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Whole-Exome Analysis Of Adolescents With Low Vwf And Heavy Menstrual Bleeding Identifies Novel Genetic Associations, Brooke Sadler, Christina A Gurnett, Jorge Di Paola, Et Al

Open Access Publications

Adolescents with low von Willebrand factor (VWF) levels and heavy menstrual bleeding (HMB) experience significant morbidity. There is a need to better characterize these patients genetically and improve our understanding of the pathophysiology of bleeding. We performed whole-exome sequencing on 86 postmenarchal patients diagnosed with low VWF levels (30-50 IU/dL) and HMB and compared them with 660 in-house controls. We compared the number of rare stop-gain/stop-loss and rare ClinVar "pathogenic" variants between cases and controls, as well as performed gene burden and gene-set burden analyses. We found an enrichment in cases of rare stop-gain/stop-loss variants in genes involved in bleeding …

Inhibiting Mycobacterium Abscessus Cell Wall Synthesis: Using A Novel Diazabicyclooctane Β-Lactamase Inhibitor To Augment Β-Lactam Action, Khalid M Dousa, David C Nguyen, Sebastian G Kurz, Magdalena A Taracila, Christopher R Bethel, William Schinabeck, Barry N Kreiswirth, Sheldon T Brown, W Henry Boom, Richard S Hotchkiss, Kenneth E Remy, Frank J Jacono, Charles L Daley, Steven M Holland, Alita A Miller, Robert A Bonomo

Open Access Publications

Mycobacterium abscessus (

Bicyclic Azetidines Target Acute And Chronic Stages Of Toxoplasma Gondii By Inhibiting Parasite Phenylalanyl T-Rna Synthetase, Joshua B Radke, Bruno Melillo, Payal Mittal, Manmohan Sharma, Amit Sharma, Yong Fu, Taher Uddin, Arthur Gonse, Eamon Comer, Stuart L Schreiber, Anil K Gupta, Arnab K Chatterjee, L David Sibley

Open Access Publications

Toxoplasma gondii commonly infects humans and while most infections are controlled by the immune response, currently approved drugs are not capable of clearing chronic infection in humans. Hence, approximately one third of the world's human population is at risk of reactivation, potentially leading to severe sequelae. To identify new candidates for treating chronic infection, we investigated a series of compounds derived from diversity-oriented synthesis. Bicyclic azetidines are potent low nanomolar inhibitors of phenylalanine tRNA synthetase (PheRS) in T. gondii, with excellent selectivity. Biochemical and genetic studies validate PheRS as the primary target of bicyclic azetidines in T. gondii, providing a …

Neural Signatures Of Data-Driven Psychopathology Dimensions At The Transition To Adolescence, Amirhossein Modabbernia, Giorgia Michelini, Abraham Reichenberg, Roman Kotov, Deanna Barch, Sophia Frangou

Open Access Publications

BACKGROUND: One of the challenges in human neuroscience is to uncover associations between brain organization and psychopathology in order to better understand the biological underpinnings of mental disorders. Here, we aimed to characterize the neural correlates of psychopathology dimensions obtained using two conceptually different data-driven approaches.

METHODS: Dimensions of psychopathology that were either maximally dissociable or correlated were respectively extracted by independent component analysis (ICA) and exploratory factor analysis (EFA) applied to the Childhood Behavior Checklist items from 9- to 10-year-olds (n = 9983; 47.8% female, 50.8% white) participating in the Adolescent Brain Cognitive Development study. The patterns of brain …

American Society Of Hematology Living Guidelines On The Use Of Anticoagulation For Thromboprophylaxis In Patients With Covid-19: July 2021 Update On Postdischarge Thromboprophylaxis, Adam Cuker, Kristen M. Sanfilippo, Et Al

Open Access Publications

No abstract provided.

Improving The Diagnosis Of Menstrual Dysfunction Through Quality Improvement, Kayla Daniel, Anastasia Fischer, Michael Welty, Amy E Valasek

Open Access Publications

Introduction: Prevalence of menstrual dysfunction (MD) in high school athletes ranges from 7% to 54%. Early recognition and intervention are crucial to prevent future consequences. The purpose of this Quality Improvement project was to optimize the institution's Epic Best Practice Advisory (BPA) screening tool and synthesize new patient questionnaires to diagnose MD in athletes greater than 12 years of age presenting to a pediatric sports medicine clinic.

Methods: Using Quality Improvement methodology, we evaluated clinic flow, the Epic BPA tool, and actions by the physician following the appropriate triggering of the BPA. Diagnoses targeted were primary amenorrhea, oligomenorrhea, or irregular …

Resting State Functional Connectivity Provides Mechanistic Predictions Of Future Changes In Sedentary Behavior, Timothy P Morris, Aaron Kucyi, Sheeba Arnold Anteraper, Maiya Rachel Geddes, Alfonso Nieto-Castañon, Agnieszka Burzynska, Neha P Gothe, Jason Fanning, Elizabeth A Salerno, Susan Whitfield-Gabrieli, Charles H Hillman, Edward Mcauley, Arthur F Kramer

Open Access Publications

Sedentary behaviors are increasing at the cost of millions of dollars spent in health care and productivity losses due to physical inactivity-related deaths worldwide. Understanding the mechanistic predictors of sedentary behaviors will improve future intervention development and precision medicine approaches. It has been posited that humans have an innate attraction towards effort minimization and that inhibitory control is required to overcome this prepotent disposition. Consequently, we hypothesized that individual differences in the functional connectivity of brain regions implicated in inhibitory control and physical effort decision making at the beginning of an exercise intervention in older adults would predict the change …

Comparative Genomics Of Borderline Oxacillin-Resistant Staphylococcus Aureus Detected During A Pseudo-Outbreak Of Methicillin-Resistant S. Aureus In A Neonatal Intensive Care Unit, Sanjam S Sawhney, Eric M Ransom, Meghan A Wallace, Patrick J Reich, Gautam Dantas, Carey-Ann D Burnham

Open Access Publications

Active surveillance for methicillin-resistant Staphylococcus aureus (MRSA) is a component of our neonatal intensive care unit (NICU) infection prevention efforts. Recent atypical trends prompted review of 42 suspected MRSA isolates. Species identification was confirmed by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS), and methicillin resistance was reevaluated by PBP2a lateral flow assay, cefoxitin/oxacillin susceptibility testing,

Dansr: A Tool For The Detection Of Annotated And Novel Small Rnas, Jin Zhang, Abdallah M Eteleeb, Emily B Rozycki, Matthew J Inkman, Amy Ly, Russell E Scharf, Kay Jayachandran, Bradley A Krasnick, Thomas Mazur, Nicole M White, Ryan C Fields, Christopher A Maher

Open Access Publications

Existing small noncoding RNA analysis tools are optimized for processing short sequencing reads (17-35 nucleotides) to monitor microRNA expression. However, these strategies under-represent many biologically relevant classes of small noncoding RNAs in the 36-200 nucleotides length range (tRNAs, snoRNAs, etc.). To address this, we developed DANSR, a tool for the detection of annotated and novel small RNAs using sequencing reads with variable lengths (ranging from 17-200 nt). While DANSR is broadly applicable to any small RNA dataset, we applied it to a cohort of matched normal, primary, and distant metastatic colorectal cancer specimens to demonstrate its ability to quantify annotated …

Metabolic Sensing In Agrp Neurons Integrates Homeostatic State With Dopamine Signalling In The Striatum, Alex Reichenbach, Alexxai V. Kravitz, Et Al

Open Access Publications

Agouti-related peptide (AgRP) neurons increase motivation for food, however, whether metabolic sensing of homeostatic state in AgRP neurons potentiates motivation by interacting with dopamine reward systems is unexplored. As a model of impaired metabolic-sensing, we used the AgRP-specific deletion of carnitine acetyltransferase (

Myocardial Afterload Is A Key Biomechanical Regulator Of Atrioventricular Myocyte Differentiation In Zebrafish, Neha Ahuja, Paige Ostwald, Alex Gendernalik, Elena Guzzolino, Letizia Pitto, David Bark, Deborah M Garrity

Open Access Publications

Heart valve development is governed by both genetic and biomechanical inputs. Prior work has demonstrated that oscillating shear stress associated with blood flow is required for normal atrioventricular (AV) valve development. Cardiac afterload is defined as the pressure the ventricle must overcome in order to pump blood throughout the circulatory system. In human patients, conditions of high afterload can cause valve pathology. Whether high afterload adversely affects embryonic valve development remains poorly understood. Here we describe a zebrafish model exhibiting increased myocardial afterload, caused by vasopressin, a vasoconstrictive drug. We show that the application of vasopressin reliably produces an increase …

Serpinb3 (Scca1) Inhibits Cathepsin L And Lysoptosis, Protecting Cervical Cancer Cells From Chemoradiation, Songyan Wang, Cliff J Luke, Stephen C Pak, Victoria Shi, Liyun Chen, Jonathan Moore, Arlise P Andress, Kay Jayachandran, Jin Zhang, Yi Huang, Marina Platik, Anthony A Apicelli, Julie K Schwarz, Perry W Grigsby, Gary A Silverman, Stephanie Markovina

Open Access Publications

The endogenous lysosomal cysteine protease inhibitor SERPINB3 (squamous cell carcinoma antigen 1, SCCA1) is elevated in patients with cervical cancer and other malignancies. High serum SERPINB3 is prognostic for recurrence and death following chemoradiation therapy. Cervical cancer cells genetically lacking SERPINB3 are more sensitive to ionizing radiation (IR), suggesting this protease inhibitor plays a role in therapeutic response. Here we demonstrate that SERPINB3-deficient cells have enhanced sensitivity to IR-induced cell death. Knock out of SERPINB3 sensitizes cells to a greater extent than cisplatin, the current standard of care. IR in SERPINB3 deficient cervical carcinoma cells induces predominantly necrotic cell death, …

Lysoptosis Is An Evolutionarily Conserved Cell Death Pathway Moderated By Intracellular Serpins, Cliff J Luke, Stephanie Markovina, Misty Good, Ira E Wight, Brian J Thomas, John M Linneman, Wyatt E Lanik, Olga Koroleva, Maggie R Coffman, Mark T Miedel, Qingqing Gong, Arlise Andress, Marlene Campos Guerrero, Songyan Wang, Liyun Chen, Wandy L Beatty, Kelsey N Hausmann, Frances V White, James A J Fitzpatrick, Anthony Orvedahl, Stephen C Pak, Gary A Silverman

Open Access Publications

Lysosomal membrane permeabilization (LMP) and cathepsin release typifies lysosome-dependent cell death (LDCD). However, LMP occurs in most regulated cell death programs suggesting LDCD is not an independent cell death pathway, but is conscripted to facilitate the final cellular demise by other cell death routines. Previously, we demonstrated that Caenorhabditis elegans (C. elegans) null for a cysteine protease inhibitor, srp-6, undergo a specific LDCD pathway characterized by LMP and cathepsin-dependent cytoplasmic proteolysis. We designated this cell death routine, lysoptosis, to distinguish it from other pathways employing LMP. In this study, mouse and human epithelial cells lacking srp-6 homologues, mSerpinb3a and SERPINB3, …

Targeting The Fusion Process Of Sars-Cov-2 Infection By Small Molecule Inhibitors, Seung Bum Park, Parker Irvin, Zongyi Hu, Mohsin Khan, Xin Hu, Qiru Zeng, Catherine Chen, Miao Xu, Madeleine Leek, Ruochen Zang, James Brett Case, Wei Zheng, Siyuan Ding, T. Jake Liang

Open Access Publications

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a serious threat to global public health, underscoring the urgency of developing effective therapies. Therapeutics and, more specifically, direct-acting antiviral development are still very much in their infancy. Here, we report that two hepatitis C virus (HCV) fusion inhibitors identified in our previous study, dichlorcyclizine and fluoxazolevir, broadly block human coronavirus entry into various cell types. Both compounds were effective against various human-pathogenic CoVs in multiple assays based on vesicular stomatitis virus (VSV) pseudotyped with the spike protein and spike-mediated syncytium formation. The antiviral effects …

Astrocytic 4r Tau Expression Drives Astrocyte Reactivity And Dysfunction, Lubov A. Ezerskiy, Kathleen M. Schoch, Chihiro Sato, Mariana Beltcheva, Kanta Horie, Frank Rigo, Ryan Martynowicz, Celeste M. Karch, Randall J. Bateman, Timothy M. Miller

Open Access Publications

The protein tau and its isoforms are associated with several neurodegenerative diseases, many of which are characterized by greater deposition of the 4-repeat (4R) tau isoform; however, the role of 4R tau in disease pathogenesis remains unclear. We created antisense oligonucleotides (ASOs) that alter the ratio of 3R to 4R tau to investigate the role of specific tau isoforms in disease. Preferential expression of 4R tau in human tau-expressing (hTau-expressing) mice was previously shown to increase seizure severity and phosphorylated tau deposition without neuronal or synaptic loss. In this study, we observed strong colocalization of 4R tau within reactive astrocytes …

Fasn-Dependent De Novo Lipogenesis Is Required For Brain Development, Daniel Gonzalez-Bohorquez, Isabel M Gallego López, Baptiste N Jaeger, Sibylle Pfammatter, Megan Bowers, Clay F Semenkovich, Sebastian Jessberger

Open Access Publications

Fate and behavior of neural progenitor cells are tightly regulated during mammalian brain development. Metabolic pathways, such as glycolysis and oxidative phosphorylation, that are required for supplying energy and providing molecular building blocks to generate cells govern progenitor function. However, the role of de novo lipogenesis, which is the conversion of glucose into fatty acids through the multienzyme protein fatty acid synthase (FASN), for brain development remains unknown. Using Emx1Cre-mediated, tissue-specific deletion of

Microbial Enzymes Induce Colitis By Reactivating Triclosan In The Mouse Gastrointestinal Tract, Jianan Zhang, Morgan E. Walker, Katherine Z. Sanidad, Hongna Zhang, Michael B. Major, Dennis Goldfarb, Et Al

Open Access Publications

No abstract provided.

Total Energy Expenditure Is Repeatable In Adults But Not Associated With Short-Term Changes In Body Composition, Rebecca Rimbach, Susan B. Racette, John R. Speakman, Herman Pontzer, Et Al

Open Access Publications

No abstract provided.

Transcriptomes Of Peripheral Blood Mononuclear Cells From Juvenile Dermatomyositis Patients Show Elevated Inflammation Even When Clinically Inactive, Elisha D O Roberson, Rosana A Mesa, Gabrielle A Morgan, Li Cao, Wilfredo Marin, Lauren M Pachman

Open Access Publications

In juvenile dermatomyositis (JDM), the most common pediatric inflammatory myopathy, weakness is accompanied by a characteristic rash that often becomes chronic and is associated with vascular damage. We hoped to understand the molecular underpinnings of JDM, particularly when untreated, which would facilitate the identification of novel mechanisms and clinical targets that might disrupt disease progression. We studied the RNA-Seq data from untreated JDM peripheral blood mononuclear cells (PBMCs; n = 11), PBMCs from a subset of the same patients when clinically inactive (n = 8/11), and separate samples of untreated JDM skin and muscle (n = 4 each). All JDM …

Polyunsaturated Fatty Acids Inhibit A Pentameric Ligand-Gated Ion Channel Through One Of Two Binding Sites, Noah M. Dietzen, Mark J. Arcario, Lawrence J. Chen, John T. Petroff, K. Trent Moreland, Kathiresan Krishnan, Grace Brannigan, Douglas F. Covey, Wayland W.I. Cheng

Open Access Publications

Polyunsaturated fatty acids (PUFAs) inhibit pentameric ligand-gated ion channels (pLGICs) but the mechanism of inhibition is not well understood. The PUFA, docosahexaenoic acid (DHA), inhibits agonist responses of the pLGIC, ELIC, more effectively than palmitic acid, similar to the effects observed in the GABA

Procedural Risk In Congenital Cardiac Catheterization (Predic3t), Brian P Quinn, David Balzer, Et Al

Open Access Publications

Background Advancements in the field, including novel procedures and multiple interventions, require an updated approach to accurately assess patient risk. This study aims to modernize patient hemodynamic and procedural risk classification through the creation of risk assessment tools to be used in congenital cardiac catheterization. Methods and Results Data were collected for all cases performed at sites participating in the C3PO (Congenital Cardiac Catheterization Project on Outcomes) multicenter registry. Between January 2014 and December 2017, 23 119 cases were recorded in 13 participating institutions, of which 88% of patients were <18 years of age and 25% <1 year of age; a high-severity adverse event occurred in 1193 (5.2%). Case types were defined by procedure(s) performed and grouped on the basis of association with the outcome, high-severity adverse event. Thirty-four unique case types were determined and stratified into 6 risk categories. Six hemodynamic indicator variables were empirically assessed, and a novel hemodynamic vulnerability score was determined by the frequency of high-severity adverse events. In a multivariable model, case-type risk category (odds ratios for category: 0=0.46, 1=1.00, 2=1.40, 3=2.68, 4=3.64, and 5=5.25; all

Swi/Snf Senses Carbon Starvation With A Ph-Sensitive Low-Complexity Sequence, J. Ignacio Gutierrez, Gregory P. Brittingham, Yonca Karadeniz, Kathleen D. Tran, Arnob Dutta, Alex S. Holehouse, Craig L. Peterson, Liam J. Holt

Open Access Publications

It is increasingly appreciated that intracellular pH changes are important biological signals. This motivates the elucidation of molecular mechanisms of pH sensing. We determined that a nucleocytoplasmic pH oscillation was required for the transcriptional response to carbon starvation in

Leveraging Large Multi-Center Cohorts Of Alzheimer Disease Endophenotypes To Understand The Role Of Klotho Heterozygosity On Disease Risk, Muhammad Ali, Yun Ju Sung, Fengxian Wang, Maria V. Fernández, John C. Morris, Anne M. Fagan, Richard J. Perrin, Carlos Cruchaga, Et Al

Open Access Publications

Two genetic variants in strong linkage disequilibrium (rs9536314 and rs9527025) in the Klotho (KL) gene, encoding a transmembrane protein, implicated in longevity and associated with brain resilience during normal aging, were recently shown to be associated with Alzheimer disease (AD) risk in cognitively normal participants who are APOE ε4 carriers. Specifically, the participants heterozygous for this variant (KL-SVHET+) showed lower risk of developing AD. Furthermore, a neuroprotective effect of KL-VSHET+ has been suggested against amyloid burden for cognitively normal participants, potentially mediated via the regulation of redox pathways. However, inconsistent associations and a smaller sample size of existing studies pose …

What Clonal Hematopoiesis Can Teach Us About Mds, Irenaeus C C Chan, Brian J Wiley, Kelly L Bolton

Open Access Publications

Clonal hematopoiesis (CH), defined as the clonal expansion of mutated hematopoietic stem and progenitor cells (HSPCs), is a common aging process. CH is a risk factor for the development of hematologic malignancies, most commonly myeloid neoplasms (MNs) including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and myeloproliferative neoplasm (MPN). Recent work has elucidated how the development and cellular fitness of CH is shaped by aging, environmental exposures, and the germline (inherited) genetic background of an individual. This in turn has provided valuable insights into the pathogenesis of MNs including MDS. Here, in this review, we discuss the genetic origins of …

High-Dimensional Analysis Reveals Distinct Endotypes In Patients With Idiopathic Inflammatory Myopathies, Erin M Wilfong, Todd Bartkowiak, Katherine N Vowell, Camille S Westlake, Jonathan M Irish, Peggy L Kendall, Leslie J Crofford, Rachel H Bonami

Open Access Publications

The idiopathic inflammatory myopathies (IIM) are a rare clinically heterogeneous group of conditions affecting the skin, muscle, joint, and lung in various combinations. While myositis specific autoantibodies are well described, we postulate that broader immune endotypes exist in IIM spanning B cell, T cell, and monocyte compartments. This study aims to identify immune endotypes through detailed immunophenotyping of peripheral blood mononuclear cells (PBMCs) in IIM patients compared to healthy controls. We collected PBMCs from 17 patients with a clinical diagnosis of inflammatory myositis and characterized the B, T, and myeloid cell subsets using mass cytometry by time of flight (CyTOF). …

Externalizing Personality Characteristics Define Clinically Relevant Subgroups Of Alcohol Use Disorder, Ildikó Kovács, Bernadett I Gál, Zsolt Horváth, Ildikó Demeter, Sándor Rózsa, Zoltán Janka, Róbert Urbán, Zsolt Demetrovics, Bálint Andó

Open Access Publications

AIMS: Higher levels of externalizing characteristics, i.e. impulsivity, novelty seeking and aggression, could contribute to the development, progression and severity of alcohol use disorder (AUD). The present study aims to explore whether these externalizing characteristics together have a potential group-forming role in AUD using latent profile analysis (LPA).

METHODS: Externalizing characteristics of 102 AUD patients were analyzed using LPA to explore the group-forming role of externalizing symptoms; groups were compared in terms of demographic and alcohol-related variables, indices of psychopathological, depressive and anxiety symptom severity.

RESULTS: LPA revealed and supported a two-group model based on externalizing symptoms. The group with …

Contralateral Limb Specificity For Movement Preparation In The Parietal Reach Region, Eric Mooshagian, Eric A. Yttri, Arthur D. Loewy, Lawrence H. Snyder

Open Access Publications

The canonical view of motor control is that distal musculature is controlled primarily by the contralateral cerebral hemisphere; unilateral brain lesions typically affect contralateral but not ipsilateral musculature. Contralateral-only limb deficits following a unilateral lesion suggest but do not prove that control is strictly contralateral: the loss of a contribution of the lesioned hemisphere to the control of the ipsilesional limb could be masked by the intact contralateral drive from the nonlesioned hemisphere. To distinguish between these possibilities, we serially inactivated the parietal reach region, comprising the posterior portion of medial intraparietal area, the anterior portion of V6a, and portions …

Analysis And Classification Of Postcatheterization Femoral Arteriovenous Fistulas Based On Color Doppler Examinations, William D Middleton, Kathryn A Robinson

Open Access Publications

OBJECTIVE: To analyze and classify arterial supply and venous drainage of postcatheterization femoral arteriovenous fistulas (AVFs).

METHODS: A review of extremity Doppler reports identified 77 femoral AVFs in 75 patients. Doppler exams were reviewed retrospectively. Fistulas were classified as above or below the common femoral artery bifurcation and subclassified based on the location of arterial inflow and venous outflow.

RESULTS: Arterial inflow originated above the femoral bifurcation in 32 cases. The communication was between the common femoral artery and the superficial circumflex iliac vein in 25 of 32 cases and between a branch of the common femoral or external iliac …

Increased Connectivity Among Sensory And Motor Regions During Visual And Audiovisual Speech Perception, Jonathan E. Peelle, Brent Spehar, Michael S. Jones, Sarah Mcconkey, Joel Myerson, Sandra Hale, Mitchell S. Sommers, Nancy Tye-Murray

Open Access Publications

In everyday conversation, we usually process the talker's face as well as the sound of the talker's voice. Access to visual speech information is particularly useful when the auditory signal is degraded. Here, we used fMRI to monitor brain activity while adult humans (

Assessment Of A Plasma Amyloid Probability Score To Estimate Amyloid Positron Emission Tomography Findings Among Adults With Cognitive Impairment, Yan Hu, Barry A. Siegel, David M. Holtzman, Et Al

Open Access Publications

Importance: The diagnostic evaluation for Alzheimer disease may be improved by a blood-based diagnostic test identifying presence of brain amyloid plaque pathology.

Objective: To determine the clinical performance associated with a diagnostic algorithm incorporating plasma amyloid-β (Aβ) 42:40 ratio, patient age, and apoE proteotype to identify brain amyloid status.

Design, Setting, and Participants: This cohort study includes analysis from 2 independent cross-sectional cohort studies: the discovery cohort of the Plasma Test for Amyloidosis Risk Screening (PARIS) study, a prospective add-on to the Imaging Dementia-Evidence for Amyloid Scanning study, including 249 patients from 2018 to 2019, and MissionAD, a dataset of …