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Rn7sk Small Nuclear Rna Controls Bidirectional Transcription Of Highly Expressed Gene Pairs In Skin, Roberto Bandiera, Rebecca E Wagner, Thiago Britto-Borges, Christoph Dieterich, Sabine Dietmann, Susanne Bornelöv, Michaela Frye Oct 2021

Rn7sk Small Nuclear Rna Controls Bidirectional Transcription Of Highly Expressed Gene Pairs In Skin, Roberto Bandiera, Rebecca E Wagner, Thiago Britto-Borges, Christoph Dieterich, Sabine Dietmann, Susanne Bornelöv, Michaela Frye

Open Access Publications

Pausing of RNA polymerase II (Pol II) close to promoters is a common regulatory step in RNA synthesis, and is coordinated by a ribonucleoprotein complex scaffolded by the noncoding RNA RN7SK. The function of RN7SK-regulated gene transcription in adult tissue homoeostasis is currently unknown. Here, we deplete RN7SK during mouse and human epidermal stem cell differentiation. Unexpectedly, loss of this small nuclear RNA specifically reduces transcription of numerous cell cycle regulators leading to cell cycle exit and differentiation. Mechanistically, we show that RN7SK is required for efficient transcription of highly expressed gene pairs with bidirectional promoters, which in the epidermis …


Inhibition Of The Nlrp3 Inflammasome Improves Lifespan In Animal Murine Model Of Hutchinson-Gilford Progeria, Alvaro González-Dominguez, Raúl Montañez, Beatriz Castejón-Vega, Jéssica Nuñez-Vasco, Débora Lendines-Cordero, Chun Wang, Gabriel Mbalaviele, José M Navarro-Pando, Elísabet Alcocer-Gómez, Mario D Cordero Oct 2021

Inhibition Of The Nlrp3 Inflammasome Improves Lifespan In Animal Murine Model Of Hutchinson-Gilford Progeria, Alvaro González-Dominguez, Raúl Montañez, Beatriz Castejón-Vega, Jéssica Nuñez-Vasco, Débora Lendines-Cordero, Chun Wang, Gabriel Mbalaviele, José M Navarro-Pando, Elísabet Alcocer-Gómez, Mario D Cordero

Open Access Publications

Inflammation is a hallmark of aging and accelerated aging syndromes such as Hutchinson-Gilford progeria syndrome (HGPS). In this study, we present evidence of increased expression of the components of the NLRP3 inflammasome pathway in HGPS skin fibroblasts, an outcome that was associated with morphological changes of the nuclei of the cells. Lymphoblasts from HGPS patients also showed increased basal levels of NLRP3 and caspase 1. Consistent with these results, the expression of caspase 1 and Nlrp3, but not of the other inflammasome receptors was higher in the heart and liver of Zmpste24


Role Of Enhancers In Development And Diseases, Shailendra S Maurya Oct 2021

Role Of Enhancers In Development And Diseases, Shailendra S Maurya

Open Access Publications

Enhancers are cis-regulatory elements containing short DNA sequences that serve as binding sites for pioneer/regulatory transcription factors, thus orchestrating the regulation of genes critical for lineage determination. The activity of enhancer elements is believed to be determined by transcription factor binding, thus determining the cell state identity during development. Precise spatio-temporal control of the transcriptome during lineage specification requires the coordinated binding of lineage-specific transcription factors to enhancers. Thus, enhancers are the primary determinants of cell identity. Numerous studies have explored the role and mechanism of enhancers during development and disease, and various basic questions related to the functions and …


A Transcriptomic And Epigenomic Cell Atlas Of The Mouse Primary Motor Cortex, Zizhen Yao, Hanqing Liu, Fangming Xie, Stephan Fischer, Xinxin Wang, Et Al Oct 2021

A Transcriptomic And Epigenomic Cell Atlas Of The Mouse Primary Motor Cortex, Zizhen Yao, Hanqing Liu, Fangming Xie, Stephan Fischer, Xinxin Wang, Et Al

Open Access Publications

Single-cell transcriptomics can provide quantitative molecular signatures for large, unbiased samples of the diverse cell types in the brain


Structure Of Venezuelan Equine Encephalitis Virus In Complex With The Ldlrad3 Receptor, Katherine Basore, Hongming Ma, Natasha M Kafai, Samantha Mackin, Arthur S Kim, Christopher A Nelson, Michael S Diamond, Daved H Fremont Oct 2021

Structure Of Venezuelan Equine Encephalitis Virus In Complex With The Ldlrad3 Receptor, Katherine Basore, Hongming Ma, Natasha M Kafai, Samantha Mackin, Arthur S Kim, Christopher A Nelson, Michael S Diamond, Daved H Fremont

Open Access Publications

LDLRAD3 is a recently defined attachment and entry receptor for Venezuelan equine encephalitis virus (VEEV)


Parasitic Nematode Fatty Acid- And Retinol-Binding Proteins Compromise Host Immunity By Interfering With Host Lipid Signaling Pathways, Sophia C. Parks, Susan Nguyen, Shyon Nasrolahi, Chaitra Bhat, Damian Juncaj, Dihong Lu, Raghavendran Ramaswamy, Harpal Dhillon, Hideji Fujiwara, Anna Buchman, Omar S. Akbari, Naoki Yamanaka, Martin J. Boulanger, Adler R. Dillman Oct 2021

Parasitic Nematode Fatty Acid- And Retinol-Binding Proteins Compromise Host Immunity By Interfering With Host Lipid Signaling Pathways, Sophia C. Parks, Susan Nguyen, Shyon Nasrolahi, Chaitra Bhat, Damian Juncaj, Dihong Lu, Raghavendran Ramaswamy, Harpal Dhillon, Hideji Fujiwara, Anna Buchman, Omar S. Akbari, Naoki Yamanaka, Martin J. Boulanger, Adler R. Dillman

Open Access Publications

Parasitic nematodes cause significant morbidity and mortality globally. Excretory/secretory products (ESPs) such as fatty acid- and retinol- binding proteins (FARs) are hypothesized to suppress host immunity during nematode infection, yet little is known about their interactions with host tissues. Leveraging the insect parasitic nematode, Steinernema carpocapsae, we describe here the first in vivo study demonstrating that FARs modulate animal immunity, causing an increase in susceptibility to bacterial co-infection. Moreover, we show that FARs dampen key components of the fly immune response including the phenoloxidase cascade and antimicrobial peptide (AMP) production. Our data also reveal that FARs deplete lipid signaling precursors …


X-Treme Loss Of Sequence Diversity Linked To Neo-X Chromosomes In Filarial Nematodes, John Mattick, Ramakrishna Rao, Et Al Oct 2021

X-Treme Loss Of Sequence Diversity Linked To Neo-X Chromosomes In Filarial Nematodes, John Mattick, Ramakrishna Rao, Et Al

Open Access Publications

The sequence diversity of natural and laboratory populations of Brugia pahangi and Brugia malayi was assessed with Illumina resequencing followed by mapping in order to identify single nucleotide variants and insertions/deletions. In natural and laboratory Brugia populations, there is a lack of sequence diversity on chromosome X relative to the autosomes (πX/πA = 0.2), which is lower than the expected (πX/πA = 0.75). A reduction in diversity is also observed in other filarial nematodes with neo-X chromosome fusions in the genera Onchocerca and Wuchereria, but not those without neo-X chromosome fusions in the genera Loa and Dirofilaria. In the species …


Protocol For Draup: A Deimplementation Programme To Decrease Routine Chest Radiographs After Central Venous Catheter Insertion, Enyo Ablordeppey, Byron Powell, Virginia Mckay, Shannon Keating, Aimee James, Christopher Carpenter, Marin Kollef, Richard Griffey Oct 2021

Protocol For Draup: A Deimplementation Programme To Decrease Routine Chest Radiographs After Central Venous Catheter Insertion, Enyo Ablordeppey, Byron Powell, Virginia Mckay, Shannon Keating, Aimee James, Christopher Carpenter, Marin Kollef, Richard Griffey

Open Access Publications

INTRODUCTION: Avoiding low value medical practices is an important focus in current healthcare utilisation. Despite advantages of point-of-care ultrasound (POCUS) over chest X-ray including improved workflow and timeliness of results, POCUS-guided central venous catheter (CVC) position confirmation has slow rate of adoption. This demonstrates a gap that is ripe for the development of an intervention.

METHODS: The intervention is a deimplementation programme called DRAUP (

ETHICS AND DISSEMINATION: Approval of the study by the Human Research Protection Office has been obtained. This work will be disseminated by publication of peer-reviewed manuscripts, presentation in abstract form at scientific meetings and data …


Cd177 Modulates The Function And Homeostasis Of Tumor-Infiltrating Regulatory T Cells, Myung-Chul Kim, Nicholas Borcherding, Kawther K. Ahmed, Andrew P. Voigt, Gaurav Pandey, Et Al Oct 2021

Cd177 Modulates The Function And Homeostasis Of Tumor-Infiltrating Regulatory T Cells, Myung-Chul Kim, Nicholas Borcherding, Kawther K. Ahmed, Andrew P. Voigt, Gaurav Pandey, Et Al

Open Access Publications

No abstract provided.


Falls: A Marker Of Preclinical Alzheimer Disease: A Cohort Study Protocol, Rebecca M Bollinger, Audrey Keleman, Regina Thompson, Elizabeth Westerhaus, Anne M Fagan, Tammie Ls Benzinger, Suzanne E Schindler, Chengjie Xiong, David Balota, John C Morris, Beau M Ances, Susan L Stark Sep 2021

Falls: A Marker Of Preclinical Alzheimer Disease: A Cohort Study Protocol, Rebecca M Bollinger, Audrey Keleman, Regina Thompson, Elizabeth Westerhaus, Anne M Fagan, Tammie Ls Benzinger, Suzanne E Schindler, Chengjie Xiong, David Balota, John C Morris, Beau M Ances, Susan L Stark

Open Access Publications

INTRODUCTION: Progression to symptomatic Alzheimer disease (AD) occurs slowly over a series of preclinical stages. Declining functional mobility may be an early indicator of loss of brain network integration and may lead to an increased risk of experiencing falls. It is unknown whether measures of functional mobility and falls are preclinical markers of AD. The purpose of this study is to examine (1) the relationship between falls and functional mobility with AD biomarkers to determine when falls occur within the temporal progression to symptomatic Alzheimer disease, and (2) the attentional compared with perceptual/motor systems that underlie falls and functional mobility …


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 Sep 2021

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 …


A Comparison Of Machine Learning Classifiers For Pediatric Epilepsy Using Resting-State Functional Mri Latency Data, Ryan D Nguyen, Matthew D Smyth, Liang Zhu, Ludovic P Pao, Shannon K Swisher, Emmett H Kennady, Anish Mitra, Rajan P Patel, Jeremy E Lankford, Gretchen Von Allmen, Michael W Watkins, Michael E Funke, Manish N Shah Sep 2021

A Comparison Of Machine Learning Classifiers For Pediatric Epilepsy Using Resting-State Functional Mri Latency Data, Ryan D Nguyen, Matthew D Smyth, Liang Zhu, Ludovic P Pao, Shannon K Swisher, Emmett H Kennady, Anish Mitra, Rajan P Patel, Jeremy E Lankford, Gretchen Von Allmen, Michael W Watkins, Michael E Funke, Manish N Shah

Open Access Publications

Epilepsy affects 1 in 150 children under the age of 10 and is the most common chronic pediatric neurological condition; poor seizure control can irreversibly disrupt normal brain development. The present study compared the ability of different machine learning algorithms trained with resting-state functional MRI (rfMRI) latency data to detect epilepsy. Preoperative rfMRI and anatomical MRI scans were obtained for 63 patients with epilepsy and 259 healthy controls. The normal distribution of latency z-scores from the epilepsy and healthy control cohorts were analyzed for overlap in 36 seed regions. In these seed regions, overlap between the study cohorts ranged from …


Cryptorchidism As An Obscure Cause Of Adhesive Small Bowel Obstruction In An Adult, A Case Report, Savni Satoskar, Sarang Kashyap, Joshua Ziehm, Francisco Benavides, Avian Chang, Vinay Singhal Sep 2021

Cryptorchidism As An Obscure Cause Of Adhesive Small Bowel Obstruction In An Adult, A Case Report, Savni Satoskar, Sarang Kashyap, Joshua Ziehm, Francisco Benavides, Avian Chang, Vinay Singhal

Open Access Publications

INTRODUCTION AND IMPORTANCE: Cryptorchidism is seen in 3% of fullterm neonates. Rarely, it may cause small bowel obstruction. Knowledge of this presentation of cryptorchidism is essential to treat bowel obstruction arising due to cryptorchidism before the patient suffers complications.

CASE PRESENTATION: We present a case of a patient who underwent exploratory laparotomy for small bowel obstruction that did not resolve with conservative management. At laparotomy, on initial exploration, this patient had adhesive bands causing the small bowel obstruction. On further exploration, the bands were found to arise from a cryptorchid testis.

CLINICAL DISCUSSION: Cryptorchidism is a common finding among newborns …


Hypoglycemia Secondary To Insulinoma Masking The Onset Of Type 1 Diabetes In An Adolescent, Sriya Subramani, Andrew M Bellizzi, Nicholas Borcherding, Simon C Kao, Joseph Dillon, James Howe, Andrew W Norris, Michael J Tansey, Catherina T Pinnaro Sep 2021

Hypoglycemia Secondary To Insulinoma Masking The Onset Of Type 1 Diabetes In An Adolescent, Sriya Subramani, Andrew M Bellizzi, Nicholas Borcherding, Simon C Kao, Joseph Dillon, James Howe, Andrew W Norris, Michael J Tansey, Catherina T Pinnaro

Open Access Publications

Type 1 diabetes and insulinoma can co-occur in pediatric patients and may present with episodes of hypo- and hyperglycemia, significant glycemic variability, and weight gain. Surgical resection leads to development of fulminant diabetes.


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 Sep 2021

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 …


A Novel Intervention Combining Supplementary Food And Infection Control Measures To Improve Birth Outcomes In Undernourished Pregnant Women In Sierra Leone: A Randomized, Controlled Clinical Effectiveness Trial, David Taylor Hendrixson, Kristie Smith, Patrick Lasowski, Meghan Callaghan-Gillespie, Jacklyn Weber, Peggy Papathakis, Per Ole Iversen, Aminata Shamit Koroma, Mark J. Manary Sep 2021

A Novel Intervention Combining Supplementary Food And Infection Control Measures To Improve Birth Outcomes In Undernourished Pregnant Women In Sierra Leone: A Randomized, Controlled Clinical Effectiveness Trial, David Taylor Hendrixson, Kristie Smith, Patrick Lasowski, Meghan Callaghan-Gillespie, Jacklyn Weber, Peggy Papathakis, Per Ole Iversen, Aminata Shamit Koroma, Mark J. Manary

Open Access Publications

BACKGROUND: Innovations for undernourished pregnant women that improve newborn survival and anthropometry are needed to achieve the Sustainable Development Goals 1 and 3. This study tested the hypothesis that a combination of a nutritious supplementary food and several proven chemotherapeutic interventions to control common infections would increase newborn weight and length in undernourished pregnant women.

METHODS AND FINDINGS: This was a prospective, randomized, controlled clinical effectiveness trial of a ready-to-use supplementary food (RUSF) plus anti-infective therapies compared to standard therapy in undernourished pregnant women in rural Sierra Leone. Women with a mid-upper arm circumference (MUAC) ≤23.0 cm presenting for antenatal …


Impact Of Nerve Surgery On Opioid And Medication Use In Patients With Chronic Nerve Injuries, John M Felder, Ivica Ducic Sep 2021

Impact Of Nerve Surgery On Opioid And Medication Use In Patients With Chronic Nerve Injuries, John M Felder, Ivica Ducic

Open Access Publications

Introduction: Limited information is available regarding the ability of nerve surgery to affect medication use patterns in patients with chronic pain or neuropathy due to nerve injury.

Methods: A retrospective survey was distributed to all operative patients (N = 767) from a single nerve surgeon's practice between 2014 and 2020. Data collected included demographics, specifics of the injury and symptoms, medication and opioid use before surgery, and medication/opioid use following surgery.

Results: Out of the 767 patients, 209 (27.2%) completed the survey. Average age was 48.8 (SD = 19.1) years; 68.9% female and 31.1% male. More than 50% of the …


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 Aug 2021

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 …


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 Aug 2021

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


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 Aug 2021

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 Aug 2021

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 Aug 2021

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 Aug 2021

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 …


Cell-Free Dna Ultra-Low-Pass Whole Genome Sequencing To Distinguish Malignant Peripheral Nerve Sheath Tumor (Mpnst) From Its Benign Precursor Lesion: A Cross-Sectional Study, Jeffrey J. Szymanski, R. Taylor Sundby, Paul A. Jones, Divya Srihari, Noah Earland, Peter K. Harris, Wenjia Feng, Faridi Qaium, Haiyan Lei, David Roberts, Michele Landeau, Jamie Bell, Yi Huang, Leah Hoffman, Melissa Spencer, Matthew B. Spraker, Li Ding, Brigitte C. Widemann, Jack F. Shern, Angela C. Hirbe, Aadel A. Chaudhuri Aug 2021

Cell-Free Dna Ultra-Low-Pass Whole Genome Sequencing To Distinguish Malignant Peripheral Nerve Sheath Tumor (Mpnst) From Its Benign Precursor Lesion: A Cross-Sectional Study, Jeffrey J. Szymanski, R. Taylor Sundby, Paul A. Jones, Divya Srihari, Noah Earland, Peter K. Harris, Wenjia Feng, Faridi Qaium, Haiyan Lei, David Roberts, Michele Landeau, Jamie Bell, Yi Huang, Leah Hoffman, Melissa Spencer, Matthew B. Spraker, Li Ding, Brigitte C. Widemann, Jack F. Shern, Angela C. Hirbe, Aadel A. Chaudhuri

Open Access Publications

BACKGROUND: The leading cause of mortality for patients with the neurofibromatosis type 1 (NF1) cancer predisposition syndrome is the development of malignant peripheral nerve sheath tumor (MPNST), an aggressive soft tissue sarcoma. In the setting of NF1, this cancer type frequently arises from within its common and benign precursor, plexiform neurofibroma (PN). Transformation from PN to MPNST is challenging to diagnose due to difficulties in distinguishing cross-sectional imaging results and intralesional heterogeneity resulting in biopsy sampling errors.

METHODS AND FINDINGS: This multi-institutional study from the National Cancer Institute and Washington University in St. Louis used fragment size analysis and ultra-low-pass …


Normative Promis Scores In Healthy Collegiate Athletes: Establishing A Target For Return To Function In The Young Adult Athlete, Arya Minaie, David L Bernholt, Andrew M Block, Ronak M Patel, Rick W Wright, Matthew J Matava, Jeffrey J Nepple Aug 2021

Normative Promis Scores In Healthy Collegiate Athletes: Establishing A Target For Return To Function In The Young Adult Athlete, Arya Minaie, David L Bernholt, Andrew M Block, Ronak M Patel, Rick W Wright, Matthew J Matava, Jeffrey J Nepple

Open Access Publications

Background: The Patient-Reported Outcomes Measurement Information System (PROMIS) computer-adaptive testing (CAT) has been shown to be a valid and reliable means of assessing patient-reported outcomes. However, normal scores and distributions for a subset of a healthy young athletic population have not been established.

Purpose: To establish normative PROMIS scores for the domains of Physical Function (PF-CAT), Mobility (M-CAT), Upper Extremity Function (UE-CAT), and Pain Interference (PI-CAT) and determine the frequency of floor and ceiling effects in a population of healthy collegiate athletes.

Study Design: Cross-sectional study; Level of evidence, 3.

Methods: Healthy collegiate athletes (18-23 years of age) were prospectively …


The Alternative Serotonin Transporter Promoter P2 Impacts Gene Function In Females With Irritable Bowel Syndrome, Sandra Mohr, Gregory Sayuk, Et Al Aug 2021

The Alternative Serotonin Transporter Promoter P2 Impacts Gene Function In Females With Irritable Bowel Syndrome, Sandra Mohr, Gregory Sayuk, Et Al

Open Access Publications

Irritable bowel syndrome (IBS) is a gut-brain disorder in which symptoms are shaped by serotonin acting centrally and peripherally. The serotonin transporter gene SLC6A4 has been implicated in IBS pathophysiology, but the underlying genetic mechanisms remain unclear. We sequenced the alternative P2 promoter driving intestinal SLC6A4 expression and identified single nucleotide polymorphisms (SNPs) that were associated with IBS in a discovery sample. Identified SNPs built different haplotypes, and the tagging SNP rs2020938 seems to associate with constipation-predominant IBS (IBS-C) in females. rs2020938 validation was performed in 1978 additional IBS patients and 6,038 controls from eight countries. Meta-analysis on data from …


Non-Motor Phenotypic Subgroups In Adult-Onset Idiopathic, Isolated, Focal Cervical Dystonia, Megan E Wadon, Joel S Perlmutter, Et Al Aug 2021

Non-Motor Phenotypic Subgroups In Adult-Onset Idiopathic, Isolated, Focal Cervical Dystonia, Megan E Wadon, Joel S Perlmutter, Et Al

Open Access Publications

BACKGROUND: Non-motor symptoms are well established phenotypic components of adult-onset idiopathic, isolated, focal cervical dystonia (AOIFCD). However, improved understanding of their clinical heterogeneity is needed to better target therapeutic intervention. Here, we examine non-motor phenotypic features to identify possible AOIFCD subgroups.

METHODS: Participants diagnosed with AOIFCD were recruited via specialist neurology clinics (dystonia wales: n = 114, dystonia coalition: n = 183). Non-motor assessment included psychiatric symptoms, pain, sleep disturbance, and quality of life, assessed using self-completed questionnaires or face-to-face assessment. Both cohorts were analyzed independently using Cluster, and Bayesian multiple mixed model phenotype analyses to investigate the relationship between …


Decreased Antiviral Immune Response Within The Central Nervous System Of Aged Mice Is Associated With Increased Lethality Of West Nile Virus Encephalitis, Kristen E Funk, Artem D Arutyunov, Pritesh Desai, James P White, Allison L Soung, Sarah F Rosen, Michael S Diamond, Robyn S Klein Aug 2021

Decreased Antiviral Immune Response Within The Central Nervous System Of Aged Mice Is Associated With Increased Lethality Of West Nile Virus Encephalitis, Kristen E Funk, Artem D Arutyunov, Pritesh Desai, James P White, Allison L Soung, Sarah F Rosen, Michael S Diamond, Robyn S Klein

Open Access Publications

West Nile virus (WNV) is an emerging pathogen that causes disease syndromes ranging from a mild flu-like illness to encephalitis. While the incidence of WNV infection is fairly uniform across age groups, the risk of lethal encephalitis increases with advanced age. Prior studies have demonstrated age-related, functional immune deficits that limit systemic antiviral immunity and increase mortality; however, the effect of age on antiviral immune responses specifically within the central nervous system (CNS) is unknown. Here, we show that aged mice exhibit increased peripheral organ and CNS tissue viral burden, the latter of which is associated with alterations in activation …


Long-Term Complications In Youth-Onset Type 2 Diabetes, Petter Bjornstad, Kimberly L Drews, Sonia Caprio, Rose Gubitosi-Klug, David M Nathan, Bereket Tesfaldet, Jeanie Tryggestad, Neil H White, Philip Zeitler, Today Study Group Jul 2021

Long-Term Complications In Youth-Onset Type 2 Diabetes, Petter Bjornstad, Kimberly L Drews, Sonia Caprio, Rose Gubitosi-Klug, David M Nathan, Bereket Tesfaldet, Jeanie Tryggestad, Neil H White, Philip Zeitler, Today Study Group

Open Access Publications

BACKGROUND: The prevalence of type 2 diabetes in youth is increasing, but little is known regarding the occurrence of related complications as these youths transition to adulthood.

METHODS: We previously conducted a multicenter clinical trial (from 2004 to 2011) to evaluate the effects of one of three treatments (metformin, metformin plus rosiglitazone, or metformin plus an intensive lifestyle intervention) on the time to loss of glycemic control in participants who had onset of type 2 diabetes in youth. After completion of the trial, participants were transitioned to metformin with or without insulin and were enrolled in an observational follow-up study …


Predicting Mortality Risk For Preterm Infants Using Deep Learning Models With Time-Series Vital Sign Data, Jiarui Feng, Jennifer Lee, Zachary A Vesoulis, Fuhai Li Jul 2021

Predicting Mortality Risk For Preterm Infants Using Deep Learning Models With Time-Series Vital Sign Data, Jiarui Feng, Jennifer Lee, Zachary A Vesoulis, Fuhai Li

Open Access Publications

Mortality remains an exceptional burden of extremely preterm birth. Current clinical mortality prediction scores are calculated using a few static variable measurements, such as gestational age, birth weight, temperature, and blood pressure at admission. While these models do provide some insight, numerical and time-series vital sign data are also available for preterm babies admitted to the NICU and may provide greater insight into outcomes. Computational models that predict the mortality risk of preterm birth in the NICU by integrating vital sign data and static clinical variables in real time may be clinically helpful and potentially superior to static prediction models. …