Digital Commons Network^™

Genome Assemblies Across The Diverse Evolutionary Spectrum Of Leishmania Protozoan Parasites, Wesley C. Warren, Natalia S. Akopyants, Deborah E. Dobson, Christiane Hertz-Fowler, Lon-Fye Lye, Peter J. Myler, Gowthaman Ramasamy, Achchuthan Shanmugasundram, Fatima Silva-Franco, Sascha Steinbiss, Chad Tomlinson, Richard K. Wilson, Stephen M. Beverley

2020-Current year OA Pubs

We report the high-quality draft assemblies and gene annotations for 13 species and/or strains of the protozoan parasite genera

Msisensor-Ct: Microsatellite Instability Detection Using Cfdna Sequencing Data, Xinyin Han, Shuying Zhang, Daniel Cui Zhou, Dongliang Wang, Xiaoyu He, Danyang Yuan, Ruilin Li, Jiayin He, Xiaohong Duan, Michael C Wendl, Li Ding, Beifang Niu

2020-Current year OA Pubs

MOTIVATION: Microsatellite instability (MSI) is a promising biomarker for cancer prognosis and chemosensitivity. Techniques are rapidly evolving for the detection of MSI from tumor-normal paired or tumor-only sequencing data. However, tumor tissues are often insufficient, unavailable, or otherwise difficult to procure. Increasing clinical evidence indicates the enormous potential of plasma circulating cell-free DNA (cfNDA) technology as a noninvasive MSI detection approach.

RESULTS: We developed MSIsensor-ct, a bioinformatics tool based on a machine learning protocol, dedicated to detecting MSI status using cfDNA sequencing data with a potential stable MSIscore threshold of 20%. Evaluation of MSIsensor-ct on independent testing datasets with various …

Loss Of Synergistic Transcriptional Feedback Loops Drives Diverse B-Cell Cancers, Jared M Andrews, Sarah C Pyfrom, Jennifer A Schmidt, Olivia I Koues, Rodney A Kowalewski, Nicholas R Grams, Jessica J Sun, Leigh R Berman, Eric J Duncavage, Yi-Shan Lee, Amanda F Cashen, Eugene M Oltz, Jacqueline E Payton

Open Access Publications

BACKGROUND: The most common B-cell cancers, chronic lymphocytic leukemia/lymphoma (CLL), follicular and diffuse large B-cell (FL, DLBCL) lymphomas, have distinct clinical courses, yet overlapping "cell-of-origin". Dynamic changes to the epigenome are essential regulators of B-cell differentiation. Therefore, we reasoned that these distinct cancers may be driven by shared mechanisms of disruption in transcriptional circuitry.

METHODS: We compared purified malignant B-cells from 52 patients with normal B-cell subsets (germinal center centrocytes and centroblasts, naïve and memory B-cells) from 36 donor tonsils using >325 high-resolution molecular profiling assays for histone modifications, open chromatin (ChIP-, FAIRE-seq), transcriptome (RNA-seq), transcription factor (TF) binding, and …

Phagocytes Produce Prostaglandin E2 In Response To Cytosolic Listeria Monocytogenes, Courtney E. Mcdougal, Zachary T. Morrow, Tighe Christopher, Seonyoung Kim, Drake Carter, David M. Stevenson, Daniel Amador-Noguez, Mark J. Miller, John-Demian Sauer

Open Access Publications

Listeria monocytogenes is an intracellular bacterium that elicits robust CD8+ T-cell responses. Despite the ongoing development of L. monocytogenes-based platforms as cancer vaccines, our understanding of how L. monocytogenes drives robust CD8+ T-cell responses remains incomplete. One overarching hypothesis is that activation of cytosolic innate pathways is critical for immunity, as strains of L. monocytogenes that are unable to access the cytosol fail to elicit robust CD8+ T-cell responses and in fact inhibit optimal T-cell priming. Counterintuitively, however, activation of known cytosolic pathways, such as the inflammasome and type I IFN, lead to impaired immunity. Conversely, production of prostaglandin E2 …

Endothelial Fgf Signaling Is Protective In Hypoxia-Induced Pulmonary Hypertension, Kel Vin Woo, Isabel Y Shen, Carla J Weinheimer, Attila Kovacs, Jessica Nigro, Chieh-Yu Lin, Murali Chakinala, Derek E Byers, David M Ornitz

Open Access Publications

Hypoxia-induced pulmonary hypertension (PH) is one of the most common and deadliest forms of PH. Fibroblast growth factor receptors 1 and 2 (FGFR1/2) are elevated in patients with PH and in mice exposed to chronic hypoxia. Endothelial FGFR1/2 signaling is important for the adaptive response to several injury types and we hypothesized that endothelial FGFR1/2 signaling would protect against hypoxia-induced PH. Mice lacking endothelial FGFR1/2, mice with activated endothelial FGFR signaling, and human pulmonary artery endothelial cells (HPAECs) were challenged with hypoxia. We assessed the effect of FGFR activation and inhibition on right ventricular pressure, vascular remodeling, and endothelial-mesenchymal transition …

Memory-Like Differentiation Enhances Nk Cell Responses To Melanoma, Nancy D Marin, Bradley A Krasnick, Michelle Becker-Hapak, Leah Conant, Simon P Goedegebuure, Melissa M Berrien-Elliott, Keenan J Robbins, Jennifer A Foltz, Mark Foster, Pamela Wong, Celia C Cubitt, Jennifer Tran, Christopher B Wetzel, Miriam Jacobs, Alice Y Zhou, David Russler-Germain, Lynne Marsala, Timothy Schappe, Ryan C Fields, Todd A Fehniger

Open Access Publications

PURPOSE: Treatment of advanced melanoma is a clinical challenge. Natural killer (NK) cells are a promising cellular therapy for T cell-refractory cancers, but are frequently deficient or dysfunctional in patients with melanoma. Thus, new strategies are needed to enhance NK-cell antitumor responses. Cytokine-induced memory-like (ML) differentiation overcomes many barriers in the NK-cell therapeutics field, resulting in potent cytotoxicity and enhanced cytokine production against blood cancer targets. However, the preclinical activity of ML NK against solid tumors remains largely undefined.

EXPERIMENTAL DESIGN: Phenotypic and functional alterations of blood and advanced melanoma infiltrating NK cells were evaluated using mass cytometry. ML NK …

Alzheimer's Disease Alters Oligodendrocytic Glycolytic And Ketolytic Gene Expression, Erin R Saito, Justin B Miller, Oscar Harari, Carlos Cruchaga, Kathie A Mihindukulasuriya, John S K Kauwe, Benjamin T Bikman

2020-Current year OA Pubs

INTRODUCTION: Sporadic Alzheimer's disease (AD) is strongly correlated with impaired brain glucose metabolism, which may affect AD onset and progression. Ketolysis has been suggested as an alternative pathway to fuel the brain.

METHODS: RNA-seq profiles of post mortem AD brains were used to determine whether dysfunctional AD brain metabolism can be determined by impairments in glycolytic and ketolytic gene expression. Data were obtained from the Knight Alzheimer's Disease Research Center (62 cases; 13 controls), Mount Sinai Brain Bank (110 cases; 44 controls), and the Mayo Clinic Brain Bank (80 cases; 76 controls), and were normalized to cell type: astrocytes, microglia, …

Ascaris Suum Informs Extrasynaptic Volume Transmission In Nematodes, Louise E Atkinson, Yang Liu, Fiona Mckay, Elke Vandewyer, Charles Viau, Allister Irvine, Bruce A Rosa, Zihui Li, Qingxiao Liang, Nikki J Marks, Aaron G Maule, Makedonka Mitreva, Isabel Beets, Lingjun Li, Angela Mousley

2020-Current year OA Pubs

Neural circuit synaptic connectivities (the connectome) provide the anatomical foundation for our understanding of nematode nervous system function. However, other nonsynaptic routes of communication are known in invertebrates including extrasynaptic volume transmission (EVT), which enables short- and/or long-range communication in the absence of synaptic connections. Although EVT has been highlighted as a facet of

Alterations Of The Gut Mycobiome In Patients With Ms, Saumya Shah, Alberto Locca, Claudia Cantoni, Laura Ghezzi, Emily Evans, Robert Mikesell, Kathleen Obert, Amber Salter, Anne H Cross, Phillip I Tarr, Laura Piccio, Et Al

Open Access Publications

BACKGROUND: The mycobiome is the fungal component of the gut microbiome and is implicated in several autoimmune diseases. However, its role in MS has not been studied.

METHODS: In this case-control observational study, we performed ITS sequencing and characterised the gut mycobiome in people with MS (pwMS) and healthy controls at baseline and after six months.

FINDINGS: The mycobiome had significantly higher alpha diversity and inter-subject variation in pwMS than controls. Saccharomyces and Aspergillus were over-represented in pwMS. Saccharomyces was positively correlated with circulating basophils and negatively correlated with regulatory B cells, while Aspergillus was positively correlated with activated CD16 …

Interplay Of Trypanosome Lytic Factor And Innate Immune Cells In The Resolution Of Cutaneous Leishmania Infection, Jyoti Pant, Marie Samanovic, Maria T. Nelson, Mert K. Keceli, Joseph Verdi, Stephen M. Beverley, Jayne Raper

Open Access Publications

Trypanosome Lytic Factor (TLF) is a primate-specific high-density lipoprotein (HDL) complex that, through the cation channel-forming protein apolipoprotein L-1 (APOL1), provides innate immunity to select kinetoplastid parasites. The immunoprotective effects of TLF have been extensively investigated in the context of its interaction with the extracellular protozoan Trypanosoma brucei brucei, to which it confers sterile immunity. We previously showed that TLF could act against an intracellular pathogen Leishmania, and here we dissected the role of TLF and its synergy with host-immune cells. Leishmania major is transmitted by Phlebotomine sand flies, which deposit the parasite intradermally into mammalian hosts, where neutrophils are …

Covid-19 In Patients With Neuromyelitis Optica Spectrum Disorders And Myelin Oligodendrocyte Glycoprotein Antibody Disease In North America: From The Covims Registry, Scott D Newsome, Anne H Cross, Robert J Fox, June Halper, Pamela Kanellis, Bruce Bebo, David Li, Gary R Cutter, Kottil W Rammohan, Amber Salter

Open Access Publications

BACKGROUND AND OBJECTIVE: To describe the impact of coronavirus disease 2019 (COVID-19) on people with neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD).

METHODS: The COVID-19 Infections in Multiple Sclerosis (MS) and Related Diseases (COViMS) Registry collected data on North American patients with MS and related diseases with laboratory-positive or highly suspected SARS-CoV-2 infection. Deidentified data were entered into a web-based registry by health care providers. Data were analyzed using

RESULTS: As of June 7, 2021, 77 patients with NMOSD and 20 patients with MOGAD were reported in the COViMS Registry. Most patients with NMOSD were …

Efficacy And Safety Of Belimumab In Paediatric And Adult Patients With Systemic Lupus Erythematosus: An Across-Study Comparison, Hermine Brunner, Carlos Abud-Mendoza, Masaaki Mori, Clarissa Pilkington, Reema Syed, Syuji Takei, Diego Viola, Richard Furie, Sandra Navarra, Fengchun Zhang, Damon Bass, Gina Eriksson, Anne Hammer, Beulah Ji, Mohamed Okily, David Roth, Holly Quasny, Nicolino Ruperto

Open Access Publications

OBJECTIVE: To assess the efficacy and safety of belimumab in paediatric versus adult patients with systemic lupus erythematosus (SLE).

METHODS: We performed across-study comparisons of patients with active SLE who received belimumab or placebo, plus standard therapy, in PLUTO (paediatric phase II) and BLISS-52, BLISS-76, BLISS-NEA and EMBRACE (adult phase III). Analysed efficacy data included Week 52 SLE Responder Index (SRI)-4 response rate (EMBRACE: SRI with modified Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) proteinuria scoring (SRI-S2K)); SRI-4 response rate (EMBRACE: SRI-S2K) according to baseline disease activity indicators (Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity …

Early Experience Of Covid-19 Vaccination In Adults With Systemic Rheumatic Diseases: Results From The Covid-19 Global Rheumatology Alliance Vaccine Survey, Sebastian Eduardo Sattui, Jean Liew, Alfred Hyoungju Kim, Et Al

Open Access Publications

BACKGROUND: We describe the early experiences of adults with systemic rheumatic disease who received the COVID-19 vaccine.

METHODS: From 2 April to 30 April 2021, we conducted an online, international survey of adults with systemic rheumatic disease who received COVID-19 vaccination. We collected patient-reported data on clinician communication, beliefs and intent about discontinuing disease-modifying antirheumatic drugs (DMARDs) around the time of vaccination, and patient-reported adverse events after vaccination.

RESULTS: We analysed 2860 adults with systemic rheumatic diseases who received COVID-19 vaccination (mean age 55.3 years, 86.7% female, 86.3% white). Types of COVID-19 vaccines were Pfizer-BioNTech (53.2%), Oxford/AstraZeneca (22.6%), Moderna (21.3%), …

Lung Epithelial Signaling Mediates Early Vaccine-Induced Cd4 + T Cell Activation And Mycobacterium Tuberculosis Control, Shibali Das, Nancy D Marin, Ekaterina Esaulova, Mushtaq Ahmed, Amanda Swain, Bruce A Rosa, Makedonka Mitreva, Javier Rangel-Moreno, Mihai G Netea, Luis B Barreiro, Maziar Divangahi, Maxim N Artyomov, Deepak Kaushal, Shabaana A Khader

Open Access Publications

Tuberculosis (TB) is one of the leading causes of death due to a single infectious agent. The development of a TB vaccine that induces durable and effective immunity to Mycobacterium tuberculosis (

Vesicular Stomatitis Virus Chimeras Expressing The Oropouche Virus Glycoproteins Elicit Protective Immune Responses In Mice, Sarah Hulsey Stubbs, Marjorie Cornejo Pontelli, Nischay Mishra, Changhong Zhou, Juliano De Paula Souza, Rosa Maria Mendes Viana, W Ian Lipkin, David M Knipe, Eurico Arruda, Sean P J Whelan

Open Access Publications

Oropouche virus (OROV) infection of humans is associated with a debilitating febrile illness that can progress to meningitis or encephalitis. First isolated from a forest worker in Trinidad and Tobago in 1955, the arbovirus OROV has since been detected throughout the Amazon basin with an estimated 500,000 human infections over 60 years. Like other members of the family

Host Fecal Mrnas Predicted Environmental Enteric Dysfunction Among Children With Moderate Acute Malnutrition In Sierra Leone, Akriti Singh, Isabel Potani, Stacy P Griswold, Devika Suri, Breanne Langlois, Ye Shen, Shelley M Walton, Kenneth Kwan Ho Chui, Mark J Manary, Patrick Webb, Beatrice L Rogers, Irwin H Rosenberg

Open Access Publications

Examining the role of environmental enteric dysfunction (EED) in child growth requires noninvasive, field-appropriate biomarkers. Alternatives to the traditionally used lactulose:mannitol (L:M) test have been explored, but few studies have compared the L:M test to host fecal mRNA transcripts. The objectives of this study were to examine whether 1) host fecal mRNA transcripts could predict presence and severity of EED, measured using the L:M test, and 2) EED modifies the effect of specialized nutritious foods (SNFs) on recovery from moderate acute malnutrition (MAM). This substudy was nested within a cluster randomized trial comparing four SNFs in the treatment of MAM …

Device Design Modifications Informed By In Vitro Testing Of Bacterial Attachment Reduce Infection Rates Of Cochlear Implants In Clinical Practice, Lynne Turnbull, Roger Leigh, Rosalia Cavaliere, Sarah R Osvath, Laura M Nolan, Daniel Smyth, Kristien Verhoeven, Richard A Chole, Cynthia B Whitchurch

Open Access Publications

Recalcitrant chronic infections of implanted medical devices are often linked to the presence of biofilms. The prevention and treatment of medical device-associated infections is a major source of antibiotic use and driver of antimicrobial resistance globally. Lowering the incidence of infection in patients that receive implanted medical devices could therefore significantly improve antibiotic stewardship and reduce patient morbidity. Here we determined if modifying the design of an implantable medical device to reduce bacterial attachment, impacted the incidence of device-associated infections in clinical practice. Since the 1980s cochlear implants have provided long-term treatment of sensorineural hearing deficiency in hundreds of thousands …

Predictive Accuracy And Densitometric Analysis Of Point-Of-Care Immunoassay For Adenoviral Conjunctivitis, Spencer D Johnson, Mary K Migneco, Mathew S Margolis, Leonard W Haertter, Julia B Huecker, Richard S Buller, Gregory A Storch, Mae O Gordon, Et Al

Open Access Publications

Purpose: Accurate diagnosis of adenoviral conjunctivitis (Ad-Cs) is important for timely and appropriate patient management to reduce disease transmission. This study assessed the diagnostic accuracy of a commercially available point-of-care adenovirus immunoassay and determined whether its predictive accuracy is influenced by signal intensities of test result bands.

Methods: Point-of-care immunoassay (AdenoPlus) testing and quantitative polymerase chain reaction (qPCR) testing was performed on conjunctival swab samples obtained from eyes of 186 eligible adult participants with presumed infectious conjunctivitis and symptoms of ≤4 days. Masked observers assessed signal intensities of the immunoassay test and control bands using densitometry.

Results: Ad-Cs was confirmed …

Cd7-Deleted Hematopoietic Stem Cells Can Restore Immunity After Car T Cell Therapy, Miriam Y. Kim, Matthew L. Cooper, Miriam T. Jacobs, Julie K. Ritchey, Julia Hollaway, Todd A. Fehniger, John F. Dipersio

Open Access Publications

Targeting T cell malignancies with universal CD7-targeting chimeric antigen receptor T cells (UCART7) can lead to profound immune deficiency due to loss of normal T and NK cells. While a small population of endogenous CD7- T cells exists, these cells are unlikely to be able to repopulate the entire immune repertoire after UCART7 treatment, as they are limited in number and proliferative capacity. To rescue T and NK cells after UCART7, we created hematopoietic stem cells genetically deleted for CD7 (CD7-KO HSCs). CD7-KO HSCs were able to engraft immunodeficient mice and differentiate into T and NK cells lacking CD7 expression. …

Hpv Transcript Expression Affects Cervical Cancer Response To Chemoradiation, Fiona J Ruiz, Matthew Inkman, Ramachandran Rashmi, Naoshad Muhammad, Nishanth Gabriel, Christopher A Miller, Michael D Mclellan, Michael Goldstein, Stephanie Markovina, Perry W Grigsby, Jin Zhang, Julie K Schwarz

Open Access Publications

Persistent HPV infection is causative for the majority of cervical cancer cases; however, current guidelines do not require HPV testing for newly diagnosed cervical cancer. Using an institutional cohort of 88 patients with cervical cancer treated uniformly with standard-of-care chemoradiation treatment (CRT) with prospectively collected clinical outcome data, we observed that patients with cervical tumors containing HPV genotypes other than HPV 16 have worse survival outcomes after CRT compared with patients with HPV 16+ tumors, consistent with previously published studies. Using RNA sequencing analysis, we quantified viral transcription efficiency and found higher levels of E6 and the alternative transcript E6*I …

Sars-Cov-2 Infection Of The Pancreas Promotes Thrombofibrosis And Is Associated With New-Onset Diabetes, Mirza Muhammad Fahd Qadir, Manika Bhondeley, Wandy Beatty, Dina D Gaupp, Lara A Doyle-Meyers, Tracy Fischer, Ishitri Bandyopadhyay, Robert V Blair, Rudolf Bohm, Jay Rappaport, Eric Lazartigues, Richard S Vander Heide, Jay K Kolls, Xuebin Qin, Franck Mauvais-Jarvis

Open Access Publications

Evidence suggests an association between severe acute respiratory syndrome-cornavirus-2 (SARS-CoV-2) infection and the occurrence of new-onset diabetes. We examined pancreatic expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2), the cell entry factors for SARS-CoV-2, using publicly available single-cell RNA sequencing data sets, and pancreatic tissue from control male and female nonhuman primates (NHPs) and humans. We also examined SARS-CoV-2 immunolocalization in pancreatic cells of SARS-CoV-2-infected NHPs and patients who had died from coronavirus disease 2019 (COVID-19). We report expression of ACE2 in pancreatic islet, ductal, and endothelial cells in NHPs and humans. In pancreata from SARS-CoV-2-infected …

Rheumatic Heart Disease In The United States: Forgotten But Not Gone: Results Of A 10 Year Multicenter Review, Sarah R De Loizaga, Lakshmi R Gokanapudy Hahn, Et Al

Open Access Publications

Background Recent evaluation of rheumatic heart disease (RHD) mortality demonstrates disproportionate disease burden within the United States. However, there are few contemporary data on US children living with acute rheumatic fever (ARF) and RHD. Methods and Results Twenty-two US pediatric institutions participated in a 10-year review (2008-2018) of electronic medical records and echocardiographic databases of children 4 to 17 years diagnosed with ARF/RHD to determine demographics, diagnosis, and management. Geocoding was used to determine a census tract-based socioeconomic deprivation index. Descriptive statistics of patient characteristics and regression analysis of RHD classification, disease severity, and initial antibiotic prescription according to community …

Favorable Outcomes With Reduced Steroid Use In Juvenile Dermatomyositis, Amir B Orandi, Lampros Fotis, Jamie Lai, Hallie Morris, Andrew J White, Anthony R French, Kevin W Baszis

2020-Current year OA Pubs

BACKGROUND: High-intensity glucocorticoid regimens are commonly used to induce and maintain remission in Juvenile Dermatomyositis but are associated with several adverse side-effects. Evidence-based treatment guidelines from North American and European pediatric rheumatology research societies both advocate induction with intravenous pulse steroids followed by high dose oral steroids (2 mg/kg/day), which are then tapered. This study reports the time to disease control with reduced glucocorticoid dosing.

METHODS: We retrospectively reviewed the records at a single tertiary-care children's hospital of patients diagnosed with Juvenile Dermatomyositis between 2000 and 2014 who had a minimum of 2 years of follow-up. The primary outcome measure …

Variant Allele Fraction Of Genomic Alterations In Circulating Tumor Dna (%Ctdna) Correlates With Suv, Amin Haghighat Jahromi, Matthew Zabel, Ryosuke Okamura, Carl K Hoh, Razelle Kurzrock

Open Access Publications

The relationship between higher variant allele fraction (VAF) of genomic alterations in circulating tumor DNA (%ctDNA), an indicator of poor outcome, and maximum standardized uptake value (SUV

Developing Methods To Detect And Diagnose Chronic Traumatic Encephalopathy During Life: Rationale, Design, And Methodology For The Diagnose Cte Research Project, Michael L Alosco, Daniel S Marcus, Et Al.

2020-Current year OA Pubs

BACKGROUND: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that has been neuropathologically diagnosed in brain donors exposed to repetitive head impacts, including boxers and American football, soccer, ice hockey, and rugby players. CTE cannot yet be diagnosed during life. In December 2015, the National Institute of Neurological Disorders and Stroke awarded a seven-year grant (U01NS093334) to fund the "Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy (DIAGNOSE CTE) Research Project." The objectives of this multicenter project are to: develop in vivo fluid and neuroimaging biomarkers for CTE; characterize its clinical presentation; refine …

A Phase Ib/Iia Clinical Trial Of Dantrolene Sodium In Patients With Wolfram Syndrome, Damien Abreu, Stephen I. Stone, Toni S. Pearson, Robert C. Bucelli, Ashley N. Simpson, Stacy Hurst, Cris M. Brown, Kelly Kries, Chinyere Onwumere, Hongjie Gu, James Hoekel, Lawrence Tychsen, Gregory P. Van Stavern, Neil H. White, Bess A. Marshall, Tamara Hershey, Fumihiko Urano

Open Access Publications

BACKGROUNDWolfram syndrome is a rare ER disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is no treatment for Wolfram syndrome, preclinical studies in cell and rodent models suggest that therapeutic strategies targeting ER calcium homeostasis, including dantrolene sodium, may be beneficial.METHODSBased on results from preclinical studies on dantrolene sodium and ongoing longitudinal studies, we assembled what we believe is the first-ever clinical trial in pediatric and adult Wolfram syndrome patients with an open-label phase Ib/IIa trial design. The primary objective was to assess the safety and tolerability of dantrolene sodium in adult and pediatric …

Modulation Of The Effects Of Class Ib Antiarrhythmics On Cardiac Nav1.5-Encoded Channels By Accessory Navβ Subunits, Wandi Zhu, Wei Wang, Paweorn Angsutararux, Rebecca L. Mellor, Lori L. Isom, Jeanne M. Nerbonne, Jonathan R. Silva

Open Access Publications

Native myocardial voltage-gated sodium (NaV) channels function in macromolecular complexes comprising a pore-forming (α) subunit and multiple accessory proteins. Here, we investigated the impact of accessory NaVβ1 and NaVβ3 subunits on the functional effects of 2 well-known class Ib antiarrhythmics, lidocaine and ranolazine, on the predominant NaV channel α subunit, NaV1.5, expressed in the mammalian heart. We showed that both drugs stabilized the activated conformation of the voltage sensor of domain-III (DIII-VSD) in NaV1.5. In the presence of NaVβ1, the effect of lidocaine on the DIII-VSD was enhanced, whereas the effect of ranolazine was abolished. Mutating the main class Ib …

Taspase1 Orchestrates Fetal Liver Hematopoietic Stem Cell And Vertebrae Fates By Cleaving Tfiia, Hidetaka Niizuma, Adam C. Searleman, Shugaku Takeda, Scott A. Armstrong, Christopher Y. Park, Emily H. Cheng, James J. Hsieh

Open Access Publications

Taspase1, a highly conserved threonine protease encoded by TASP1, cleaves nuclear histone-modifying factors and basal transcription regulators to orchestrate diverse transcription programs. Hereditary loss-of-function mutation of TASP1 has recently been reported in humans as resulting in an anomaly complex syndrome, which manifests with hematological, facial, and skeletal abnormalities. Here, we demonstrate that Taspase1-mediated cleavage of TFIIAα-β, rather than of MLL1 or MLL2, in mouse embryos was required for proper fetal liver hematopoiesis and correct segmental identities of the axial skeleton. Homozygous genetic deletion of Taspase1 disrupted embryonic hematopoietic stem cell self-renewal and quiescence states and axial skeleton fates. Strikingly, mice …

Efficient Crispr/Cas9 Mutagenesis For Neurobehavioral Screening In Adult Zebrafish, Dana Shaw, Mayssa Mokalled

Open Access Publications

Adult zebrafish are widely used to interrogate mechanisms of disease development and tissue regeneration. Yet, the prospect of large-scale genetics in adult zebrafish has traditionally faced a host of biological and technical challenges, including inaccessibility of adult tissues to high-throughput phenotyping and the spatial and technical demands of adult husbandry. Here, we describe an experimental pipeline that combines high-efficiency CRISPR/Cas9 mutagenesis with functional phenotypic screening to identify genes required for spinal cord repair in adult zebrafish. Using CRISPR/Cas9 dual-guide ribonucleic proteins, we show selective and combinatorial mutagenesis of 17 genes at 28 target sites with efficiencies exceeding 85% in adult …

Effect Of Alteplase Use On Outcomes In Patients With Atrial Fibrillation: Analysis Of The Initiation Of Anticoagulation After Cardioembolic Stroke Study, Shadi Yaghi, James Giles, Angela Liu, Salah Keyrouz, Et Al

Open Access Publications

Background Intravenous alteplase improves outcome after acute ischemic stroke without a benefit in 90-day mortality. There are limited data on whether alteplase is associated with reduced mortality in patients with atrial fibrillation (AF)-related ischemic stroke whose mortality rate is relatively high. We sought to determine the association of alteplase with hemorrhagic transformation and mortality in patients with AF. Methods and Results We retrospectively analyzed consecutive patients with acute ischemic stroke between 2015 and 2018 diagnosed with AF included in the IAC (Initiation of Anticoagulation After Cardioembolic Stroke) study, which pooled data from stroke registries at 8 comprehensive stroke centers across …