mg intravenous dose of spesolimab or placebo. Patients in both groups could receive an open-label dose of spesolimab on day 8, an open-label dose of spesolimab as a rescue medication after day 8, …

Tricuspid Valve Intervention At The Time Of Pulmonary Valve Replacement In Adults With Congenital Heart Disease: A Systematic Review And Meta-Analysis, Jef Van Den Eynde, Connor P Callahan, Mauro Lo Rito, Nabil Hussein, Horacio Carvajal, Alvise Guariento, Arjang Ruhparwar, Alexander Weymann, Werner Budts, Marc Gewillig, Michel Pompeu Sá, Shelby Kutty

Open Access Publications

Background Tricuspid regurgitation (TR) is a common finding in adults with congenital heart disease referred for pulmonary valve replacement (PVR). However, indications for combined valve surgery remain controversial. This study aimed to evaluate early results of concomitant tricuspid valve intervention (TVI) at the time of PVR. Methods and Results Observational studies comparing TVI+PVR and isolated PVR were identified by a systematic search of published research. Random-effects meta-analysis was performed, comparing outcomes between the 2 groups. Six studies involving 749 patients (TVI+PVR, 278 patients; PVR, 471 patients) met the eligibility criteria. In the pooled analysis, both TVI+PVR and PVR reduced TR …

Myeloid-Derived Suppressor Cells Mediate T Cell Dysfunction In Nonhuman Primate Tb Granulomas, Bindu Singh, Dhiraj K Singh, Shashank R Ganatra, Ruby A Escobedo, Shabaana Khader, Larry S Schlesinger, Deepak Kaushal, Smriti Mehra

Open Access Publications

Myeloid-derived suppressor cells (MDSCs) represent an innate immune cell population comprised of immature myeloid cells and myeloid progenitors with very potent immunosuppressive potential. MDSCs are reported to be abundant in the lungs of active tuberculosis (TB) patients. We sought to perform an in-depth study of MDSCs during latent TB infection (LTBI) and active TB (ATB) using the nonhuman primate (NHP) model of pulmonary TB. We found a higher proportion of granulocytic, polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in the lungs of ATB animals compared to those with LTBI or naive control animals. Active disease in the lung, but not LTBI, was …

Ccr2 Signaling Restricts Sars-Cov-2 Infection, Abigail Vanderheiden, Jeronay Thomas, Allison L Soung, Meredith E Davis-Gardner, Katharine Floyd, Fengzhi Jin, David A Cowan, Kathryn Pellegrini, Pei-Yong Shi, Arash Grakoui, Robyn S Klein, Steven E Bosinger, Jacob E Kohlmeier, Vineet D Menachery, Mehul S Suthar

Open Access Publications

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a historic pandemic of respiratory disease (coronavirus disease 2019 [COVID-19]), and current evidence suggests that severe disease is associated with dysregulated immunity within the respiratory tract. However, the innate immune mechanisms that mediate protection during COVID-19 are not well defined. Here, we characterize a mouse model of SARS-CoV-2 infection and find that early CCR2 signaling restricts the viral burden in the lung. We find that a recently developed mouse-adapted SARS-CoV-2 (MA-SARS-CoV-2) strain as well as the emerging B.1.351 variant trigger an inflammatory response in the lung characterized by the expression of …

A Next Generation Sequencing-Based Protocol For Screening Of Variants Of Concern In Autism Spectrum Disorder, Jie Huang, Jun Liu, Ruiyi Tian, Kevin Liu, Patrick Zhuang, Hannah Tayla Sherman, Christoph Budjan, Michelle Fong, Min-Seo Jeong, Xue-Jun Kong

2020-Current year OA Pubs

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with strong genetic influences. There is an increasing demand for ASD genetic testing beyond the traditionally recommended microarray and syndromic autism testing; however, the current whole genome sequencing (WGS) and whole exome sequencing (WES) methods are lacking an academic standard for WGS variant annotation, reporting, and interpretation, tailored towards patients with ASD and offer very limited interpretation for clinical significance. Using WGS data from six family trios, we demonstrate the clinical feasibility and technical implementation of an evidence-based, fully transparent bioinformatics pipeline and report framework for an ASD-focused WGS genetic report. We …

Emerging Themes In The Molecular Pathogenesis Of Enterotoxigenic Escherichia Coli, James M Fleckenstein, Alaullah Sheikh

2020-Current year OA Pubs

Enterotoxigenic Escherichia coli (ETEC) are ubiquitous diarrheal pathogens that thrive in areas lacking basic human needs of clean water and sanitation. These genetically plastic organisms cause tremendous morbidity among disadvantaged young children, in the form of both acute diarrheal illness and sequelae of malnutrition and growth impairment. The recent discovery of additional plasmid-encoded virulence factors and elucidation of their critical role in the molecular pathogenesis of ETEC may inform new approaches to the development of broadly protective vaccines. Although the pathogens have been closely linked epidemiologically with nondiarrheal sequelae, these conditions remain very poorly understood. Similarly, while canonical effects of …

Transcriptional Reprogramming Differentiates Active From Inactive Esr1 Fusions In Endocrine Therapy-Refractory Metastatic Breast Cancer, Xuxu Gou, Shunqiang Li, Et Al.

2020-Current year OA Pubs

Genomic analysis has recently identified multiple

Antibody-Drug Conjugates Plus Janus Kinase Inhibitors Enable Mhc-Mismatched Allogeneic Hematopoietic Stem Cell Transplantation, Stephen P Persaud, Julie K Ritchey, Sena Kim, Sora Lim, Peter G Ruminski, Matthew L Cooper, Michael P Rettig, Jaebok Choi, John F Dipersio

Open Access Publications

Despite the curative potential of hematopoietic stem cell transplantation (HSCT), conditioning-associated toxicities preclude broader clinical application. Antibody-drug conjugates (ADCs) provide an attractive approach to HSCT conditioning that minimizes toxicity while retaining efficacy. Initial studies of ADC conditioning have largely focused on syngeneic HSCT. However, to treat acute leukemias or induce tolerance for solid organ transplantation, this approach must be expanded to allogeneic HSCT (allo-HSCT). Using murine allo-HSCT models, we show that pharmacologic Janus kinase 1/2 (JAK1/2) inhibition combined with CD45- or cKit-targeted ADCs enables robust multilineage alloengraftment. Strikingly, myeloid lineage donor chimerism exceeding 99% was achievable in fully MHC-mismatched HSCT …